DOI: 10.1542/peds.2011-3279; originally published online September 3, 2012; 2012;130;e829Pediatrics

Pierre-Yves Ancel, Gilles Kayem, François Goffinet and Babak KhoshnoodEnora Laas, Nathalie Lelong, Anne-Claire Thieulin, Lucile Houyel, Damien Bonnet,

Preterm Birth and Congenital Heart Defects: A Population-based Study  

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located on the World Wide Web at: The online version of this article, along with updated information and services, is

 

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

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Preterm Birth and Congenital Heart Defects:A Population-based Study

WHAT’S KNOWN ON THIS SUBJECT: Risk of preterm birth (PTB)has been noted to be higher for newborns with congenital heartdefects (CHDs). The role of associated anomalies, whether PTB isspontaneous or medically induced, or specific categories of CHDshave not been elucidated.

WHAT THIS STUDY ADDS: By using population-based data, wefound that PTB associated with CHDs was due to spontaneous PTB.Associated anomalies accounted for a small part of this increase,and there were specific associations between categories of CHDsand PTB.

abstractBACKGROUND AND OBJECTIVES: Preterm birth (PTB) and congenitalheart defect (CHD) are 2 major causes of mortality and disability ofperinatal origin. There are limited data on the relation between CHDand PTB. Our objective was to use population-based data to estimatethe risk of PTB in newborns with CHD and to study specific associationsbetween categories of CHD and PTB.

METHODS: We used data from a population-based cohort study ofCHD (EPIdémiologique sur le devenir des enfants porteurs deCARDiopathies congénitales study), including 2189 live births withCHD (excluding isolated atrial septal defects) born between 2005and 2008. We categorized CHD by using an anatomic and clinicalclassification. Data from the French National Perinatal Survey of2003 were used to compare PTB in the EPIdémiologique sur ledevenir des enfants porteurs de CARDiopathies congénitales studyto that of the general population.

RESULTS: Of the newborns with CHD, 13.5% were preterm. The odds ofPTB were twofold higher than for the general population (odds ratio2.0, 95% confidence interval 1.6–2.5), essentially due to an increase inspontaneous PTB for newborns with CHD. The risk of PTB associatedwith CHD persisted after exclusion of chromosomal or other anoma-lies. There were significant variations in risk of PTB across the cat-egories of CHD after adjustment for known risk factors of PTB andfactors 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 forcategories of CHD. Our finding may be helpful for generating hypoth-eses about the developmental links between CHD and PTB. Pediatrics2012;130:e829–e837

AUTHORS: Enora Laas, MD, MSc,a Nathalie Lelong, MSc,a

Anne-Claire Thieulin, MSc,a Lucile Houyel, MD,b DamienBonnet, MD, PhD,c Pierre-Yves Ancel, MD, PhD,a GillesKayem, MD, PhD,a François Goffinet, MD, PhD,a,d and BabakKhoshnood, MD, PhD,a on behalf of the EPICARD StudyGroupaINSERM, UMR S953, Recherche Épidémiologique sur la SantéPérinatale et la Santé des Femmes et des Enfants, UPMC,Université Paris-6, Paris, France; bService de Chirurgie desCardiopathies Congénitales, Hôpital Marie Lannelongue, LePlessis Robinson, France; and cCentre de Référence M3C-Necker,and dMaternité Port Royal, Hôpital Cochin Saint-Vincent-de-Paul,Assistance Publique Hôpitaux de Paris, UniversitéParis-Descartes, Paris, France

KEY WORDScongenital heart defects, preterm birth, population-based study,epidemiology

ABBREVIATIONSASD—atrial septal defectCHD—congenital heart defectCI—confidence intervalEPICARD—EPIdémiologique sur le devenir des enfants porteursde CARDiopathies congénitales studyIUGR—intrauterine growth restrictionNPS—National Perinatal SurveyOR—odds ratioPTB—preterm birthTOPFA—terminations of pregnancy for fetal anomalyVSD—ventricular 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,Hôpital 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 haveno financial relationships relevant to this article to disclose.

FUNDING: This work was supported by two grants from theFrench Ministry of Health (PHRC 2004 and 2008). Additionalfunding was provided by the AREMCAR (Association pour laRecherche et l’Etude des Maladies Cardiovasculaires)association. The funding sources had no role in the studydesign, data collection, data interpretation, or the writing of themanuscript.

PEDIATRICS Volume 130, Number 4, October 2012 e829

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Congenital heart defects (CHDs) arethe most frequent group of majorcongenital anomalies with a liveprevalence of ∼7 per 1000 live births.1Despite considerable progress in theirdiagnosis and medical management,2

CHDs remain themost important causeof infant mortality due to birth de-fects,3,4 and survivors may haveshort-term morbidity5,6 and adverseneurodevelopmental outcomes.6 Anextensive literature has also docu-mented higher risks of mortality,morbidity, and long-term adverseoutcomes related to preterm birth(PTB; ,37 weeks).7–9

CHD and PTB are therefore two of theleading causes of infant mortality anddisability of perinatal origin.10 Al-though known associations exist be-tween congenital anomalies andPTB,11–13 few specific data exist re-garding the risk of PTB for CHD. Moststudies report results of hospital-based studies of the clinical man-agement and outcomes of preterminfants with CHD.14,15 One previouspopulation-based study reported ahigher risk of PTB for newborns withCHD.10 This study did not assess therole of associated anomalies or theextent 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 theassociations between specific catego-ries of CHD and PTB.10

By using data from a large population-based cohort of newborns with CHD(the Etude EPIdémiologique sur ledevenir des enfants porteurs de CAR-Diopathies congénitales study; EPI-CARD), we estimated the risk of PTBin newborns with CHD, examined thenature of PTB (spontaneous versusmedically induced PTB), and studiedassociations between specific cate-gories of CHD (according to an ana-tomic and clinical classification16) andPTB.

METHODS

Data Source

EPICARD is aprospective cohort studyofall children with CHD born to women inthe greater Paris area (Paris and itssurrounding suburbs). All cases (livebirths, terminations of pregnancy forfetal anomaly [TOPFA], fetal deaths$20weeks) diagnosed in the prenatal pe-riod or up to 1 year of age in the birthcohorts between May 1, 2005 and April30, 2008 were eligible for inclusion.Multiple sources of data including allmaternity units, pediatric cardiologyand cardiac surgery centers, fetal andneonatal pathology departments, neo-natal and pediatric intensive units,infant units, and outpatient clinics ingreater Paris and a neighboring ter-tiary care center were regularly con-sulted to attain completeness of caseregistrations. Informed consent wasobtained from study participants, andthe study was approved by an ethicscommittee (French National Committeeof Information and Liberty). The lastcases included in the study were thosein the 2008 birth cohort who were di-agnosed in 2009. Follow-up of childrenin the EPICARD cohort is ongoing andwill include assessment of children’shealth and neurodevelopmental out-comes until at least 7 years of age.

The total number of cases included inthe EPICARD study was 2867. After ex-cluding TOPFA (n = 466) and fetaldeaths (n = 53), our initial study pop-ulation comprised 2348 live births. Thetotal number of live births in the studypopulation base was 314 022.

Five (0.2%) cases were excluded dueto missing information on gestationalage (Fig 1). We also excluded isolatedatrial septal defects (ASDs, n = 154)to minimize ascertainment bias. Pre-term infants are more likely to un-dergo echocardiography resulting indiagnosis of minor ASD that may oth-erwise go undiagnosed. In addition,

isolated minor ASD may be difficult todistinguish from patent foramen ovale.Our final study population included 2189newborns with CHD.

Cardiac anomalies associated with achromosomal anomaly comprised6.1% (n = 134), and those with anom-alies of other systems, including ge-netic syndromes, 13.9% (n = 285) ofcases.

Our reference population comprisedwomenresiding in thesamegeographicarea as that of the EPICARD populationbase, namely women residing in Parisand its surrounding suburbs, whowereincluded in the French National Peri-natal Survey (NPS) of 2003.7 The surveyinvolved a nationally representativesample of all births in France duringa 1-week period (N = 15 378), including1821 women residing in the samegeographic area as that of EPICARD.The NPS did not exclude newborns withCHD or other anomalies, which mayaccount for ∼2% of the live births inour population.

For both the EPICARD study and the NPS,estimate of gestational age was basedon medical records. By far, for mostnewborns in our population, this esti-mate is based on an early ultrasoundexamination.

The main outcome measure was riskof PTB. We distinguished spontaneousfrom medically induced PTB, by in-cluding in the latter PTB after inductionof labor or cesarean delivery beforelabor. Risk of PTB was examined for (1)all cases, (2) all cases excluding chro-mosomal anomalies, and (3) casesexcluding chromosomal or otheranomalies.

Detailed information on diagnosis andcoding of the CHD are provided else-where.16 To examine specific associa-tions between categories of CHD andPTB, we used an anatomic and clinicalclassification of CHD, which is basedon the Long List of the International

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Pediatric and Congenital Cardiac Code17

(Table 1). This classification, the Ana-tomic and Clinical Classification ofCongenital Heart Defects,16 categorizesCHD into 10 main categories and 23subcategories by using a multidimen-sional approach encompassing ana-tomic, echocardiographic, as well asclinical and surgical management cri-teria. It has proved useful in a previousstudy aimed at assessing specific as-sociations between a risk factor andcategories of CHD.16,18

In our analyses of the specific associa-tions between categories of CHD andPTB, we excluded the following catego-ries because of limited sample size:heterotaxy, including isomerism andmirror-imagery (n = 8); complexanomalies of atrioventricular con-nections (n = 7); and congenital anom-alies of the coronary arteries (n = 9).Hence, we compared risk of PTB for 6categories of CHD: anomalies of the ve-nous return (n = 26), anomalies of theatrioventricular junctions and valves

(n = 109), functional univentricularhearts (n = 48), ventricular septal de-fect (VSD; n = 1396), anomalies of theventricular outflow tract (n = 47), andanomalies of the extrapericardial arte-rial trunks (n = 124).

Missing Values

All variables had ,7% missing dataexcept for maternal occupation (19%).The probability of missing data was notstatistically associated with eithercategories of CHD or risk of PTB.

Statistical Analysis

We report proportions with 95%binomial exact confidence intervals(CIs). The x2 or Fisher exact test wereused to assess the associations be-tween risk of PTB and maternal orfetal characteristics. To take into ac-count the possible effect of differ-ences in the distribution of maternalcharacteristics in the NPS versus ourstudy population, we obtained stan-dardized estimates of the proportionof PTB by using the available aggre-gate data on the univariable distri-bution of maternal age, geographicorigin, maternal occupation, and par-ity in the NPS.

We used logistic regression to assessthe association between PTB and

FIGURE 1Study population. *Or nonchromosomal genetic syndromes. **One or more CHD only with no otherassociated anomalies.

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 0.01–0.05Anomalies of the venous return Anomalies of the pulmonary venous return 26 1.1 0.08 0.05–0.012Anomalies of the atria and interatrial communications Interatrial communications ostium secundum

type, patent oval foramen174 7.4 0.55 0.47–0.64

Anomalies of the atrioventricular junctions and valves Ebstein anomaly, ASD 109 4.6 0.35 0.28–0.42Complex anomalies of atrioventricular connections Congenitally corrected TGA (double discordance) 7 0.3 0.02 1025

–0.04Functionally univentricular hearts Left ventricular hypoplasia 48 2.0 0.15 0.1–0.2VSD Perimembranous VSD, muscular VSD 1396 59.4 4.4 4.2–4.7Anomalies of the ventricular outflow tract

(ventriculoarterial connections)TGA, double outlet right ventricle, tetralogy of Fallot 447 19.0 1.4 1.3–1.6

Anomalies of the extrapericardial arterial trunks Coarctation of the aorta 124 5.3 0.4 0.3–0.5Congenital anomalies of the coronary arteries 9 0.4 0.03 0.01–0.05Total 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 wereincluded as binary predictor variableswith the most frequent category (VSD)as the reference group. Potentiallyconfounding variables taken into ac-count included maternal age, occupa-tion, geographic origin, parity, diabetesmellitus, vaginal bleeding, intrauterinegrowth restriction (IUGR; ,10th per-centile), and multiple births. Thesefactors are known to be associatedwith risk of PTB even if their specificassociations with CHD are not welldocumented.19,20

Other factors taken into account werethose related to medical managementof pregnancy and delivery. These in-cluded invasive prenatal testing (am-niocentesis, chorionic villus sampling),prenatal diagnosis of CHD, and medicalinductionof labororcaesareandeliverybefore labor.

The Stata/SE software (version 11.0;Stata Corp, College Station, TX) wasused for data analysis.

RESULTS

The live birth prevalence of CHD in ourstudy population (n = 2189) was 7.0per 1000 live births (95% CI 6.7–7.3).The overall proportion of PTB was13.5%, compared with 7.2% in thegeneral population (odds ratio [OR]2.0, 95% CI 1.6–2.5).There were similarincreases for very PTB (,32 weeks;

OR 1.9, 95% CI 1.2–3.1) and moderatelyPTB (32–36 weeks; OR 2.0, 95% CI1.6–2.5).

After excluding both chromosomal andother anomalies, 11.5% of newbornswere PTB with an OR of 1.7 (95% CI 1.3–2.1) compared with the general pop-ulation (Table 2). For newborns withmajor isolated CHD ($1 CHD but noother anomalies and excluding isolatedVSD), the risk of PTB was 17.5% (OR 2.7,95% CI 2.1–3.6).

The proportion of spontaneousPTBwas9.7% (vs 3.9% in the general population,P , .001) and the proportion of medi-cally induced PTB was 3.7% (vs 3.3% inthe general population, P = .5; Table 3).There was a 2.6-fold increase in theodds of spontaneous PTB for newbornswith CHD compared with those in thegeneral population (OR 2.6, 95% CI 2.0–3.5). In contrast, we found no signifi-cant increase in medically induced PTB(OR 1.1, 95% CI 0.8–1.6). The mediangestational age was 35 weeks for bothspontaneous and medically inducedPTB (range 24–36 weeks and 27–36weeks, respectively).

Maternal demographic and newborncharacteristics of the EPICARD cohortand their association with PTB arepresented in detail in SupplementalTables 6 and 7. Mothers of newbornswith CHD who were older, of Africanorigin, unemployed, or working in

administrative/public service had higherrisks of PTB. Newborns of diabeticmothers or those with vaginal bleedingduring pregnancy, newborns withchromosomal or other anomalies, andmultiple births also had higher risksof PTB.

Specific Associations BetweenCategories of CHD and Risk of PTB

Risk of PTB varied significantly acrossthe categories of CHD, ranging from3.8% foranomalies of the venous returnto 23.8% for anomalies of the atrio-ventricular junctions and valves (Table4). Except for anomalies of venousreturn, risk of PTB was higher for allother categories of CHD when com-pared with VSD.

After taking into account maternal age,occupation, geographic origin, parity,diabetes, vaginal bleeding, IUGR, andmultiple pregnancies, aswell as factorsrelated to medical management ofpregnancy and delivery (induction oflabor, caesarean delivery before onsetof labor, prenatal diagnosis, invasiveprenatal testing), the odds of PTB was2.4-fold higher for anomalies of theatrioventricular junctions and valves(adjusted OR 2.4, 95% CI 1.4–4.2) and1.6-fold higher for functionally uni-ventricular heart (adjusted OR 1.6,95% CI 0.7–3.9) compared with VSD(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 ,.001Cases without chromosomal anomalies 2055 2.3 1.7–3.0 10.2 8.9–11.6 ,.001 12.5 11.1–14.0 ,.001Caseswithout 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 ,.001Cases without chromosomal and/or anomalies of other systems,excluding isolated VSD

667 3.9 2.6–5.6 13.6 11.1–16.5 ,.001 17.5 14.7–20.6 ,.001

French NPS 2003e 1815 1.3 0.8–2.0 5.9 4.8–7.1 7.2 6.1–8.5a P value for the overall x2 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 x2 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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Role of Associated Anomalies

Formost categories, the risk of PTBwasessentially the same after exclusion ofcases associated with chromosomal orother anomalies. However, for theanomalies of the atrioventricular junc-tions and valves, the odds of PTB de-creased somewhat after exclusion ofcases with associated chromosomalanomalies and for anomalies of theextrapericardial arterial trunk afterexclusion of cases associatedwith otheranomalies (detailed results availablefrom the authors).

DISCUSSION

By using population-based data on.2000 newborns with CHD, we founda twofold increase in the overall risk ofPTB in newborns with CHD compared

with a reference population. This wasessentially due to an increase inspontaneous PTB, and we found noevidence of an increase in medicallyinduced PTB (induction of labor/cesarean delivery before labor). Onlya small proportion (15%) of the in-crease in PTB was explained by asso-ciations between CHD and otheranomalies.

Risk of PTB was higher for certaincategories of CHD, including anomaliesof the ventricular outflow tract, andlower for isolated VSDandanomalies ofthe venous return. The higher risk ofPTB for certain categories of CHD maybe explained in part by their associa-tions with other anomalies. In particu-lar, the risk of PTBsomewhat decreasedfor the category anomalies of theatrioventricular junctions and valves

after exclusion of cases associatedwithchromosomal anomalies. This categoryincludes ASDs that are known to bemore frequent in newborns with Downsyndrome,21 and the latter are in gen-eral at a higher risk of PTB.

To our knowledge, our study is the firstto examine the nature of onset of laborfor newborns with CHD and in partic-ular the possible impact of antenatalscreening on medically induced PTB.Several studies have examined the roleof prenatal screening as a factorleading to induction of labor or electivecesarean delivery before term innewborns with congenital anom-alies.22,23 However, in the only pre-vious population-based study of therisk of PTB associated with CHD,10

spontaneous and medically inducedPTB 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 Induceda

PTBsPc

% 95% CIb % 95% CIb

All cases 2189 9.7 8.5–11.0 3.7 2.9–4.6 ,.001Cases without chromosomal anomalies 2055 8.8 7.6–10.1 3.6 2.8–4.5Caseswithout chromosomal and/or anomalies of other systemsd 1770 7.8 6.6–9.2 3.5 2.7–4.5Cases without chromosomal and/or anomalies of other systems,

excluding isolated VSD667 12.0 9.6–14.7 5.4 3.8–7.4

French NPS of 2003 1815 3.9 3.1–4.9 3.3 2.5–4.2a PTB after induction of labor or cesarean delivery before labor.b 95% binomial exact CI.c P value for the overall x2 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 ,.001Anomalies of the atrioventricular junctions and valves 4.6 1.5–10.4 19.2 12.3–27.9 23.8 16.2–33.0Functionally univentricular hearts 2.1 0.1–11.1 18.7 8.9–32.6 20.8 10.5–35.0VSDs 1.7 1.1–2.5 8.5 7.1–10.0 10.2 8.6–11.9Anomalies of the ventricular outflow tract 3.8 2.2–6.0 14.8 11.7–18.5 18.6 15.1–22.6Anomalies of the extrapericardial arterial trunks 0.8 0.02–4.4 18.5 12.1–26.5 19.3 12.8–27.4French NPS of 2003 1.3 0.8–2.0 5.9 4.8–7.1 7.2 6.1–8.5a 95% binomial exact CI.b P value for the overall x2 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 x2 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 newbornswith CHD was essentially due to an in-crease in spontaneous pretermdelivery.

Our study has certain limitations. Thedistribution of some sociodemographiccharacteristics differed somewhat be-tween our study population and thatof the NPS. To take these differencesinto account, we standardized theproportion of PTB in our study pop-ulation, by using available aggregatedata on the univariable distribution ofmaternal age, geographic origin, ma-ternal occupation, and parity in the NPSand found similar proportions of PTB tothose reported here (detailed resultsavailable from the authors). Becausethis standardization was done by usingthe distribution of 1 variable at a time,residual confounding to differencesbetween NPS and EPICARD in the mul-tivariable distribution of these or othercharacteristics for which datawere notavailable cannot be excluded. However,our estimate of the overall risk of PTBassociated with CHD was consistentwith that given by Tanner by usinga different reference population.10

Moreover, in our analyses of the spe-cific associations between categoriesof CHD and PTB, we adjusted our esti-mates for sociodemographic charac-teristics and several other known riskfactors of PTB. Nevertheless, we werenot able to adjust for certain riskfactors of PTB such as tobacco, alcohol

consumption, and obesity, which mayalso be risk factors for CHD.24

Newbornswith CHD or other congenitalanomalies were not systematically ex-cluded from the NPS. This can result inan underestimation of the true risk ofPTB associated with CHD in our studybecause newborns with congenitalanomalies tend to have a higher riskof PTB. This underestimation biasshould be small or negligible, how-ever, because newborns with congen-ital anomalies would comprise ∼2% ofthe NPS.

Although our study included a largenumber of cases of CHD, certain cate-gories of CHD could not be studiedbecause of limited sample size. Forcertain other categories, CIs for theassociations were wide, indicatingthe limited precision of some of ourestimates.

Cases of CHD diagnosed after the firstyear of life25 may have been a source ofselection bias. If there are associa-tions between these usually minordefects and PTB, risk of PTB may beunderestimated. However, given thewide availability of specialized ser-vices for pre- and postnatal diagnosisof CHD in our population, this is likelyto have had a minor impact, if any, inour study. Moreover, the live birthprevalence of CHD in our study washigher than the average live birthprevalence of CHD in Europe,1 which

suggests that diagnoses of CHD afterthe first year of life are unlikely to befrequent in our population.

The proportion of prenatally diagnosedcasesandTOPFA tend tobehigher inourpopulation than those in other Euro-pean countries.1 This may result ina lower proportion of PTB amongnewborns with CHD because our find-ings suggest that the more severetypes of CHD, which are more likely toundergo TOPFA, tend to be at higherrisk of PTB.

Our results, particularly those relatedto specific associations between CHDand PTB, may be helpful for generatinghypotheses on the underlying mecha-nisms for the association between CHDand PTB. Possible mechanisms includethose related to (1) existence of acommon cause or risk factor, (2) clin-ical management of fetuses with CHD,and (3) direct or indirect effects of theCHD itself.

A genetically programmed deterior-ation of fetal development and themembranes may cause both CHD andPTB.Genetic disordersof theconnectivetissue (Marfan or Ehlers-Danlos syn-drome), for example, are known fortheirassociationwith CHDandmayalsocause PTB by a weakening, followed bypreterm rupture of membranes.26

A higher risk of PTB in newborns withchromosomal or other congenitalanomalies has been described.11–13,27–29

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 ,.001Anomalies of the atrioventricular junctions and valves 2.7 1.7–4.4 2.4 1.4–4.0 2.4 1.4–4.2Functionally univentricular hearts 2.3 1.1–4.8 1.5 0.6–3.5 1.6 0.7–3.9Anomalies of the ventricular outflow tract 2.0 1.5–2.7 2.2 1.6–3.1 2.3 1.7–3.3Anomalies of the extrapericardial arterial trunks 2.1 1.3–3.4 2.2 1.3–3.8 2.3 1.3–4.0VSD 1.0 Ref 1.0 Ref 1.0 Refa Anatomic and Clinical Classification of CHD.16b 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).

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Indeed, we found that the risk of PTBfor some categories of CHD was lowerafter excluding newborns with associ-ated anomalies, including genetic syn-dromes.

There may be common environmentalrisk factors for both CHD and PTB.In particular, air pollution has beenreported as a risk factor for CHD,30 aswell as low birth weight and PTB.31,32

Viral infection (rubella) and maternaldiabetes are also known to be associ-ated with an increase in the risk ofCHD33,34 and polyhydramnios, whichmay result in PTB.35

Preterm newborns are more likely toundergo echocardiography in the NICU.The associations between CHD and PTBmay thenbedue to adiagnostic bias.Weexcluded isolated cases of ASD thatmaybe particularly prone to such bias. It isworth noting, however, that, if in-dependent of diagnostic issues, ASD istruly associated with a higher risk ofPTB, we may have underestimated therisk of PTB associated with CHD by ex-cluding the ASD.

Another explanation for the higher riskof PTB in newborns with CHD could be ahigher likelihood of medically inducedPTB, which has been shown to bethe case for certain other congenitalanomalies.22,36 However, we found noevidence of an increase for medicallyinduced PTB for newborns with CHD.

PTB may also be a direct or indirectresult of the CHD itself. Polyhydramnios,associated with fetal heart failure, mayincrease the risk of preterm labor35 andthus PTB. IUGR, which is known to beassociated with PTB,37 is also morefrequent for newborns with CHD.23,38 Inour study, the proportion of PTB innewborns with IUGR was almost 20%.

We adjusted our estimates of the as-sociations between specific catego-ries of CHD and PTB for IUGR. However,this strategy may result in biasedestimates of the association between

those categories of CHD that cause bothIUGR and PTB if IUGR is on the causalpathway between CHD and PTB. Never-theless, when IUGR was excluded, theestimates of the associations betweencategories of CHD and PTB were es-sentially the same as those reportedhere.

The circulatory alterations associatedwith CHD may directly cause both IUGRand PTB. Rosenthal showed that thealteration of the fetal circulation wasnot compatible with optimal growth.39

Fetal growth was altered globally incases of generalized hypoperfusion,whereas a localized low oxygen supplyled to localized growth retardation. Wefound that the category of anomalies ofthe ventricular outflow tract had thehighest risk of PTB. Some of the CHD inthis category, particularly tetralogy ofFallot and pulmonary atresia with VSD,have been found to be associated withgrowth retardation,40 fetal death, andPTB.10

In conclusion, we found a higher risk ofspontaneous PTB for newborns withCHD. Risk of PTB varied significantlyacross categories of CHD definedbased on anatomic and clinical crite-ria.16 Associations of CHD with chro-mosomal or other congenital anomaliesexplained only a small part of the higherrisk of PTB for newborns with CHD.Our results may be helpful for gener-ating hypotheses regarding the de-velopmental links between PTB andCHD.

EPICARD STUDY GROUPPrincipal Investigators: François Goffinetand Babak Khoshnood

Steering Committee: Damien Bonnet(Hôpital Necker Enfants Malades, AP-HP, Centre de référence M3C, UniversitéParis Descartes, Paris); Drina Candilis(Université Paris-Diderot, Paris); Anne-Lise Delezoide (Hôpital Robert Debré,AP-HP, Service de biologie du Dével-oppement, Université Paris-Diderot,

Paris); Catherine De Vigan (INSERMU953); François Goffinet (GroupeHospitalier Cochin-Hôtel Dieu, AP-HP,Maternité Port-Royal et INSERM U953,Université Paris Descartes, Paris);Lucile Houyel (HôpitalMarie Lannelongue,Service de chirurgie des cardiopathiescongénitales, Le Plessis-Robinson); Jean-Marie Jouannic (Hôpital Trousseau,AP-HP, Centre pluridisciplinaire de di-agnostic prénatal, UPMC, Paris); BabakKhoshnood (INSERM U953, Paris);Nathalie Lelong (INSERM U953, Paris);Suzel Magnier (Hôpital Robert Debré,AP-HP, Service de cardiologie, Paris);Jean-François Magny (Institut dePuériculture et de périnatologie, Ser-vice de néonatologie, Paris); CarolineRambaud (Hôpital Raymond Poincarré,AP-HP, Service d’anatomie et cytologiepathologiques—Médecine légale, UVSQ,Garches); Dominique Salomon (INSERMU953, Paris); Véronique Vodovar (INSERMU953, Paris)

Project Coordination and Data AnalysisCommittee: François Goffinet, BabakKhoshnood, Nathalie Lelong, Anne-ClaireThieulin, Thibaut Andrieu, VéroniqueVodovar; Independent Data MonitoringCommittee (URC Paris Centre et CICCochin Necker Mère Enfant): MaggyChausson, Anissa Brinis, Laure Faure,Maryline Delattre, Jean-Marc Treluyer(Groupe Hospitalier Cochin-Hôtel Dieu,AP-HP, Université Paris Descartes,Paris)

External Scientific Committee: GérardBréart, Dominique Cabrol, Alain Sérraf,Daniel Sidi, Marcel Voyer

ParticipatingCenters: ThegreaterParisarea (Paris and its surrounding sub-urbs) public (AP-HP) and privatemater-nity units, Departments of PediatricCardiology and Pediatric Cardiac Sur-gery, pediatric cardiologists in privatepractice, NICUs, PICUs, EmergencyTransfer Services (SMUR), Depart-ments of Pathology, Sudden DeathCenters, Departments of Family and In-fant Protection (DFPE)

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DOI: 10.1542/peds.2011-3279; originally published online September 3, 2012; 2012;130;e829Pediatrics

Pierre-Yves Ancel, Gilles Kayem, François Goffinet and Babak KhoshnoodEnora Laas, Nathalie Lelong, Anne-Claire Thieulin, Lucile Houyel, Damien Bonnet,

Preterm Birth and Congenital Heart Defects: A Population-based Study  

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