DOI: 10.1542/peds.

2011-3279
; originally published online September 3, 2012; 2012;130;e829 Pediatrics
Pierre-Yves Ancel, Gilles Kayem, Franois Goffinet and Babak Khoshnood
Enora Laas, Nathalie Lelong, Anne-Claire Thieulin, Lucile Houyel, Damien Bonnet,
Preterm Birth and Congenital Heart Defects: A Population-based Study

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of Pediatrics. All rights reserved. Print ISSN: 0031-4005. Online ISSN: 1098-4275.
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Preterm Birth and Congenital Heart Defects:
A Population-based Study
WHATS KNOWN ON THIS SUBJECT: Risk of preterm birth (PTB)
has been noted to be higher for newborns with congenital heart
defects (CHDs). The role of associated anomalies, whether PTB is
spontaneous or medically induced, or specic categories of CHDs
have not been elucidated.
WHAT THIS STUDY ADDS: By using population-based data, we
found that PTB associated with CHDs was due to spontaneous PTB.
Associated anomalies accounted for a small part of this increase,
and there were specic associations between categories of CHDs
and PTB.
abstract
BACKGROUND AND OBJECTIVES: Preterm birth (PTB) and congenital
heart defect (CHD) are 2 major causes of mortality and disability of
perinatal origin. There are limited data on the relation between CHD
and PTB. Our objective was to use population-based data to estimate
the risk of PTB in newborns with CHD and to study specic associations
between categories of CHD and PTB.
METHODS: We used data from a population-based cohort study of
CHD (EPIdmiologique sur le devenir des enfants porteurs de
CARDiopathies congnitales study), including 2189 live births with
CHD (excluding isolated atrial septal defects) born between 2005
and 2008. We categorized CHD by using an anatomic and clinical
classication. Data from the French National Perinatal Survey of
2003 were used to compare PTB in the EPIdmiologique sur le
devenir des enfants porteurs de CARDiopathies congnitales study
to that of the general population.
RESULTS: Of the newborns with CHD, 13.5% were preterm. The odds of
PTB were twofold higher than for the general population (odds ratio
2.0, 95% condence interval 1.62.5), essentially due to an increase in
spontaneous PTB for newborns with CHD. The risk of PTB associated
with CHD persisted after exclusion of chromosomal or other anoma-
lies. There were signicant variations in risk of PTB across the cat-
egories of CHD after adjustment for known risk factors of PTB and
factors related to medical management of pregnancy and delivery.
CONCLUSIONS: We found a higher risk of PTB in newborns with CHD,
which was essentially due to spontaneous PTB. Risk of PTB varied for
categories of CHD. Our nding may be helpful for generating hypoth-
eses about the developmental links between CHD and PTB. Pediatrics
2012;130:e829e837
AUTHORS: Enora Laas, MD, MSc,
a
Nathalie Lelong, MSc,
a
Anne-Claire Thieulin, MSc,
a
Lucile Houyel, MD,
b
Damien
Bonnet, MD, PhD,
c
Pierre-Yves Ancel, MD, PhD,
a
Gilles
Kayem, MD, PhD,
a
Franois Gofnet, MD, PhD,
a,d
and Babak
Khoshnood, MD, PhD,
a
on behalf of the EPICARD Study
Group
a
INSERM, UMR S953, Recherche pidmiologique sur la Sant
Prinatale et la Sant des Femmes et des Enfants, UPMC,
Universit Paris-6, Paris, France;
b
Service de Chirurgie des
Cardiopathies Congnitales, Hpital Marie Lannelongue, Le
Plessis Robinson, France; and
c
Centre de Rfrence M3C-Necker,
and
d
Maternit Port Royal, Hpital Cochin Saint-Vincent-de-Paul,
Assistance Publique Hpitaux de Paris, Universit
Paris-Descartes, Paris, France
KEY WORDS
congenital heart defects, preterm birth, population-based study,
epidemiology
ABBREVIATIONS
ASDatrial septal defect
CHDcongenital heart defect
CIcondence interval
EPICARDEPIdmiologique sur le devenir des enfants porteurs
de CARDiopathies congnitales study
IUGRintrauterine growth restriction
NPSNational Perinatal Survey
ORodds ratio
PTBpreterm birth
TOPFAterminations of pregnancy for fetal anomaly
VSDventricular septal defect
www.pediatrics.org/cgi/doi/10.1542/peds.2011-3279
doi:10.1542/peds.2011-3279
Accepted for publication Jun 4, 2012
Address correspondence to Enora Laas, MD, MSc, INSERM U953,
Hpital Saint Vincent de Paul, 82 avenue Denfert Rochereau,
75014 Paris, France. E-mail: enolaas@gmail.com
PEDIATRICS (ISSN Numbers: Print, 0031-4005; Online, 1098-4275).
Copyright 2012 by the American Academy of Pediatrics
FINANCIAL DISCLOSURE: The authors have indicated they have
no nancial relationships relevant to this article to disclose.
FUNDING: This work was supported by two grants from the
French Ministry of Health (PHRC 2004 and 2008). Additional
funding was provided by the AREMCAR (Association pour la
Recherche et lEtude des Maladies Cardiovasculaires)
association. The funding sources had no role in the study
design, data collection, data interpretation, or the writing of the
manuscript.
PEDIATRICS Volume 130, Number 4, October 2012 e829
ARTICLE
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Congenital heart defects (CHDs) are
the most frequent group of major
congenital anomalies with a live
prevalence of 7 per 1000 live births.
1
Despite considerable progress in their
diagnosis and medical management,
2
CHDs remain the most important cause
of infant mortality due to birth de-
fects,
3,4
and survivors may have
short-term morbidity
5,6
and adverse
neurodevelopmental outcomes.
6
An
extensive literature has also docu-
mented higher risks of mortality,
morbidity, and long-term adverse
outcomes related to preterm birth
(PTB; ,37 weeks).
79
CHD and PTB are therefore two of the
leading causes of infant mortality and
disability of perinatal origin.
10
Al-
though known associations exist be-
tween congenital anomalies and
PTB,
1113
few specic data exist re-
garding the risk of PTB for CHD. Most
studies report results of hospital-
based studies of the clinical man-
agement and outcomes of preterm
infants with CHD.
14,15
One previous
population-based study reported a
higher risk of PTB for newborns with
CHD.
10
This study did not assess the
role of associated anomalies or the
extent to which risk of PTB for new-
borns with CHD may be due to spon-
taneous versus medically induced PTB.
Moreover, few data are available on the
associations between specic catego-
ries of CHD and PTB.
10
By using data from a large population-
based cohort of newborns with CHD
(the Etude EPIdmiologique sur le
devenir des enfants porteurs de CAR-
Diopathies congnitales study; EPI-
CARD), we estimated the risk of PTB
in newborns with CHD, examined the
nature of PTB (spontaneous versus
medically induced PTB), and studied
associations between specic cate-
gories of CHD (according to an ana-
tomic and clinical classication
16
) and
PTB.
METHODS
Data Source
EPICARDis aprospectivecohort study of
all children with CHD born to women in
the greater Paris area (Paris and its
surrounding suburbs). All cases (live
births, terminations of pregnancy for
fetal anomaly [TOPFA], fetal deaths $20
weeks) diagnosed in the prenatal pe-
riod or up to 1 year of age in the birth
cohorts between May 1, 2005 and April
30, 2008 were eligible for inclusion.
Multiple sources of data including all
maternity units, pediatric cardiology
and cardiac surgery centers, fetal and
neonatal pathology departments, neo-
natal and pediatric intensive units,
infant units, and outpatient clinics in
greater Paris and a neighboring ter-
tiary care center were regularly con-
sulted to attain completeness of case
registrations. Informed consent was
obtained from study participants, and
the study was approved by an ethics
committee (French National Committee
of Information and Liberty). The last
cases included in the study were those
in the 2008 birth cohort who were di-
agnosed in 2009. Follow-up of children
in the EPICARD cohort is ongoing and
will include assessment of childrens
health and neurodevelopmental out-
comes until at least 7 years of age.
The total number of cases included in
the EPICARD study was 2867. After ex-
cluding TOPFA (n = 466) and fetal
deaths (n = 53), our initial study pop-
ulation comprised 2348 live births. The
total number of live births in the study
population base was 314 022.
Five (0.2%) cases were excluded due
to missing information on gestational
age (Fig 1). We also excluded isolated
atrial septal defects (ASDs, n = 154)
to minimize ascertainment bias. Pre-
term infants are more likely to un-
dergo echocardiography resulting in
diagnosis of minor ASD that may oth-
erwise go undiagnosed. In addition,
isolated minor ASD may be difcult to
distinguish from patent foramen ovale.
Our nal study population included 2189
newborns with CHD.
Cardiac anomalies associated with a
chromosomal anomaly comprised
6.1% (n = 134), and those with anom-
alies of other systems, including ge-
netic syndromes, 13.9% (n = 285) of
cases.
Our reference population comprised
womenresidinginthesamegeographic
area as that of the EPICARD population
base, namely women residing in Paris
and its surrounding suburbs, who were
included in the French National Peri-
natal Survey (NPS) of 2003.
7
The survey
involved a nationally representative
sample of all births in France during
a 1-week period (N = 15 378), including
1821 women residing in the same
geographic area as that of EPICARD.
The NPS did not exclude newborns with
CHD or other anomalies, which may
account for 2% of the live births in
our population.
For both the EPICARDstudy and the NPS,
estimate of gestational age was based
on medical records. By far, for most
newborns in our population, this esti-
mate is based on an early ultrasound
examination.
The main outcome measure was risk
of PTB. We distinguished spontaneous
from medically induced PTB, by in-
cluding in the latter PTB after induction
of labor or cesarean delivery before
labor. Risk of PTB was examined for (1)
all cases, (2) all cases excluding chro-
mosomal anomalies, and (3) cases
excluding chromosomal or other
anomalies.
Detailed information on diagnosis and
coding of the CHD are provided else-
where.
16
To examine specic associa-
tions between categories of CHD and
PTB, we used an anatomic and clinical
classication of CHD, which is based
on the Long List of the International
e830 LAAS et al
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Pediatric and Congenital Cardiac Code
17
(Table 1). This classication, the Ana-
tomic and Clinical Classication of
Congenital Heart Defects,
16
categorizes
CHD into 10 main categories and 23
subcategories by using a multidimen-
sional approach encompassing ana-
tomic, echocardiographic, as well as
clinical and surgical management cri-
teria. It has proved useful in a previous
study aimed at assessing specic as-
sociations between a risk factor and
categories of CHD.
16,18
In our analyses of the specic associa-
tions between categories of CHD and
PTB, we excluded the following catego-
ries because of limited sample size:
heterotaxy, including isomerism and
mirror-imagery (n = 8); complex
anomalies of atrioventricular con-
nections (n = 7); and congenital anom-
alies of the coronary arteries (n = 9).
Hence, we compared risk of PTB for 6
categories of CHD: anomalies of the ve-
nous return (n = 26), anomalies of the
atrioventricular junctions and valves
(n = 109), functional univentricular
hearts (n = 48), ventricular septal de-
fect (VSD; n = 1396), anomalies of the
ventricular outow tract (n = 47), and
anomalies of the extrapericardial arte-
rial trunks (n = 124).
Missing Values
All variables had ,7% missing data
except for maternal occupation (19%).
The probability of missing data was not
statistically associated with either
categories of CHD or risk of PTB.
Statistical Analysis
We report proportions with 95%
binomial exact condence intervals
(CIs). The x
2
or Fisher exact test were
used to assess the associations be-
tween risk of PTB and maternal or
fetal characteristics. To take into ac-
count the possible effect of differ-
ences in the distribution of maternal
characteristics in the NPS versus our
study population, we obtained stan-
dardized estimates of the proportion
of PTB by using the available aggre-
gate data on the univariable distri-
bution of maternal age, geographic
origin, maternal occupation, and par-
ity in the NPS.
We used logistic regression to assess
the association between PTB and
FIGURE 1
Study population. *Or nonchromosomal genetic syndromes. **One or more CHD only with no other
associated anomalies.
TABLE 1 Anatomic and Clinical Classication of CHD
16
CHD Categories Examples n
a
% Prevalence
b
% 95% CI
Heterotaxy, including isomerism and mirror-imagery Heterotaxy syndromes 8 0.3 0.02 0.010.05
Anomalies of the venous return Anomalies of the pulmonary venous return 26 1.1 0.08 0.050.012
Anomalies of the atria and interatrial communications Interatrial communications ostium secundum
type, patent oval foramen
174 7.4 0.55 0.470.64
Anomalies of the atrioventricular junctions and valves Ebstein anomaly, ASD 109 4.6 0.35 0.280.42
Complex anomalies of atrioventricular connections Congenitally corrected TGA (double discordance) 7 0.3 0.02 10
25
0.04
Functionally univentricular hearts Left ventricular hypoplasia 48 2.0 0.15 0.10.2
VSD Perimembranous VSD, muscular VSD 1396 59.4 4.4 4.24.7
Anomalies of the ventricular outow tract
(ventriculoarterial connections)
TGA, double outlet right ventricle, tetralogy of Fallot 447 19.0 1.4 1.31.6
Anomalies of the extrapericardial arterial trunks Coarctation of the aorta 124 5.3 0.4 0.30.5
Congenital anomalies of the coronary arteries 9 0.4 0.03 0.010.05
Total 2348 100 7.5 7.27.8
TGA, transposition of the great arteries.
a
Number of live births in each category in the EPICARD study.
b
Live birth prevalence (per 1000 live births) in the EPICARD population, including cases of isolated ASDs.
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different categories of CHD, which were
included as binary predictor variables
with the most frequent category (VSD)
as the reference group. Potentially
confounding variables taken into ac-
count included maternal age, occupa-
tion, geographic origin, parity, diabetes
mellitus, vaginal bleeding, intrauterine
growth restriction (IUGR; ,10th per-
centile), and multiple births. These
factors are known to be associated
with risk of PTB even if their specic
associations with CHD are not well
documented.
19,20
Other factors taken into account were
those related to medical management
of pregnancy and delivery. These in-
cluded invasive prenatal testing (am-
niocentesis, chorionic villus sampling),
prenatal diagnosis of CHD, and medical
inductionof labororcaesareandelivery
before labor.
The Stata/SE software (version 11.0;
Stata Corp, College Station, TX) was
used for data analysis.
RESULTS
The live birth prevalence of CHD in our
study population (n = 2189) was 7.0
per 1000 live births (95% CI 6.77.3).
The overall proportion of PTB was
13.5%, compared with 7.2% in the
general population (odds ratio [OR]
2.0, 95% CI 1.62.5).There were similar
increases for very PTB (,32 weeks;
OR 1.9, 95% CI 1.23.1) and moderately
PTB (3236 weeks; OR 2.0, 95% CI
1.62.5).
After excluding both chromosomal and
other anomalies, 11.5% of newborns
were PTB with an OR of 1.7 (95% CI 1.3
2.1) compared with the general pop-
ulation (Table 2). For newborns with
major isolated CHD ($1 CHD but no
other anomalies and excluding isolated
VSD), the risk of PTB was 17.5% (OR 2.7,
95% CI 2.13.6).
The proportionof spontaneous PTBwas
9.7%(vs 3.9%in the general population,
P , .001) and the proportion of medi-
cally induced PTB was 3.7% (vs 3.3% in
the general population, P = .5; Table 3).
There was a 2.6-fold increase in the
odds of spontaneous PTB for newborns
with CHD compared with those in the
general population (OR 2.6, 95% CI 2.0
3.5). In contrast, we found no signi-
cant increase in medically induced PTB
(OR 1.1, 95% CI 0.81.6). The median
gestational age was 35 weeks for both
spontaneous and medically induced
PTB (range 2436 weeks and 2736
weeks, respectively).
Maternal demographic and newborn
characteristics of the EPICARD cohort
and their association with PTB are
presented in detail in Supplemental
Tables 6 and 7. Mothers of newborns
with CHD who were older, of African
origin, unemployed, or working in
administrative/public service had higher
risks of PTB. Newborns of diabetic
mothers or those with vaginal bleeding
during pregnancy, newborns with
chromosomal or other anomalies, and
multiple births also had higher risks
of PTB.
Specic Associations Between
Categories of CHD and Risk of PTB
Risk of PTB varied signicantly across
the categories of CHD, ranging from
3.8%for anomalies of the venous return
to 23.8% for anomalies of the atrio-
ventricular junctions and valves (Table
4). Except for anomalies of venous
return, risk of PTB was higher for all
other categories of CHD when com-
pared with VSD.
After taking into account maternal age,
occupation, geographic origin, parity,
diabetes, vaginal bleeding, IUGR, and
multiple pregnancies, aswell as factors
related to medical management of
pregnancy and delivery (induction of
labor, caesarean delivery before onset
of labor, prenatal diagnosis, invasive
prenatal testing), the odds of PTB was
2.4-fold higher for anomalies of the
atrioventricular junctions and valves
(adjusted OR 2.4, 95% CI 1.44.2) and
1.6-fold higher for functionally uni-
ventricular heart (adjusted OR 1.6,
95% CI 0.73.9) compared with VSD
(Table 5).
TABLE 2 Proportion of PTBs for Newborns With CHD (Excluding Isolated ASD), Compared With the General Population
a
CHD n Gestational Age (wk)
,32 3236 ,37
% 95% CI
a
% 95% CI
a
P
b
% 95% CI
a
P
c
All cases 2189 2.4 1.83.1 11.1 9.812.5 ,.001 13.5 12.115.0 ,.001
Cases without chromosomal anomalies 2055 2.3 1.73.0 10.2 8.911.6 ,.001 12.5 11.114.0 ,.001
Cases without chromosomal and/or anomalies of other systems
d
1770 2.1 1.52.9 9.4 8.110.8 ,.001 11.5 10.113.1 ,.001
Cases without chromosomal and/or anomalies of other systems,
excluding isolated VSD
667 3.9 2.65.6 13.6 11.116.5 ,.001 17.5 14.720.6 ,.001
French NPS 2003
e
1815 1.3 0.82.0 5.9 4.87.1 7.2 6.18.5
a
P value for the overall x
2
test comparing the distribution of gestational age (,32, 3236, $37 wk) between newborns with CHD versus that of the general population (French NPS of 2003).
b
P value for the x
2
test comparing proportion of PTB for newborns with CHD versus that of the general population (French NPS of 2003).
c
95% binomial exact CI.
d
Structural defects other than CHD.
e
French NPS 2003: women residing in the same geographic area as that of the EPICARD population base (Paris and its surrounding suburbs).
e832 LAAS et al
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Role of Associated Anomalies
For most categories, the risk of PTBwas
essentially the same after exclusion of
cases associated with chromosomal or
other anomalies. However, for the
anomalies of the atrioventricular junc-
tions and valves, the odds of PTB de-
creased somewhat after exclusion of
cases with associated chromosomal
anomalies and for anomalies of the
extrapericardial arterial trunk after
exclusionof cases associated with other
anomalies (detailed results available
from the authors).
DISCUSSION
By using population-based data on
.2000 newborns with CHD, we found
a twofold increase in the overall risk of
PTB in newborns with CHD compared
with a reference population. This was
essentially due to an increase in
spontaneous PTB, and we found no
evidence of an increase in medically
induced PTB (induction of labor/
cesarean delivery before labor). Only
a small proportion (15%) of the in-
crease in PTB was explained by asso-
ciations between CHD and other
anomalies.
Risk of PTB was higher for certain
categories of CHD, including anomalies
of the ventricular outow tract, and
lower for isolated VSDandanomalies of
the venous return. The higher risk of
PTB for certain categories of CHD may
be explained in part by their associa-
tions with other anomalies. In particu-
lar, therisk of PTBsomewhat decreased
for the category anomalies of the
atrioventricular junctions and valves
after exclusionof cases associatedwith
chromosomal anomalies. This category
includes ASDs that are known to be
more frequent in newborns with Down
syndrome,
21
and the latter are in gen-
eral at a higher risk of PTB.
To our knowledge, our study is the rst
to examine the nature of onset of labor
for newborns with CHD and in partic-
ular the possible impact of antenatal
screening on medically induced PTB.
Several studies have examined the role
of prenatal screening as a factor
leading to induction of labor or elective
cesarean delivery before term in
newborns with congenital anom-
alies.
22,23
However, in the only pre-
vious population-based study of the
risk of PTB associated with CHD,
10
spontaneous and medically induced
PTB were not distinguished. We found
TABLE 3 Proportion of Spontaneous and Medically Induced PTB (,37 wk) for Newborns With CHD
CHD n Spontaneous PTBs Medically Induced
a
PTBs
P
c
% 95% CI
b
% 95% CI
b
All cases 2189 9.7 8.511.0 3.7 2.94.6 ,.001
Cases without chromosomal anomalies 2055 8.8 7.610.1 3.6 2.84.5
Cases without chromosomal and/or anomalies of other systems
d
1770 7.8 6.69.2 3.5 2.74.5
Cases without chromosomal and/or anomalies of other systems,
excluding isolated VSD
667 12.0 9.614.7 5.4 3.87.4
French NPS of 2003 1815 3.9 3.14.9 3.3 2.54.2
a
PTB after induction of labor or cesarean delivery before labor.
b
95% binomial exact CI.
c
P value for the overall x
2
test comparing the proportions of spontaneous preterm, medically induced PTB and term births for newborns with CHD versus that of the general population
(French NPS of 2003).
d
Structural defects other than CHD.
TABLE 4 Proportion of PTB for Different Categories of CHD (Anatomic and Clinical Classication of CHD
16
)
CHD Categories Gestational Age (wk)
,32 3236 ,37
% 95% CI
a
% 95% CI
a
P
b
% 95% CI
a
P
c
Anomalies of the venous return 0 013.2
c
3.8 0.119.6 ,.001 3.8 0.119.6 ,.001
Anomalies of the atrioventricular junctions and valves 4.6 1.510.4 19.2 12.327.9 23.8 16.233.0
Functionally univentricular hearts 2.1 0.111.1 18.7 8.932.6 20.8 10.535.0
VSDs 1.7 1.12.5 8.5 7.110.0 10.2 8.611.9
Anomalies of the ventricular outow tract 3.8 2.26.0 14.8 11.718.5 18.6 15.122.6
Anomalies of the extrapericardial arterial trunks 0.8 0.024.4 18.5 12.126.5 19.3 12.827.4
French NPS of 2003 1.3 0.82.0 5.9 4.87.1 7.2 6.18.5
a
95% binomial exact CI.
b
P value for the overall x
2
test comparing the distribution of gestational age (,32, 3236, $37 wk) for categories of CHD and that of the general population (French NPS of 2003).
c
P value for the overall x
2
test comparing the proportion of PTB for categories of CHD and that of the general population (French NPS of 2003).
d
97.5% 1-sided CI.
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that the higher risk of PTB in newborns
with CHD was essentially due to an in-
crease in spontaneous pretermdelivery.
Our study has certain limitations. The
distributionof some sociodemographic
characteristics differed somewhat be-
tween our study population and that
of the NPS. To take these differences
into account, we standardized the
proportion of PTB in our study pop-
ulation, by using available aggregate
data on the univariable distribution of
maternal age, geographic origin, ma-
ternal occupation, and parity in the NPS
and found similar proportions of PTB to
those reported here (detailed results
available from the authors). Because
this standardization was done by using
the distribution of 1 variable at a time,
residual confounding to differences
between NPS and EPICARD in the mul-
tivariable distribution of these or other
characteristics for which data were not
available cannot be excluded. However,
our estimate of the overall risk of PTB
associated with CHD was consistent
with that given by Tanner by using
a different reference population.
10
Moreover, in our analyses of the spe-
cic associations between categories
of CHD and PTB, we adjusted our esti-
mates for sociodemographic charac-
teristics and several other known risk
factors of PTB. Nevertheless, we were
not able to adjust for certain risk
factors of PTB such as tobacco, alcohol
consumption, and obesity, which may
also be risk factors for CHD.
24
Newborns with CHD or other congenital
anomalies were not systematically ex-
cluded from the NPS. This can result in
an underestimation of the true risk of
PTB associated with CHD in our study
because newborns with congenital
anomalies tend to have a higher risk
of PTB. This underestimation bias
should be small or negligible, how-
ever, because newborns with congen-
ital anomalies would comprise 2% of
the NPS.
Although our study included a large
number of cases of CHD, certain cate-
gories of CHD could not be studied
because of limited sample size. For
certain other categories, CIs for the
associations were wide, indicating
the limited precision of some of our
estimates.
Cases of CHD diagnosed after the rst
year of life
25
may have been a source of
selection bias. If there are associa-
tions between these usually minor
defects and PTB, risk of PTB may be
underestimated. However, given the
wide availability of specialized ser-
vices for pre- and postnatal diagnosis
of CHD in our population, this is likely
to have had a minor impact, if any, in
our study. Moreover, the live birth
prevalence of CHD in our study was
higher than the average live birth
prevalence of CHD in Europe,
1
which
suggests that diagnoses of CHD after
the rst year of life are unlikely to be
frequent in our population.
The proportion of prenatally diagnosed
casesandTOPFAtendtobehigher inour
population than those in other Euro-
pean countries.
1
This may result in
a lower proportion of PTB among
newborns with CHD because our nd-
ings suggest that the more severe
types of CHD, which are more likely to
undergo TOPFA, tend to be at higher
risk of PTB.
Our results, particularly those related
to specic associations between CHD
and PTB, may be helpful for generating
hypotheses on the underlying mecha-
nisms for the association between CHD
and PTB. Possible mechanisms include
those related to (1) existence of a
common cause or risk factor, (2) clin-
ical management of fetuses with CHD,
and (3) direct or indirect effects of the
CHD itself.
A genetically programmed deterior-
ation of fetal development and the
membranes may cause both CHD and
PTB. Genetic disordersof theconnective
tissue (Marfan or Ehlers-Danlos syn-
drome), for example, are known for
theirassociationwithCHDandmay also
cause PTB by a weakening, followed by
preterm rupture of membranes.
26
A higher risk of PTB in newborns with
chromosomal or other congenital
anomalies has been described.
1113,2729
TABLE 5 Logistic Regression Analysis of the Specic Associations Between Categories of CHD
a
and PTBs
CHD Categories Unadjusted Model 1 Model 2
OR 95% CI
b
P
c
Adjusted OR
d
95% CI
b
P
c
Adjusted OR
e
95% CI
b
P
c
Anomalies of the venous return 0.3 0.052.6 ,.001 0.6 0.074.3 ,.001 0.6 0.074.3 ,.001
Anomalies of the atrioventricular junctions and valves 2.7 1.74.4 2.4 1.44.0 2.4 1.44.2
Functionally univentricular hearts 2.3 1.14.8 1.5 0.63.5 1.6 0.73.9
Anomalies of the ventricular outow tract 2.0 1.52.7 2.2 1.63.1 2.3 1.73.3
Anomalies of the extrapericardial arterial trunks 2.1 1.33.4 2.2 1.33.8 2.3 1.34.0
VSD 1.0 Ref 1.0 Ref 1.0 Ref
a
Anatomic and Clinical Classication of CHD.
16
b
95% binomial exact CI.
c
Likelihood ratio test: difference of association between PTB and categories of CHD.
d
Adjusted for maternal age, occupation, geographic origin, parity, multiple pregnancy, diabetes, vaginal bleeding, and IUGR.
e
Adjusted for factors included in model 1 plus induction of labor, cesarean delivery before labor, prenatal diagnosis, and invasive prenatal testing (amniocentesis, chorionic villus sampling).
e834 LAAS et al
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Indeed, we found that the risk of PTB
for some categories of CHD was lower
after excluding newborns with associ-
ated anomalies, including genetic syn-
dromes.
There may be common environmental
risk factors for both CHD and PTB.
In particular, air pollution has been
reported as a risk factor for CHD,
30
as
well as low birth weight and PTB.
31,32
Viral infection (rubella) and maternal
diabetes are also known to be associ-
ated with an increase in the risk of
CHD
33,34
and polyhydramnios, which
may result in PTB.
35
Preterm newborns are more likely to
undergo echocardiography in the NICU.
The associations between CHD and PTB
may thenbedue toadiagnostic bias. We
excluded isolated cases of ASDthat may
be particularly prone to such bias. It is
worth noting, however, that, if in-
dependent of diagnostic issues, ASD is
truly associated with a higher risk of
PTB, we may have underestimated the
risk of PTB associated with CHD by ex-
cluding the ASD.
Another explanation for the higher risk
of PTB in newborns with CHD could be a
higher likelihood of medically induced
PTB, which has been shown to be
the case for certain other congenital
anomalies.
22,36
However, we found no
evidence of an increase for medically
induced PTB for newborns with CHD.
PTB may also be a direct or indirect
result of the CHDitself. Polyhydramnios,
associated with fetal heart failure, may
increase therisk of pretermlabor
35
and
thus PTB. IUGR, which is known to be
associated with PTB,
37
is also more
frequent for newborns with CHD.
23,38
In
our study, the proportion of PTB in
newborns with IUGR was almost 20%.
We adjusted our estimates of the as-
sociations between specic catego-
ries of CHD and PTB for IUGR. However,
this strategy may result in biased
estimates of the association between
those categories of CHDthat cause both
IUGR and PTB if IUGR is on the causal
pathway between CHD and PTB. Never-
theless, when IUGR was excluded, the
estimates of the associations between
categories of CHD and PTB were es-
sentially the same as those reported
here.
The circulatory alterations associated
with CHD may directly cause both IUGR
and PTB. Rosenthal showed that the
alteration of the fetal circulation was
not compatible with optimal growth.
39
Fetal growth was altered globally in
cases of generalized hypoperfusion,
whereas a localized low oxygen supply
led to localized growth retardation. We
found that the category of anomalies of
the ventricular outow tract had the
highest risk of PTB. Some of the CHD in
this category, particularly tetralogy of
Fallot and pulmonary atresia with VSD,
have been found to be associated with
growth retardation,
40
fetal death, and
PTB.
10
In conclusion, we found a higher risk of
spontaneous PTB for newborns with
CHD. Risk of PTB varied signicantly
across categories of CHD dened
based on anatomic and clinical crite-
ria.
16
Associations of CHD with chro-
mosomal or other congenital anomalies
explained only a small part of the higher
risk of PTB for newborns with CHD.
Our results may be helpful for gener-
ating hypotheses regarding the de-
velopmental links between PTB and
CHD.
EPICARD STUDY GROUP
Principal Investigators: Franois Gofnet
and Babak Khoshnood
Steering Committee: Damien Bonnet
(Hpital Necker Enfants Malades, AP-
HP, Centre de rfrence M3C, Universit
Paris Descartes, Paris); Drina Candilis
(Universit Paris-Diderot, Paris); Anne-
Lise Delezoide (Hpital Robert Debr,
AP-HP, Service de biologie du Dvel-
oppement, Universit Paris-Diderot,
Paris); Catherine De Vigan (INSERM
U953); Franois Gofnet (Groupe
Hospitalier Cochin-Htel Dieu, AP-HP,
Maternit Port-Royal et INSERM U953,
Universit Paris Descartes, Paris);
Lucile Houyel (Hpital Marie Lannelongue,
Service de chirurgie des cardiopathies
congnitales, Le Plessis-Robinson); Jean-
Marie Jouannic (Hpital Trousseau,
AP-HP, Centre pluridisciplinaire de di-
agnostic prnatal, UPMC, Paris); Babak
Khoshnood (INSERM U953, Paris);
Nathalie Lelong (INSERM U953, Paris);
Suzel Magnier (Hpital Robert Debr,
AP-HP, Service de cardiologie, Paris);
Jean-Franois Magny (Institut de
Puriculture et de prinatologie, Ser-
vice de nonatologie, Paris); Caroline
Rambaud (Hpital Raymond Poincarr,
AP-HP, Service danatomie et cytologie
pathologiquesMdecine lgale, UVSQ,
Garches); Dominique Salomon (INSERM
U953, Paris); Vronique Vodovar (INSERM
U953, Paris)
Project Coordination and Data Analysis
Committee: Franois Gofnet, Babak
Khoshnood, Nathalie Lelong, Anne-Claire
Thieulin, Thibaut Andrieu, Vronique
Vodovar; Independent Data Monitoring
Committee (URC Paris Centre et CIC
Cochin Necker Mre Enfant): Maggy
Chausson, Anissa Brinis, Laure Faure,
Maryline Delattre, Jean-Marc Treluyer
(Groupe Hospitalier Cochin-Htel Dieu,
AP-HP, Universit Paris Descartes,
Paris)
External Scientic Committee: Grard
Brart, Dominique Cabrol, Alain Srraf,
Daniel Sidi, Marcel Voyer
ParticipatingCenters: Thegreater Paris
area (Paris and its surrounding sub-
urbs) public (AP-HP) and private mater-
nity units, Departments of Pediatric
Cardiology and Pediatric Cardiac Sur-
gery, pediatric cardiologists in private
practice, NICUs, PICUs, Emergency
Transfer Services (SMUR), Depart-
ments of Pathology, Sudden Death
Centers, Departments of Family and In-
fant Protection (DFPE)
ARTICLE
PEDIATRICS Volume 130, Number 4, October 2012 e835
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ARTICLE
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DOI: 10.1542/peds.2011-3279
; originally published online September 3, 2012; 2012;130;e829 Pediatrics
Pierre-Yves Ancel, Gilles Kayem, Franois Goffinet and Babak Khoshnood
Enora Laas, Nathalie Lelong, Anne-Claire Thieulin, Lucile Houyel, Damien Bonnet,
Preterm Birth and Congenital Heart Defects: A Population-based Study

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