ARTICLE

Preterm Birth and Congenital Heart Defects:

A Population-based Study
AUTHORS: Enora Laas, MD, MSc,a Nathalie Lelong, MSc,a WHAT’S KNOWN ON THIS SUBJECT: Risk of preterm birth (PTB)
Anne-Claire Thieulin, MSc,a Lucile Houyel, MD,b Damien has been noted to be higher for newborns with congenital heart
Bonnet, MD, PhD,c Pierre-Yves Ancel, MD, PhD,a Gilles defects (CHDs). The role of associated anomalies, whether PTB is
Kayem, MD, PhD,a François Goffinet, MD, PhD,a,d and Babak spontaneous or medically induced, or specific categories of CHDs
Khoshnood, MD, PhD,a on behalf of the EPICARD Study have not been elucidated.
Group
aINSERM, UMR S953, Recherche Épidémiologique sur la Santé
WHAT THIS STUDY ADDS: By using population-based data, we
Périnatale et la Santé des Femmes et des Enfants, UPMC,
found that PTB associated with CHDs was due to spontaneous PTB.
Université Paris-6, Paris, France; bService de Chirurgie des
Cardiopathies Congénitales, Hôpital Marie Lannelongue, Le Associated anomalies accounted for a small part of this increase,
Plessis Robinson, France; and cCentre de Référence M3C-Necker, and there were specific associations between categories of CHDs
and dMaternité Port Royal, Hôpital Cochin Saint-Vincent-de-Paul, and PTB.
Assistance Publique Hôpitaux de Paris, Université
Paris-Descartes, Paris, France
KEY WORDS
congenital heart defects, preterm birth, population-based study,
epidemiology
ABBREVIATIONS
abstract
ASD—atrial septal defect BACKGROUND AND OBJECTIVES: Preterm birth (PTB) and congenital
CHD—congenital heart defect
heart defect (CHD) are 2 major causes of mortality and disability of
CI—confidence interval
EPICARD—EPIdémiologique sur le devenir des enfants porteurs perinatal origin. There are limited data on the relation between CHD
de CARDiopathies congénitales study and PTB. Our objective was to use population-based data to estimate
IUGR—intrauterine growth restriction the risk of PTB in newborns with CHD and to study specific associations
NPS—National Perinatal Survey
OR—odds ratio between categories of CHD and PTB.
PTB—preterm birth METHODS: We used data from a population-based cohort study of
TOPFA—terminations of pregnancy for fetal anomaly
VSD—ventricular septal defect
CHD (EPIdémiologique sur le devenir des enfants porteurs de
CARDiopathies congénitales study), including 2189 live births with
www.pediatrics.org/cgi/doi/10.1542/peds.2011-3279
CHD (excluding isolated atrial septal defects) born between 2005
doi:10.1542/peds.2011-3279
and 2008. We categorized CHD by using an anatomic and clinical
Accepted for publication Jun 4, 2012
classification. Data from the French National Perinatal Survey of
Address correspondence to Enora Laas, MD, MSc, INSERM U953,
2003 were used to compare PTB in the EPIdémiologique sur le
Hôpital Saint Vincent de Paul, 82 avenue Denfert Rochereau,
75014 Paris, France. E-mail: enolaas@gmail.com devenir des enfants porteurs de CARDiopathies congénitales study
PEDIATRICS (ISSN Numbers: Print, 0031-4005; Online, 1098-4275). to that of the general population.
Copyright © 2012 by the American Academy of Pediatrics RESULTS: Of the newborns with CHD, 13.5% were preterm. The odds of
FINANCIAL DISCLOSURE: The authors have indicated they have PTB were twofold higher than for the general population (odds ratio
no financial relationships relevant to this article to disclose. 2.0, 95% confidence interval 1.6–2.5), essentially due to an increase in
FUNDING: This work was supported by two grants from the spontaneous PTB for newborns with CHD. The risk of PTB associated
French Ministry of Health (PHRC 2004 and 2008). Additional with CHD persisted after exclusion of chromosomal or other anoma-
funding was provided by the AREMCAR (Association pour la
Recherche et l’Etude des Maladies Cardiovasculaires)
lies. There were significant variations in risk of PTB across the cat-
association. The funding sources had no role in the study egories of CHD after adjustment for known risk factors of PTB and
design, data collection, data interpretation, or the writing of the factors related to medical management of pregnancy and delivery.
manuscript.
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 finding may be helpful for generating hypoth-
eses about the developmental links between CHD and PTB. Pediatrics
2012;130:e829–e837

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Congenital heart defects (CHDs) are METHODS isolated minor ASD may be difficult to
the most frequent group of major distinguish from patent foramen ovale.
Data Source
congenital anomalies with a live Our final study population included 2189
prevalence of ∼7 per 1000 live births.1 EPICARD is a prospective cohort study of newborns with CHD.
Despite considerable progress in their all children with CHD born to women in
Cardiac anomalies associated with a
diagnosis and medical management,2 the greater Paris area (Paris and its
chromosomal anomaly comprised
CHDs remain the most important cause surrounding suburbs). All cases (live
6.1% (n = 134), and those with anom-
of infant mortality due to birth de- births, terminations of pregnancy for
alies of other systems, including ge-
fects,3,4 and survivors may have fetal anomaly [TOPFA], fetal deaths $20
netic syndromes, 13.9% (n = 285) of
short-term morbidity5,6 and adverse weeks) diagnosed in the prenatal pe-
cases.
neurodevelopmental outcomes. 6 An riod or up to 1 year of age in the birth
cohorts between May 1, 2005 and April Our reference population comprised
extensive literature has also docu-
30, 2008 were eligible for inclusion. women residing in the same geographic
mented higher risks of mortality,
Multiple sources of data including all area as that of the EPICARD population
morbidity, and long-term adverse
maternity units, pediatric cardiology base, namely women residing in Paris
outcomes related to preterm birth
and its surrounding suburbs, who were
(PTB; ,37 weeks). 7–9 and cardiac surgery centers, fetal and
neonatal pathology departments, neo- included in the French National Peri-
CHD and PTB are therefore two of the natal Survey (NPS) of 2003.7 The survey
leading causes of infant mortality and natal and pediatric intensive units,
infant units, and outpatient clinics in involved a nationally representative
disability of perinatal origin.10 Al- sample of all births in France during
though known associations exist be- greater Paris and a neighboring ter-
a 1-week period (N = 15 378), including
tween congenital anomalies and tiary care center were regularly con-
1821 women residing in the same
PTB,11–13 few specific data exist re- sulted to attain completeness of case
geographic area as that of EPICARD.
garding the risk of PTB for CHD. Most registrations. Informed consent was
The NPS did not exclude newborns with
studies report results of hospital- obtained from study participants, and
CHD or other anomalies, which may
based studies of the clinical man- the study was approved by an ethics
account for ∼2% of the live births in
agement and outcomes of preterm committee (French National Committee
our population.
infants with CHD.14,15 One previous of Information and Liberty). The last
population-based study reported a cases included in the study were those For both the EPICARD study and the NPS,
higher risk of PTB for newborns with in the 2008 birth cohort who were di- estimate of gestational age was based
CHD.10 This study did not assess the agnosed in 2009. Follow-up of children on medical records. By far, for most
role of associated anomalies or the in the EPICARD cohort is ongoing and newborns in our population, this esti-
extent to which risk of PTB for new- will include assessment of children’s mate is based on an early ultrasound
borns with CHD may be due to spon- health and neurodevelopmental out- examination.
taneous versus medically induced PTB. comes until at least 7 years of age. The main outcome measure was risk
Moreover, few data are available on the The total number of cases included in of PTB. We distinguished spontaneous
associations between specific catego- the EPICARD study was 2867. After ex- from medically induced PTB, by in-
ries of CHD and PTB.10 cluding TOPFA (n = 466) and fetal cluding in the latter PTB after induction
By using data from a large population- deaths (n = 53), our initial study pop- of labor or cesarean delivery before
based cohort of newborns with CHD ulation comprised 2348 live births. The labor. Risk of PTB was examined for (1)
(the Etude EPIdémiologique sur le total number of live births in the study all cases, (2) all cases excluding chro-
devenir des enfants porteurs de CAR- population base was 314 022. mosomal anomalies, and (3) cases
Diopathies congénitales study; EPI- Five (0.2%) cases were excluded due excluding chromosomal or other
CARD), we estimated the risk of PTB to missing information on gestational anomalies.
in newborns with CHD, examined the age (Fig 1). We also excluded isolated Detailed information on diagnosis and
nature of PTB (spontaneous versus atrial septal defects (ASDs, n = 154) coding of the CHD are provided else-
medically induced PTB), and studied to minimize ascertainment bias. Pre- where.16 To examine specific associa-
associations between specific cate- term infants are more likely to un- tions between categories of CHD and
gories of CHD (according to an ana- dergo echocardiography resulting in PTB, we used an anatomic and clinical
tomic and clinical classification16) and diagnosis of minor ASD that may oth- classification of CHD, which is based
PTB. erwise go undiagnosed. In addition, on the Long List of the International

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 ARTICLE

Pediatric and Congenital Cardiac Code17 In our analyses of the specific associa- (n = 109), functional univentricular
(Table 1). This classification, the Ana- tions between categories of CHD and hearts (n = 48), ventricular septal de-
tomic and Clinical Classification of PTB, we excluded the following catego- fect (VSD; n = 1396), anomalies of the
Congenital Heart Defects,16 categorizes ries because of limited sample size: ventricular outflow tract (n = 47), and
CHD into 10 main categories and 23 heterotaxy, including isomerism and anomalies of the extrapericardial arte-
subcategories by using a multidimen- mirror-imagery (n = 8); complex rial trunks (n = 124).
sional approach encompassing ana- anomalies of atrioventricular con-
tomic, echocardiographic, as well as nections (n = 7); and congenital anom- Missing Values
clinical and surgical management cri- alies of the coronary arteries (n = 9). All variables had ,7% missing data
teria. It has proved useful in a previous Hence, we compared risk of PTB for 6 except for maternal occupation (19%).
study aimed at assessing specific as- categories of CHD: anomalies of the ve- The probability of missing data was not
sociations between a risk factor and nous return (n = 26), anomalies of the statistically associated with either
categories of CHD.16,18 atrioventricular junctions and valves categories of CHD or risk of PTB.

Statistical Analysis
We report proportions with 95%
binomial exact confidence 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.
FIGURE 1
Study population. *Or nonchromosomal genetic syndromes. **One or more CHD only with no other We used logistic regression to assess
associated anomalies. the association between PTB and

TABLE 1 Anatomic and Clinical Classification of CHD16

CHD Categories Examples na % Prevalenceb

% 95% CI
Heterotaxy, including isomerism and mirror-imagery Heterotaxy syndromes 8 0.3 0.02 0.01–0.05
Anomalies of the venous return Anomalies of the pulmonary venous return 26 1.1 0.08 0.05–0.012
Anomalies of the atria and interatrial communications Interatrial communications ostium secundum 174 7.4 0.55 0.47–0.64
type, patent oval foramen
Anomalies of the atrioventricular junctions and valves Ebstein anomaly, ASD 109 4.6 0.35 0.28–0.42
Complex anomalies of atrioventricular connections Congenitally corrected TGA (double discordance) 7 0.3 0.02 1025–0.04
Functionally univentricular hearts Left ventricular hypoplasia 48 2.0 0.15 0.1–0.2
VSD Perimembranous VSD, muscular VSD 1396 59.4 4.4 4.2–4.7
Anomalies of the ventricular outflow tract TGA, double outlet right ventricle, tetralogy of Fallot 447 19.0 1.4 1.3–1.6
(ventriculoarterial connections)
Anomalies of the extrapericardial arterial trunks Coarctation of the aorta 124 5.3 0.4 0.3–0.5
Congenital anomalies of the coronary arteries 9 0.4 0.03 0.01–0.05
Total 2348 100 7.5 7.2–7.8
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 OR 1.9, 95% CI 1.2–3.1) and moderately administrative/public service had higher
included as binary predictor variables PTB (32–36 weeks; OR 2.0, 95% CI risks of PTB. Newborns of diabetic
with the most frequent category (VSD) 1.6–2.5). mothers or those with vaginal bleeding
as the reference group. Potentially After excluding both chromosomal and during pregnancy, newborns with
confounding variables taken into ac- other anomalies, 11.5% of newborns chromosomal or other anomalies, and
count included maternal age, occupa- were PTB with an OR of 1.7 (95% CI 1.3– multiple births also had higher risks
tion, geographic origin, parity, diabetes 2.1) compared with the general pop- of PTB.
mellitus, vaginal bleeding, intrauterine ulation (Table 2). For newborns with
growth restriction (IUGR; ,10th per- major isolated CHD ($1 CHD but no Specific Associations Between
centile), and multiple births. These other anomalies and excluding isolated Categories of CHD and Risk of PTB
factors are known to be associated VSD), the risk of PTB was 17.5% (OR 2.7, Risk of PTB varied significantly across
with risk of PTB even if their specific 95% CI 2.1–3.6). the categories of CHD, ranging from
associations with CHD are not well
The proportion of spontaneous PTB was 3.8% for anomalies of the venous return
documented.19,20
9.7% (vs 3.9% in the general population, to 23.8% for anomalies of the atrio-
Other factors taken into account were P , .001) and the proportion of medi- ventricular junctions and valves (Table
those related to medical management cally induced PTB was 3.7% (vs 3.3% in 4). Except for anomalies of venous
of pregnancy and delivery. These in- the general population, P = .5; Table 3). return, risk of PTB was higher for all
cluded invasive prenatal testing (am- There was a 2.6-fold increase in the other categories of CHD when com-
niocentesis, chorionic villus sampling), odds of spontaneous PTB for newborns pared with VSD.
prenatal diagnosis of CHD, and medical with CHD compared with those in the After taking into account maternal age,
induction of labor or caesarean delivery general population (OR 2.6, 95% CI 2.0– occupation, geographic origin, parity,
before labor. 3.5). In contrast, we found no signifi- diabetes, vaginal bleeding, IUGR, and
The Stata/SE software (version 11.0; cant increase in medically induced PTB multiple pregnancies, as well as factors
Stata Corp, College Station, TX) was (OR 1.1, 95% CI 0.8–1.6). The median related to medical management of
used for data analysis. gestational age was 35 weeks for both pregnancy and delivery (induction of
spontaneous and medically induced labor, caesarean delivery before onset
RESULTS PTB (range 24–36 weeks and 27–36 of labor, prenatal diagnosis, invasive
The live birth prevalence of CHD in our weeks, respectively). prenatal testing), the odds of PTB was
study population (n = 2189) was 7.0 Maternal demographic and newborn 2.4-fold higher for anomalies of the
per 1000 live births (95% CI 6.7–7.3). characteristics of the EPICARD cohort atrioventricular junctions and valves
The overall proportion of PTB was and their association with PTB are (adjusted OR 2.4, 95% CI 1.4–4.2) and
13.5%, compared with 7.2% in the presented in detail in Supplemental 1.6-fold higher for functionally uni-
general population (odds ratio [OR] Tables 6 and 7. Mothers of newborns ventricular heart (adjusted OR 1.6,
2.0, 95% CI 1.6–2.5).There were similar with CHD who were older, of African 95% CI 0.7–3.9) compared with VSD
increases for very PTB (,32 weeks; origin, unemployed, or working in (Table 5).

TABLE 2 Proportion of PTBs for Newborns With CHD (Excluding Isolated ASD), Compared With the General Populationa
CHD n Gestational Age (wk)

,32 32–36 ,37

% 95% CIa % 95% CIa Pb % 95% CIa Pc

All cases 2189 2.4 1.8–3.1 11.1 9.8–12.5 ,.001 13.5 12.1–15.0 ,.001
Cases without chromosomal anomalies 2055 2.3 1.7–3.0 10.2 8.9–11.6 ,.001 12.5 11.1–14.0 ,.001
Cases without chromosomal and/or anomalies of other systemsd 1770 2.1 1.5–2.9 9.4 8.1–10.8 ,.001 11.5 10.1–13.1 ,.001
Cases without chromosomal and/or anomalies of other systems, 667 3.9 2.6–5.6 13.6 11.1–16.5 ,.001 17.5 14.7–20.6 ,.001
excluding isolated VSD
French NPS 2003e 1815 1.3 0.8–2.0 5.9 4.8–7.1 7.2 6.1–8.5
a P value for the overall x 2 test comparing the distribution of gestational age (,32, 32–36, $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).

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 ARTICLE

TABLE 3 Proportion of Spontaneous and Medically Induced PTB (,37 wk) for Newborns With CHD
CHD n Spontaneous PTBs Medically Induceda Pc
PTBs

% 95% CIb % 95% CIb

All cases 2189 9.7 8.5–11.0 3.7 2.9–4.6 ,.001
Cases without chromosomal anomalies 2055 8.8 7.6–10.1 3.6 2.8–4.5
Cases without chromosomal and/or anomalies of other systemsd 1770 7.8 6.6–9.2 3.5 2.7–4.5
Cases without chromosomal and/or anomalies of other systems, 667 12.0 9.6–14.7 5.4 3.8–7.4
excluding isolated VSD
French NPS of 2003 1815 3.9 3.1–4.9 3.3 2.5–4.2
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 Classification of CHD16)
CHD Categories Gestational Age (wk)

,32 32–36 ,37

% 95% CIa % 95% CIa Pb % 95% CIa Pc

Anomalies of the venous return 0 0–13.2c 3.8 0.1–19.6 ,.001 3.8 0.1–19.6 ,.001
Anomalies of the atrioventricular junctions and valves 4.6 1.5–10.4 19.2 12.3–27.9 23.8 16.2–33.0
Functionally univentricular hearts 2.1 0.1–11.1 18.7 8.9–32.6 20.8 10.5–35.0
VSDs 1.7 1.1–2.5 8.5 7.1–10.0 10.2 8.6–11.9
Anomalies of the ventricular outflow tract 3.8 2.2–6.0 14.8 11.7–18.5 18.6 15.1–22.6
Anomalies of the extrapericardial arterial trunks 0.8 0.02–4.4 18.5 12.1–26.5 19.3 12.8–27.4
French NPS of 2003 1.3 0.8–2.0 5.9 4.8–7.1 7.2 6.1–8.5
a 95% binomial exact CI.
b P value for the overall x 2 test comparing the distribution of gestational age (,32, 32–36, $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.

Role of Associated Anomalies with a reference population. This was after exclusion of cases associated with
For most categories, the risk of PTB was essentially due to an increase in chromosomal anomalies. This category
essentially the same after exclusion of spontaneous PTB, and we found no includes ASDs that are known to be
cases associated with chromosomal or evidence of an increase in medically more frequent in newborns with Down
other anomalies. However, for the induced PTB (induction of labor/ syndrome,21 and the latter are in gen-
anomalies of the atrioventricular junc- cesarean delivery before labor). Only eral at a higher risk of PTB.
tions and valves, the odds of PTB de- a small proportion (15%) of the in- To our knowledge, our study is the first
creased somewhat after exclusion of crease in PTB was explained by asso- to examine the nature of onset of labor
cases with associated chromosomal ciations between CHD and other for newborns with CHD and in partic-
anomalies and for anomalies of the anomalies. ular the possible impact of antenatal
extrapericardial arterial trunk after Risk of PTB was higher for certain screening on medically induced PTB.
exclusion of cases associated with other categories of CHD, including anomalies Several studies have examined the role
anomalies (detailed results available of the ventricular outflow tract, and of prenatal screening as a factor
from the authors). lower for isolated VSD and anomalies of leading to induction of labor or elective
the venous return. The higher risk of cesarean delivery before term in
PTB for certain categories of CHD may newborns with congenital anom-
DISCUSSION be explained in part by their associa- alies. 22,23 However, in the only pre-
By using population-based data on tions with other anomalies. In particu- vious population-based study of the
.2000 newborns with CHD, we found lar, the risk of PTB somewhat decreased risk of PTB associated with CHD,10
a twofold increase in the overall risk of for the category anomalies of the spontaneous and medically induced
PTB in newborns with CHD compared atrioventricular junctions and valves PTB were not distinguished. We found

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TABLE 5 Logistic Regression Analysis of the Specific Associations Between Categories of CHDa and PTBs
CHD Categories Unadjusted Model 1 Model 2

OR 95% CIb Pc Adjusted ORd 95% CIb Pc Adjusted ORe 95% CIb Pc
Anomalies of the venous return 0.3 0.05–2.6 ,.001 0.6 0.07–4.3 ,.001 0.6 0.07–4.3 ,.001
Anomalies of the atrioventricular junctions and valves 2.7 1.7–4.4 2.4 1.4–4.0 2.4 1.4–4.2
Functionally univentricular hearts 2.3 1.1–4.8 1.5 0.6–3.5 1.6 0.7–3.9
Anomalies of the ventricular outflow tract 2.0 1.5–2.7 2.2 1.6–3.1 2.3 1.7–3.3
Anomalies of the extrapericardial arterial trunks 2.1 1.3–3.4 2.2 1.3–3.8 2.3 1.3–4.0
VSD 1.0 Ref 1.0 Ref 1.0 Ref
a Anatomic and Clinical Classification 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).

that the higher risk of PTB in newborns consumption, and obesity, which may suggests that diagnoses of CHD after
with CHD was essentially due to an in- also be risk factors for CHD.24 the first year of life are unlikely to be
crease in spontaneous preterm delivery. Newborns with CHD or other congenital frequent in our population.
Our study has certain limitations. The anomalies were not systematically ex- The proportion of prenatally diagnosed
distribution of some sociodemographic cluded from the NPS. This can result in cases and TOPFA tend to be higher in our
characteristics differed somewhat be- an underestimation of the true risk of population than those in other Euro-
tween our study population and that PTB associated with CHD in our study pean countries.1 This may result in
of the NPS. To take these differences because newborns with congenital a lower proportion of PTB among
into account, we standardized the anomalies tend to have a higher risk newborns with CHD because our find-
proportion of PTB in our study pop- of PTB. This underestimation bias ings suggest that the more severe
ulation, by using available aggregate should be small or negligible, how- types of CHD, which are more likely to
data on the univariable distribution of ever, because newborns with congen- undergo TOPFA, tend to be at higher
maternal age, geographic origin, ma- ital anomalies would comprise ∼2% of risk of PTB.
ternal occupation, and parity in the NPS the NPS. Our results, particularly those related
and found similar proportions of PTB to Although our study included a large to specific associations between CHD
those reported here (detailed results number of cases of CHD, certain cate- and PTB, may be helpful for generating
available from the authors). Because gories of CHD could not be studied hypotheses on the underlying mecha-
this standardization was done by using because of limited sample size. For nisms for the association between CHD
the distribution of 1 variable at a time, certain other categories, CIs for the and PTB. Possible mechanisms include
residual confounding to differences associations were wide, indicating those related to (1) existence of a
between NPS and EPICARD in the mul- the limited precision of some of our common cause or risk factor, (2) clin-
tivariable distribution of these or other estimates. ical management of fetuses with CHD,
characteristics for which data were not Cases of CHD diagnosed after the first and (3) direct or indirect effects of the
available cannot be excluded. However, year of life25 may have been a source of CHD itself.
our estimate of the overall risk of PTB selection bias. If there are associa- A genetically programmed deterior-
associated with CHD was consistent tions between these usually minor ation of fetal development and the
with that given by Tanner by using defects and PTB, risk of PTB may be membranes may cause both CHD and
a different reference population.10 underestimated. However, given the PTB. Genetic disorders of the connective
Moreover, in our analyses of the spe- wide availability of specialized ser- tissue (Marfan or Ehlers-Danlos syn-
cific associations between categories vices for pre- and postnatal diagnosis drome), for example, are known for
of CHD and PTB, we adjusted our esti- of CHD in our population, this is likely their association with CHD and may also
mates for sociodemographic charac- to have had a minor impact, if any, in cause PTB by a weakening, followed by
teristics and several other known risk our study. Moreover, the live birth preterm rupture of membranes.26
factors of PTB. Nevertheless, we were prevalence of CHD in our study was A higher risk of PTB in newborns with
not able to adjust for certain risk higher than the average live birth chromosomal or other congenital
factors of PTB such as tobacco, alcohol prevalence of CHD in Europe,1 which anomalies has been described.11–13,27–29

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 ARTICLE

Indeed, we found that the risk of PTB those categories of CHD that cause both Paris); Catherine De Vigan (INSERM
for some categories of CHD was lower IUGR and PTB if IUGR is on the causal U953); François Goffinet (Groupe
after excluding newborns with associ- pathway between CHD and PTB. Never- Hospitalier Cochin-Hôtel Dieu, AP-HP,
ated anomalies, including genetic syn- theless, when IUGR was excluded, the Maternité Port-Royal et INSERM U953,
dromes. estimates of the associations between Université Paris Descartes, Paris);
There may be common environmental categories of CHD and PTB were es- Lucile Houyel (Hôpital Marie Lannelongue,
risk factors for both CHD and PTB. sentially the same as those reported Service de chirurgie des cardiopathies
In particular, air pollution has been here. congénitales, Le Plessis-Robinson); Jean-
reported as a risk factor for CHD,30 as The circulatory alterations associated Marie Jouannic (Hôpital Trousseau,
well as low birth weight and PTB.31,32 with CHD may directly cause both IUGR AP-HP, Centre pluridisciplinaire de di-
Viral infection (rubella) and maternal and PTB. Rosenthal showed that the agnostic prénatal, UPMC, Paris); Babak
diabetes are also known to be associ- alteration of the fetal circulation was Khoshnood (INSERM U953, Paris);
ated with an increase in the risk of not compatible with optimal growth.39 Nathalie Lelong (INSERM U953, Paris);
CHD33,34 and polyhydramnios, which Fetal growth was altered globally in Suzel Magnier (Hôpital Robert Debré,
may result in PTB.35 cases of generalized hypoperfusion, AP-HP, Service de cardiologie, Paris);
whereas a localized low oxygen supply Jean-François Magny (Institut de
Preterm newborns are more likely to
led to localized growth retardation. We Puériculture et de périnatologie, Ser-
undergo echocardiography in the NICU.
found that the category of anomalies of vice de néonatologie, Paris); Caroline
The associations between CHD and PTB
the ventricular outflow tract had the Rambaud (Hôpital Raymond Poincarré,
may then be due to a diagnostic bias. We
highest risk of PTB. Some of the CHD in AP-HP, Service d’anatomie et cytologie
excluded isolated cases of ASD that may pathologiques—Médecine légale, UVSQ,
this category, particularly tetralogy of
be particularly prone to such bias. It is Garches); Dominique Salomon (INSERM
Fallot and pulmonary atresia with VSD,
worth noting, however, that, if in- U953, Paris); Véronique Vodovar (INSERM
have been found to be associated with
dependent of diagnostic issues, ASD is U953, Paris)
growth retardation,40 fetal death, and
truly associated with a higher risk of PTB.10 Project Coordination and Data Analysis
PTB, we may have underestimated the
In conclusion, we found a higher risk of Committee: François Goffinet, Babak
risk of PTB associated with CHD by ex-
spontaneous PTB for newborns with Khoshnood, Nathalie Lelong, Anne-Claire
cluding the ASD.
CHD. Risk of PTB varied significantly Thieulin, Thibaut Andrieu, Véronique
Another explanation for the higher risk across categories of CHD defined Vodovar; Independent Data Monitoring
of PTB in newborns with CHD could be a based on anatomic and clinical crite- Committee (URC Paris Centre et CIC
higher likelihood of medically induced ria.16 Associations of CHD with chro- Cochin Necker Mère Enfant): Maggy
PTB, which has been shown to be mosomal or other congenital anomalies Chausson, Anissa Brinis, Laure Faure,
the case for certain other congenital explained only a small part of the higher Maryline Delattre, Jean-Marc Treluyer
anomalies.22,36 However, we found no risk of PTB for newborns with CHD. (Groupe Hospitalier Cochin-Hôtel Dieu,
evidence of an increase for medically Our results may be helpful for gener- AP-HP, Université Paris Descartes,
induced PTB for newborns with CHD. ating hypotheses regarding the de- Paris)
PTB may also be a direct or indirect velopmental links between PTB and External Scientific Committee: Gérard
result of the CHD itself. Polyhydramnios, CHD. Bréart, Dominique Cabrol, Alain Sérraf,
associated with fetal heart failure, may Daniel Sidi, Marcel Voyer
increase the risk of preterm labor35 and EPICARD STUDY GROUP Participating Centers: The greater Paris
thus PTB. IUGR, which is known to be Principal Investigators: François Goffinet area (Paris and its surrounding sub-
associated with PTB,37 is also more and Babak Khoshnood urbs) public (AP-HP) and private mater-
frequent for newborns with CHD.23,38 In Steering Committee: Damien Bonnet nity units, Departments of Pediatric
our study, the proportion of PTB in (Hôpital Necker Enfants Malades, AP- Cardiology and Pediatric Cardiac Sur-
newborns with IUGR was almost 20%. HP, Centre de référence M3C, Université gery, pediatric cardiologists in private
We adjusted our estimates of the as- Paris Descartes, Paris); Drina Candilis practice, NICUs, PICUs, Emergency
sociations between specific catego- (Université Paris-Diderot, Paris); Anne- Transfer Services (SMUR), Depart-
ries of CHD and PTB for IUGR. However, Lise Delezoide (Hôpital Robert Debré, ments of Pathology, Sudden Death
this strategy may result in biased AP-HP, Service de biologie du Dével- Centers, Departments of Family and In-
estimates of the association between oppement, Université Paris-Diderot, fant Protection (DFPE)

PEDIATRICS Volume 130, Number 4, October 2012 e835

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 Preterm Birth and Congenital Heart Defects: A Population-based Study
Enora Laas, Nathalie Lelong, Anne-Claire Thieulin, Lucile Houyel, Damien Bonnet,
Pierre-Yves Ancel, Gilles Kayem, François Goffinet and Babak Khoshnood
Pediatrics 2012;130;e829; originally published online September 3, 2012;
DOI: 10.1542/peds.2011-3279
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PEDIATRICS is the official journal of the American Academy of Pediatrics. A monthly

publication, it has been published continuously since 1948. PEDIATRICS is owned, published,
and trademarked by the American Academy of Pediatrics, 141 Northwest Point Boulevard, Elk
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 Preterm Birth and Congenital Heart Defects: A Population-based Study
Enora Laas, Nathalie Lelong, Anne-Claire Thieulin, Lucile Houyel, Damien Bonnet,
Pierre-Yves Ancel, Gilles Kayem, François Goffinet and Babak Khoshnood
Pediatrics 2012;130;e829; originally published online September 3, 2012;
DOI: 10.1542/peds.2011-3279

The online version of this article, along with updated information and services, is
located on the World Wide Web at:
http://pediatrics.aappublications.org/content/130/4/e829.full.html

PEDIATRICS is the official journal of the American Academy of Pediatrics. A monthly

publication, it has been published continuously since 1948. PEDIATRICS is owned,
published, and trademarked by the American Academy of Pediatrics, 141 Northwest Point
Boulevard, Elk Grove Village, Illinois, 60007. Copyright © 2012 by the American Academy
of Pediatrics. All rights reserved. Print ISSN: 0031-4005. Online ISSN: 1098-4275.

Downloaded from pediatrics.aappublications.org at Univ Of Georgia Libraries on May 26, 2015