Prevalência e MI por CC na Europa de 2000 a 2005

(EUROCAT) Working GroupHelen Dolk, Maria Loane, Ester Garne and a European Surveillance of Congenital AnomaliesCongenital Heart Defects in Europe : Prevalence and Perinatal Mortality, 2000 to 2005

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Congenital Heart Disease

Congenital Heart Defects in EuropePrevalence and Perinatal Mortality, 2000 to 2005

Helen Dolk, DrPh; Maria Loane, MA; Ester Garne, MD; and a European Surveillance of CongenitalAnomalies (EUROCAT) Working Group

Background—This study determines the prevalence of Congenital Heart Defects (CHD), diagnosed prenatally or ininfancy, and fetal and perinatal mortality associated with CHD in Europe.

Methods and Results—Data were extracted from the European Surveillance of Congenital Anomalies central database for29 population-based congenital anomaly registries in 16 European countries covering 3.3 million births during theperiod 2000 to 2005. CHD cases (n�26 598) comprised live births, fetal deaths from 20 weeks gestation, andterminations of pregnancy for fetal anomaly (TOPFA). The average total prevalence of CHD was 8.0 per 1000 births,and live birth prevalence was 7.2 per 1000 births, varying between countries. The total prevalence of nonchromosomalCHD was 7.0 per 1000 births, of which 3.6% were perinatal deaths, 20% prenatally diagnosed, and 5.6% TOPFA.Severe nonchromosomal CHD (ie, excluding ventricular septal defects, atrial septal defects, and pulmonary valvestenosis) occurred in 2.0 per 1000 births, of which 8.1% were perinatal deaths, 40% were prenatally diagnosed, and 14%were TOPFA (TOPFA range between countries 0% to 32%). Live-born CHD associated with Down syndrome occurredin 0.5 per 1000 births, with �4-fold variation between countries.

Conclusion—Annually in the European Union, we estimate 36 000 children are live born with CHD and 3000 who arediagnosed with CHD die as a TOFPA, late fetal death, or early neonatal death. Investing in primary prevention andpathogenetic research is essential to reduce this burden, as well as continuing to improve cardiac services from in uteroto adulthood. (Circulation. 2011;123:841-849.)

Key Words: congenital heart defects � epidemiology � Europe � prevalence � perinatal mortality

Congenital heart defects (CHD) account for nearly onethird of babies with major congenital anomalies diag-

nosed prenatally or in infancy in Europe.1,2 Great advances intreatment in recent decades have led to a decrease in infantmortality and an increase in children and adults withCHD.3,4,5 Pressure on pediatric and adult services for CHDsurvivors has been widely documented, as well as the needfor special management when CHD survivors themselvesbecome pregnant.6 There is also increasing recognition ofneurodevelopmental problems in childhood among CHDsurvivors.7

Clinical Perspective on p 849

Prenatal ultrasound screening for the detection of congen-ital anomalies is now offered to the majority of women inmost countries of Europe, although the prenatal screeningpolicies and prenatal detection rates vary greatly.8 Except forthe most severe CHD, prenatal diagnosis may improvetreatment success by allowing appropriate preparation forbirth and the neonatal period,9–11 and methods of fetal cardiac

intervention are under development.12 For severe CHD,prenatal diagnosis may lead to a decision to terminate thepregnancy. There is a need for updated CHD prevalence datataking these developments into account.13

Primary prevention measures currently include rubellavaccination, good diabetic control, and avoidance of knownteratogenic drugs such as some antiepileptic drugs andisotretinoin.14 There is also increasing evidence that folic acidmay be protective,14–16 and recent recommendations includeavoiding contact with influenza and febrile illnesses andavoidance of exposure to organic solvents.14 There is growingevidence of a link with maternal obesity18,19 and limitedevidence of a link with maternal smoking and exposure to airpollution.14 Primary prevention is particularly difficult be-cause the heart may be fully formed before the mother knowsshe is pregnant and many pregnancies are unplanned. Moni-toring of the prevalence of CHD is needed to determine theoverall impact of changes in risk factors and the implemen-tation of primary preventive measures based on current andfuture research evidence.

Received April 4, 2010; accepted November 3, 2010.From the EUROCAT Central Registry, Centre for Maternal, Fetal and Infant Research, Institute of Nursing Research, University of Ulster, UK (H.D.,

M.L.); and Department of Pediatrics, Hospital Lillebaelt, Kolding, Denmark (E.G.).The online-only Data Supplement is available with this article at http://circ.ahajournals.org/cgi/content/full/CIRCULATIONAHA.110.958405/DC1.Correspondence to Helen Dolk, Professor of Epidemiology and Health Services Research, University of Ulster, Jordanstown Campus, Shore Rd, Co

Antrim, BT370QB, Northern Ireland, UK. E-mail [email protected]© 2011 American Heart Association, Inc.

Circulation is available at http://circ.ahajournals.org DOI: 10.1161/CIRCULATIONAHA.110.958405

841 by guest on September 23, 2012http://circ.ahajournals.org/Downloaded from


European Surveillance of Congenital Anomalies (EUROCAT) isa population-based surveillance system based on a networkof congenital anomaly registers in Europe covering morethan one quarter of births in 20 European countries.1,19 Thegreat advantage of such a population-based system is thatprevalence can be estimated without biases caused by referralof high-risk pregnancies or babies between hospitals, andascertainment includes fetal and early neonatal deaths as wellas terminations of pregnancy for fetal anomaly (TOPFA)after prenatal diagnosis who do not reach pediatric cardiologyreferral centers.

In this article, we present recent EUROCAT data on theprevalence of CHD in Europe, diagnosed prenatally or ininfancy, and on the outcome of pregnancy in terms of fetaland early postnatal survival. This information is needed as abaseline from which to monitor future progress in primaryprevention; to monitor the impact of termination of preg-nancy for fetal anomaly on prevalence; to plan for high-quality services; and to allow individual regions to comparetheir rates with the European average and range. This articletherefore investigates CHD from a public health rather than aclinical perspective.

MethodsData were extracted from the EUROCAT database, which is fullydescribed elsewhere20 and was last updated in February 2009.Twenty-nine population-based registries in 16 European countries(including 3 non–European Union [EU] countries) contributed data(Table 1). The total population coverage for 2000 to 2005 was 3.3million births. From 12% to 100% of annual births in each countrywere covered by �1 EUROCAT registries (Table 1).

Registries contributing individual-anonymized case data to theEUROCAT central database at least as recent as 2004 were included.Registries use multiple sources of information to ascertain cases inorder to cover all types of cases (live birth [LB], late fetal death, andtermination of pregnancy; surgical and nonsurgical; and with andwithout additional major non-CHD anomalies). Sources, dependingon registry,3,21–27 include maternity, neonatal, and pediatric records;fetal medicine, cytogenetic, pathology, and medical genetics records;specialist services including pediatric cardiology; and hospital dis-charge and child health records. Twenty-one of the registries(covering 2.6 million births) included in the study ascertained casesof CHD diagnosed up to at least 1 year of life. The exceptions arenoted as a footnote to Table 1.

Cases of CHD occurring in LBs, late fetal deaths/stillbirths from20 weeks of gestation (FDs), and TOPFA after prenatal diagnosis atany gestational age were included.

All cases were coded to the International Classification of Dis-eases (ICD) version 9 or 10 with 1-digit BPA extension.28,29 Cases

Table 1. Population* (No. EUROCAT Registries, Births, Percentage National Coverage) and Total Prevalence† (95% CI) of All,Nonchromosomal and Nonchromosomal SI and SII CHDs per 1000 Births by Country, 2000 to 2005

Countries*Registries,*

n

Total Births, 2000to 2005, in

Registry Regions,n

Annual NationalBirths Covered,

2005, %

All CHD Nonchromosomal CHDNonchromosomal CHD, SI

and SII

No.Prevalence per 1000

Births (95% CI) No.Prevalence per 1000

Births (95% CI) No.Prevalence per 1,000

Births (95% CI)

Austria 1 62 667 13 960 15.32 (14.37–16.32) 871 13.90 (12.99–14.85) 163 2.60 (2.22–3.03)

Belgium 2 182 467 27 1212 6.64 (6.27–7.03) 1058 5.80 (5.45–6.16) 343 1.88 (1.69–2.09)

Croatia‡ 1 33 933 14 182 5.36 (4.61–6.20) 161 4.74 (4.04–5.54) 41 1.21 (0.87–1.64)

Denmark 1 32 003 8 291 9.09 (8.08–10.20) 265 8.28 (7.31–9.34) 65 2.03 (1.57–2.59)

France‡ 3 343 715 8 2853 8.30 (8.00–8.61) 2447 7.12 (6.84–7.41) 879 2.56 (2.39–2.73)

Germany‡ 2 124 952 3 1457 11.66 (11.07–12.28) 1315 10.52 (9.96–11.11) 269 2.15 (1.90–2.43)

Ireland 3 215 021 63 1423 6.62 (6.28–6.97) 1083 5.04 (4.74–5.35) 476 2.21 (2.02–2.42)

Italy‡ 3 431 727 15 2944 6.82 (6.58–7.07) 2744 6.36 (6.12–6.60) 754 1.75 (1.62–1.88)

Malta 1 23 668 100 348 14.70 (13.20–16.33) 301 12.72 (11.32–14.24) 51 2.15 (1.60–2.83)

Netherlands 1 119 104 10 732 6.15 (5.71–6.61) 639 5.37 (4.96–5.80) 272 2.28 (2.02–2.57)

Norway 1 346 838 100 3538 10.20 (9.87–10.54) 3236 9.33 (9.01–9.66) 611 1.76 (1.63–1.91)

Poland 1 206 170 9 2304 11.18 (10.72–11.64) 2116 10.26 (9.83–10.71) 297 1.44 (1.28–1.61)

Spain‡ 2 194 234 7 1080 5.56 (5.23–5.90) 904 4.65 (4.36–4.97) 399 2.05 (1.86–2.27)

Switzerland 1 42 874 10 576 13.43 (12.36–14.58) 512 11.94 (10.93–13.02) 105 2.45 (2.00–2.97)

Ukraine‡ 1 25 835 6 201 7.78 (6.74–8.93) 180 6.97 (5.99–8.06) 46 1.78 (1.30–2.38)

UK‡ 5 951 001 26 6497 6.83 (6.67–7.00) 5516 5.80 (5.65–5.96) 1974 2.08 (1.99–2.17)

Total 29 3 336 209 13 26 598 7.97 (7.88–8.07) 23 348 7.00 (6.91–7.09) 6745 2.02 (1.97–2.07)

SI and SII include All Nonchromosomal CHD except ventricular septal defects, atrial septal defects, pulmonary valve stenoses, and unclassified severity defects.*Registries per country (2000 to 2005 unless otherwise stated) were: Austria: Styria; Belgium: Antwerp, Hainaut; Croatia: Zagreb; Denmark: Odense; France: Ile

de la Reunion (2002 to 2005), Paris, Strasbourg (2000 to 2004); Germany: Mainz, Saxony-Anhalt; Ireland: Cork and Kerry (2000 to 2004), Dublin, Southeast Ireland;Italy: Emilia Romagna, Sicily (2000 to 2004), Tuscany; The Netherlands: Northern; Poland: Wielkopolska; Spain: Barcelona, Basque Country; Switzerland: Vaud; Ukraine(2005 only); UK: East Midlands and South Yorkshire, Northern England, Thames Valley, Wales, Wessex.

†Total prevalence includes LBs, fetal deaths from 20 weeks and TOPFAs. Prevalence tables for CHD subgroups can be found at http://www.eurocat-network.eu/ACCESSPREVALENCEDATA/PrevalenceTables.

‡Twenty-one registries ascertained cases of CHD diagnosed until at least 1 year of life. Exceptions were Croatia (1 week), Paris (discharge from maternity orneonatal unit), Mainz (1 week, but all newborns submitted to standard registry examination and followed up if murmur detected), Barcelona (3 days), and Ukraine(1 month). Ascertainment in Emilia Romagna and Thames Valley was more systematic for cases diagnosed in the first week, and Wessex ascertained cardiac casesdiagnosed after 1 week only if they had surgery.

842 Circulation March 1, 2011



can have up to 9 syndrome or malformation codes. The ICD codesdefining CHD were Q20–26 (ICD10) and 745, 746, and 7470 to7474 (ICD9-BPA). Cases of patent ductus arteriosus in pretermbabies (�37 weeks) and patent foramen ovale as the only CHD wereexcluded.20

EUROCAT defines 16 standard subgroups of CHD.20 We used apreviously defined hierarchical severity ranking30 based on theperinatal mortality rate for each of these subgroups among nonchro-mosomal cases (see online-only Data Supplement Figure I), with 3classes, from I (high perinatal mortality) to III (low perinatalmortality):

Severity I (SI): single ventricle, hypoplastic left heart, hypoplasticright heart, Ebstein anomaly, and tricuspid atresia

Severity II (SII): pulmonary valve atresia, common arterial truncus,atrioventricular septal defects, aortic valve atresia/stenosis, trans-position of great vessels, tetralogy of Fallot, total anomalouspulmonary venous return, and coarctation of aorta, without addi-tional CHD subgroups classified as severity I. The followinganomalies not classified to any of the 16 EUROCAT subgroupswere added to SII (finally accounting for 6% of SII cases): doubleoutlet right or left ventricle, discordant atrioventricular connec-tion, Ivemark atrial isomerism, other abnormal cardiac connec-tions, aortopulmonary window, cor triatriatum, subaortic valvestenosis, malformations of coronary arteries, atresia of aorta andinterrupted aortic arch, supravalvular aortic stenosis, and abnormalpulmonary venous connections.

Severity III (SIII): ventricular septal defect (VSD), atrial septaldefect, and pulmonary valve stenosis, without additional CHDsubgroups classified as SI or SII.

Eleven percent of all CHD cases where the ICD code was for apoorly specified CHD of unknown severity or patent ductus arteri-osus in term infants were not classified to a severity group. Thesecases were included in counts relating to all CHD but not in severitycategory counts.

Cases were classified according to the presence or absence of anassociated chromosomal anomaly (ICD10 codes Q90–93 and 96 to99 excl Q936). Nonchromosomal cases were classified by thepresence or absence of an additional major non-CHD anomaly, thelatter labeled “isolated.”

Each case is counted once only in any given prevalence rate (ie,prevalence is based on cases, not anomalies). Prevalence ratesaveraged across Europe were calculated by adding up EUROCATregions across Europe, without extrapolation to country for partiallycovered countries. Prevalence rates were calculated as:

LB prevalence rate�(No. LB cases)/(total births live and still )

FD prevalence rate�(No. FD cases)/(total births live and still )

TOPFA prevalence rate�(No. TOPFA)/(total births live and still )

Total prevalence rate�LB�FD�TOPFA prevalence rate

We present TOPFA mainly as a prevalence per 1000 births ratherthan as a proportion of all CHD cases because differences inascertainment of milder postneonatally diagnosed CHD can distortproportions greatly. The “perinatal mortality” rate was defined as

(FD from 20 weeks gestation�first week deaths)/

(total births live and still )

Data extracted for registered cases were date of birth, registry,pregnancy outcome (LB, FD, or TOPFA), all diagnosed malforma-tions and syndromes, age at diagnosis (defined as first suspicion ofany congenital anomaly, whether CHD or associated non-CHDanomaly), and whether the neonate survived the first week of life.Whether a LB/FD case had been prenatally diagnosed was notrecorded in the central database for 4 registries (see footnote to Table2), which were excluded from analysis of prenatal diagnosis.Confidence intervals (CIs) for prevalence rates were calculated in

StatsDirect statistical software version 2.7.7 (StatsDirect Ltd,Cheshire, UK).

ResultsAll CHD CasesThe reported total prevalence of CHD in Europe was 8.0 per1000 births (95% CI 7.9 to 8.1) based on 26 598 cases (Table1), including LBs (89.7%), FDs (1.6%), and TOPFA (8.7%).The range in total prevalence across countries was 5.36 to15.32 per 1000, with 5 countries reporting prevalence �10per 1000 (Table 1). The average LB prevalence was 7.2 per1000 (95% CI 7.1 to 7.3).

Nonchromosomal CHD CasesEighty-eight percent of CHD were not associated with achromosomal anomaly, giving an average total prevalence of7.0 per 1000 (95% CI 7.0 to 7.1), varying considerablybetween countries (Table 1) and registries within countries(Figure 1). Most were LBs (6.5 per 1000, Table 2), and 82%were isolated CHD (Table 2). SIII cases were more than twiceas common as SI and SII combined (Table 2). The prevalenceof VSD without other associated CHD or non-CHD anoma-lies was 1.9 per 1000.

Age at diagnosis was known for 66% of live-born non-chromosomal CHD cases. Twenty-three percent of cases withknown age at diagnosis were diagnosed after 1 week of age:8.3% 1 week to 1 month, 12.5% 1 month to 1 year, and 1.9%after 1 year. This proportion was highest for the less severecases: 5.8% for SI, 15.5% for SII, and 26.2% for SIII.Ascertainment of SIII cases diagnosed after 1 week of age, asindicated by their prevalence, varied between registries (Fig-ure 1). The 3 registries recording the highest prevalence ofSIII diagnosed after 1 week of 4 to 5 per 1000 (Figure 1) werefrom the 3 countries recording the highest overall CHDprevalence (Table 1). Average total SIII prevalence was 0.5per 1000 births higher in the 21 registries with ascertainmentup to 1 year (4.68 per 1000) than the average for all registries(4.18 per 1000, Table 2).

Perinatal mortality was 0.25 per 1000 births (95% CI 0.24to 0.27, Table 2), varying from 0.07 in Italy to a range of 0.20to 0.38 in all other countries except Ukraine at 0.93 per 1000(Figure 2 and online-only Data Supplement Table I). SI andSII contributed approximately a third each to CHD perinataldeaths (Table 1) whereas SIII contributed 19%. CHD ofunclassified severity contributed disproportionately to CHDperinatal mortality (16%) probably because of the lower levelof diagnostic specificity available from death records. Peri-natal deaths were less likely to be isolated CHD (Table 2).

Prenatal Diagnosis and TOPFA forNonchromosomal CasesA total of 20.2% of nonchromosomal CHD cases had prenataldiagnosis of a congenital anomaly (Table 2, data from 25/29registries), being the majority of SI (63.7%), nearly a third ofSII (or 40% of SI/SII combined), and less than one tenth ofSIII (Table 2). Prenatally diagnosed cases were less likely tobe isolated CHD, especially for SIII (Table 2). Prenataldiagnosis proportions for SI/SII varied by country (Figure 3).

Dolk et al Congenital Heart Defects in Europe 843



A total of 31% of prenatally diagnosed nonchromosomalCHD resulted in TOPFA (54.6% for SI, 27.5% for SII, and15.9% for SIII, data from 25/29 registries), this proportionalso varying by country (Figure 3). TOPFA were less likely tobe isolated CHD than other prenatally diagnosed or non–prenatally diagnosed cases, especially for SIII (Table 2).

TOPFA were more frequent than perinatal deaths, at 0.39per 1000. This rate varied strongly between countries (Figure2, online-only Data Supplement Table I): from 0 in Ireland,Malta, and Poland to a maximum of 1.06 per 1000 in France(Figure 2).

Chromosomal CHD CasesTwelve percent of CHD cases were associated with chromo-somal anomalies (7% Down Sydrome [DS], 2% Trisomy 18,and 1% Trisomy 13), for an average total prevalence of 0.97per 1000 births. In the study population, the total prevalenceof DS was 2.1 per 1000, of which 48.1% were TOPFA, andthe prevalence of DS among LBs was 1.0 per 1000 births. Ofthese LB DS cases, 45% (n�1521) had a recorded CHD(17.4% SI/SII, 23.8% SIII, and 3.8% unclassified severity),giving a LB prevalence of Down syndrome with CHD of 0.46per 1000 births (95% CI 0.43 to 0.48). Rates of LB Downsyndrome with CHD varied from �0.25 per 1000 in France,Italy, and Switzerland to �1 per 1000 in Ireland and Malta(Figure 4). A total of 1.2% of LB Down syndrome with CHDdied in the first week of life.

We estimate the contribution of Down syndrome withCHD to the total pediatric CHD case load to vary from 3% to4% (Italy, France, and Switzerland) to 15% to 19% (Irelandand Malta), assuming an average nonchromosomal CHD LBprevalence of 6.5 per 1000 for all countries.

DiscussionWe found the total prevalence of CHD in Europe during 2000to 2005 to be 8.0 per 1000 births, with variation between

countries and registries within countries, and LB prevalenceto be 7.2 per 1000 births. A review of 62 studies published in200213 found a median LB prevalence of 7.5 per 1000, similarto our study, with an interquartile range of 6.0 to 10.6 per1000. Variation between the studies reviewed was mainlyexplained by variation in the inclusion of small VSDs andindication for echocardiography.13 In our European popula-tion, on the basis of diagnoses reached under normal healthservice conditions, up to half of SIII cases, depending onregistry, were first detected after the first week of life, and theprevalence estimate would be 0.5 per 1000 higher if registriesnot ascertaining up to 1 year of life were excluded. However,it is not possible to standardize comparisons between regionsor countries by using age at diagnosis in order to find “real”underlying variation in prevalence, given that average age atdiagnosis itself varies according to the intensity of prenataland early neonatal screening and follow-up taking place ineach region. Moreover, even with complete ascertainment ofcases diagnosed up to 1 year of age, variation in prevalencerelating to echocardiography referral practice and registryinclusion of smaller muscular cases that close spontaneouslywould remain. During the decade preceding our study, anincrease in the prevalence of CHD, particularly SIII, wasreported in a number of European and other countries andattributed mainly to diagnostic factors.22,24,26,31

The total prevalence of severe (SI/SII) nonchromosomalCHD cases in our population was 2.0 per 1000. These casesare more uniformly ascertained and were mainly diagnosedby the end of the first week of life, including a significantproportion of prenatally diagnosed cases. To what extentcountry variation in the rate of severe (SI/SII) CHD, thehighest rate being recorded in Austria, reflects variation inrisk factors requires further investigation. Recent evidence ofa decline in severe CHD in this decade,15,32 including in

Table 2. No., Prevalence per 1,000 births (95% CI), and Proportion of Nonchromosomal CHD by Pregnancy Outcome, Whether CHDwas an Isolated Anomaly, and Whether Prenatally Diagnosed, in 29 European Registries, 2000 to 2005

Nonchromosomal CHD SI*

Outcome No.Prevalence per 1000

Births (95% CI)Total

Cases, %Isolated WithinCategory, % No.

Prevalence per 1000Births (95% CI)

TotalCases, %

Isolated WithinCategory, %

Total 23348 7.00 (6.96–6.14) 100.0 82.4 1556 0.47 (0.44–0.49) 100.0 82.8

LBs 21749 6.52 (6.48–6.65) 93.2 84.6 973 0.29 (0.27–0.31) 62.5 86.1

Fetaldeaths

291 0.09 (0.08–0.10) 1.2 52.9 63 0.02 (0.02–0.02) 4.0 76.2

TOPFA 1308 0.39 (0.37–0.41) 5.6 52.4 520 0.16 (0.14–0.17) 33.4 77.5

First–weekdeaths

554 0.17 (0.15–0.18) 2.4 63.2 191 0.06 (0.05–0.07) 12.3 83.2

Perinataldeaths†

845 0.25 (0.24–0.27) 3.6 59.6 254 0.08 (0.07–0.09) 16.3 81.5

Prenatallydiagnosed‡

3041 1.27 (1.23–1.32) 20.2 58.3 698 0.29 (0.27–0.32) 63.7 77.8

*SI: single ventricle, hypoplastic left heart, hypoplastic right heart, Ebstein anomaly, tricuspid atresia. SII: mainly pulmonary valve atresia, common arterial truncus,atrioventricular septal defects, aortic valve atresia/stenosis, transposition of great vessels, tetralogy of Fallot, total anomalous pulmonary venous return, coarctationof aorta, and without additional CHD subgroups classified as SI. SIII: VSD, atrial septal defect, and pulmonary valve stenosis without additional CHD subgroups classifiedas SI or SII.

†Perinatal deaths�fetal deaths from 20 weeks gestation�first week deaths.‡Prenatal diagnosis of CHD and/or an associated congenital anomaly. Data excludes Norway, and UK: East Midlands and South Yorkshire, Northern England, and

Thames Valley.




EUROCAT regions,32 lends support to the potential forvariation between populations in severe CHD (and by impli-cation less severe CHD) prevalence related to underlying riskfactors.

Our severity ranking was based on the proportion ofaffected births that were perinatal deaths.28 The divisionbetween SI and SII on this basis corresponds to whether thereare 1 or 2 functioning ventricles. The division between SI/SII

and SIII corresponds well with the likelihood that surgery isneeded: data from 2 EUROCAT regions show that 80% ofisolated SI/SII cases require surgery (and a further 7% are toosevere for surgery), compared to 7% of SIII cases requiringsurgery.30 The ranking is also pragmatic in that it is based onICD codes and preexisting EUROCAT subgroup classifica-tions, without the need for further expert review to assesscombinations of codes or pediatric cardiology records as

All regs

UK E Mid & S YorkUK Northern England

UK Thames Valley †UK Wales

UK Wessex †Ukraine †

All regs

Netherlands NNorway

Poland Wielkopolska Spain Barcelona †

Spain Basque Country Switzerland Vaud

UK E Mid & S York

Ireland DublinIreland SE

Italy Emilia Romagna †Italy Sicily

Italy Tuscany Malta

Netherlands NSI/II

SIII <1 wk

SIII>1 week

France Ile de ReunionFrance Paris †

France Strasbourg Germany Mainz †

Germany Saxony Anhalt Ireland Cork & Kerry

Ireland Dublin SIII NK

Austria Styria Belgium Antwerp Belgium Hainaut Croa�a Zagreb †

Denmark Odense France Ile de Reunion

0.00 2.00 4.00 6.00 8.00 10.00 12.00 14.00

Prevalence per 1,000 births

Figure 1. Total prevalence of nonchromosomal SI/SII/SIII congenital heart defects by severity grouping,* age at detection** of SIIIcases, and registry,† 2000 to 2005. *Severity is ranked from greatest severity (SI) to least severity (SIII) on the basis of perinatal mortal-ity (see footnote to Table 2). Unclassified by severity are not included. **Age at which a congenital anomaly is first suspected, shownonly for SIII cases: �1 week�prenatally or up to 1 week of age; �1 week is 1 week to registration age limit; and NK, age at detectionnot recorded in EUROCAT central database. †Registries with incomplete ascertainment after 1 week (see footnote to Table 1).

Table 2. Continued

SII* SIII*

No.Prevalence per 1000

Births (95% CI)Total

Cases, %Isolated WithinCategory, % No.

Prevalence per 1000Births (95% CI)

TotalCases, %

Isolated WithinCategory, %

5189 1.56 (1.52–1.60) 100.0 78.6 13 960 4.18 (4.13–4.23) 100.0 85.5

4671 1.40 (1.36–1.44) 90.0 82.1 13 714 4.11 (4.06–4.20) 98.2 86.5

93 0.03 (0.02–0.03) 1.8 51.6 73 0.02 (0.02–0.03) 0.5 46.6

425 0.13 (0.12–0.14) 8.2 45.4 173 0.05 (0.04–0.06) 1.2 20.9

197 0.06 (0.05–0.07) 3.8 63.5 88 0.03 (0.02–0.03) 0.6 35.2

290 0.09 (0.08–0.10) 5.6 59.7 161 0.05 (0.04–0.06) 1.2 40.4

1115 0.47 (0.44–0.50) 32.1 64.2 775 0.32 (0.30–0.35) 8.6 38.2




would be needed for other classification schemes.13,33,34

However, our SIII category combined VSD, atrial septaldefect, and pulmonary valve stenosis of all sizes because inmost cases we had no further specification. Therefore, wehave tended to underestimate the prevalence of the moresevere cardiac conditions with high mortality by including,for example, large VSD without associated SI/SII defects inSIII. These are most likely represented among the smallproportion of SIII cases that have surgery.30 Efforts byInternational Nomenclature Committee for Pediatric andCongenital Heart Disease,34 EUROCAT, and others to im-prove the World Health Organization ICD11 coding systemfor CHD are important for improving quality and compara-bility of classifications and interpretability of CHD data infuture.

Twelve percent of CHD cases in the EUROCAT serieswere chromosomal, the majority Down syndrome. Variationin total prevalence of chromosomal CHD cases can beexplained by large differences in the maternal age profile ofEuropean populations. However, ascertainment of CHDamong TOPFA for chromosomal anomaly is likely to beincomplete, especially for early terminations. CHD may alsogo undetected in perinatal deaths with chromosomal syn-dromes without full autopsy. We therefore concentrated ouranalysis of chromosomal cases on LBs. Approximately half

of live-born children with Down syndrome are usuallyconsidered to have a cardiac defect, 45% in our data set. Wefound 4-fold country variation in LB prevalence of Downsyndrome with CHD, which can be explained by differencesin maternal age profile of births together with differences inprenatal detection and TOPFA rates for Down syndrome.2,8,35

This needs to be taken into account in planning pediatriccardiology services.

Microdeletions (such as 22q11.2) were included amongnonchromosomal cases in our study because testing formicrodeletions was variable across regions and registry cod-ing of microdeletions was not yet standardized. The preva-lence of CHD with 22q11.2 for 16 of the registers for thesame time period was 0.74 per 10 000, of which one thirdwere tetralogy of Fallot (Dr Diana Wellesley, BM, personalcommunication). If extrapolated, this suggests that during thisperiod �1% of CHD cases had a diagnosed 22q11.2 microde-letion, or 8% of tetralogy of Fallot. Microdeletion 22q11.2has been estimated to be associated with up to 20% of somesevere cardiac defects such as truncus arteriosus and tetralogyof Fallot in fully tested case series.36

Most regions/countries reported prenatal detection ratesconsiderably less than those reported by tertiary centers,37

demonstrating the value of population-based appraisal. Onlyfor SI cases were the majority (64%) prenatally diagnosed.

1.60

1 00

1.20

1.40

0 bi

rths

0.60

0.80

1.00

vale

nce

per

1,00

TOPFA

0 00

0.20

0.40Prev Perinatal mortality

0.00

CountryCountry

Figure 2. Perinatal mortality and termina-tions of pregnancy for fetal anomaly(TOPFA) associated with nonchromo-somal congenital heart defects per 1000births, by country, 2000 to 2005. Preva-lence rates on which this Figure is basedare shown in Table I in the online-onlyData Supplement.

All regs

P l d

Spain

Switzerland

Ukraine

UK*

Ireland

Italy

Malta

Netherlands

Poland

SI/II PD - TOPFA

Croa�a

Denmark

France

Germany

IrelandSI/II PD - birth

0 10 20 30 40 50 60 70 80

Austria

Belgium

%%

Figure 3. Proportion of nonchromosomalSI/SII congenital heart defect cases pre-natally diagnosed (PD)* by pregnancyoutcome (terminations of pregnancy forfetal anomaly [TOPFA] or birth), by coun-try, 2000 to 2005. SI and SII include allnonchromosomal CHD except ventricularseptal defects, atrial septal defects, pul-monary valve stenoses, and unclassifiedseverity defects. *UK includes Wales andWessex data only.




For SI cases, the majority (55%) of prenatal diagnoses led toTOPFA, and thus TOPFA had a significant impact onbirth/LB prevalence. As CHD treatment success and qualityof life of CHD survivors improves, the number of CHDTOPFA may decrease. Currently, CHD TOPFA prevalence incountries, as represented by their EUROCAT coverage, fallsinto 3 groups: the maximum of 1.1 per 1000 births in France,a group of countries at 0.3 to 0.5 per 1000 (Italy, Spain, UK,Germany, and Switzerland), and all other countries at �0.3per 1000.

Perinatal mortality, mainly first week mortality, associatedwith CHD is significant in relation to overall perinatalmortality, despite a fall in infant mortality due to CHD duringthe 1990s.23,26,38,39 In the EU in 2004, about one quarter ofearly neonatal deaths were due to congenital anomalies, andof these, in EUROCAT regions, 25% were CHD and a further18% chromosomal with or without CHD.1 The high nonchro-mosomal CHD perinatal mortality rate of 0.93 per 1000 birthsin the Ukraine is probably related to low treatment success.This suggests that it may not be possible to extrapolateEUROCAT data on mortality to all other Eastern Europeancountries. Other countries at the higher end of the range ofperinatal mortality (0.37 to 0.38 per 1000) are Ireland, Malta,and the Netherlands where there are no or very few TOPFA;TOPFA are illegal in Malta and Ireland, and the Netherlandsdid not carry out routine anomaly ultrasound scanning duringthis period. The deficit in perinatal mortality below 0.4 per1000 in other countries (Figure 2) needs to be assessed foreach country in terms of whether it is due to TOPFA, lowertotal prevalence of severe CHD, better treatment outcomes(possibly related to higher prenatal diagnosis rates amongLBs), low autopsy rates, and/or poor cause of death recording(the last known to be a factor in Italy, which records thelowest perinatal mortality1).

The present study has a number of limitations. Althoughwe analyzed nearly all the population-based informationon CHD available in the countries covered, this informa-tion is not completely representative of the Europeanpopulation. In countries only partially covered by EURO-CAT registries, the results from 1 region may not reflect

the situation for the entire country, and some differencesbetween countries may be over- or underestimated as aresult. In terms of Europe as a whole, the countriesincluded are mainly EU countries, and the average resultscannot necessarily be extrapolated beyond these countries.Secondly, caution should be exercised in interpreting theprevalence of diagnosed cases as the underlying preva-lence, given the range of ascertainment problems dis-cussed. A third limitation relates to information recordedon the age at diagnosis: The data set includes whether acongenital anomaly was prenatally diagnosed or postnatalage at first detection, but if the neonate is multiplymalformed it does not specify which anomaly was firstdiagnosed. Some of these limitations relate to compro-mises that were necessary to obtain a large European dataset bringing together many regions. On the other hand, thestrengths are the population-based data from many coun-tries, all collecting a common data set and including allpregnancy outcomes.

In the 27 countries of the present EU we have �5million births per year. Assuming the data we present hereare reasonably representative for the EU, by simple ex-trapolation we can estimate that there are 36 000 LBsdiagnosed with CHD each year, 1250 perinatal deaths withnonchromosomal CHD, and nearly 2000 nonchromosomalTOPFA with CHD. Investing in primary prevention isessential to reduce this burden. Such measures need to beboth at an individual level (advice to women before theybecome pregnant) and at the population level (regulationof exposures in the domestic, occupational, and commu-nity environment) to protect women who do not yet knowthey are pregnant and to address exposures beyond thecontrol of individuals. Investing in pathogenetic researchcan further increase the potential of primary prevention.The data presented here also allow the impact of prenataldiagnosis and termination of pregnancy on CHD preva-lence and perinatal mortality to be further monitored andinform the continuing substantial investment needed incardiac services from in utero to adulthood.

13.00

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12.00

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6.00

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eval

ence

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Non-chromosomal SIII LB CHD

Non-chromosomal SI/II LB CHD

1.00

2.00

3.00

4.00Pre

Down syndrome LB and CHD

0.00

Country

Figure 4. LB prevalence of nonchromo-somal congenital heart defect (SI/SII andSIII)* and Down syndrome with congeni-tal heart defects per 1000 births (95%CI) per country, 2000 to 2005. *Severityis ranked from greatest severity (SI) toleast severity (SIII) on the basis of peri-natal mortality (see footnote to Table 2).Unclassifed severity excluded.




AppendixMembers of the EUROCAT Working GroupMarie-Claude Addor (Division of Medical Genetics, University of

Lausanne, Switzerland)Marian Bakker (Department of Genetics, University Medical Centre

Groningen, Northern Netherlands)Ingeborg Barisic (Department of Paediatrics, Children’s University

Hospital Zagreb Croatia),Sebastiano Bianca (ISMAC, Catania, Sicily, Italy),Patricia Boyd (National Perinatal Epidemiology Unit, University of

Oxford, UK)Elisa Calzolari (University of Ferrara, Emilia Romagna, Italy),Berenice Doray (Hopitale de Hautepierre, Strasbourg, France)Miriam Gatt (Malta Department of Health Information and Research,

Malta)Martin Haeusler (University of Graz, Styria, Austria)Babak Khoshnood (INSERM U953, St Vincent de Paul Hospital,

Paris, France)Kari Klungsoyr Melve (Norwegian Institute of Public Health, Ber-

gen, Norway)Anna Latos-Bielenska (Poznan University of Medical Sciences,

Poland)Bob McDonnell (Health Service Executive, Dr Steeven’s Hospital,

Dublin, Ireland)Carmel Mullaney (Department of Public Health, Health Service

Executive - South East, Kilkenny, Ireland)Vera Nelen (Provinciaal Instituut voor Hygiene, Antwerp, Belgium)Mary O’Mahony (Department of Public Health, Health Service

Executive - South, Cork, Ireland)Anna Pierini (CNR Institute of Clinical Physiology, Tuscany, Italy)Simone Poetzsch (Medical Faculty, Otto-van-Guericke Univer-

sity, Magdeburg, Germany)Annette Queisser-Luft (University Children’s Hospital, Mainz,

Germany)Hanitra Randrianaivo (Naıtre Aujourd’hui, Ile de la Reunion,

France)Judith Rankin (Institute of Health and Society, University of New-

castle, UK)Joaquin Salvador (Public Health Agency of Barcelona, Spain)David Tucker (Swansea NHS Trust, Congenital Anomaly Register

and Information Service for Wales, UK)Christine Verellen-Dumoulin (Institut de Morphologie Pathologique,

Hainaut-Namur, Belgium)Diana Wellesley (Wessex Clinical Genetics Service, Princess Anne

Hospital, UK)Wladimir Wertelecki (OMNI-Net, Ukraine)

AcknowledgmentsWe thank the many clinicians across Europe who have participatedin congenital anomaly registry activities. EUROCAT is a WorldHealth Organization Collaborating Centre for the EpidemiologicalSurveillance of Congenital Anomalies.

Sources of FundingEUROCAT is co-funded by the EC, under the framework of the EUPublic Health Programme, Grant Agreement 2006103 (ExecutiveAgency for Health and Consumers). Registries in each country arefunded by regional or national health authorities, research funders, orhospitals. These sources of funding for each registry are given athttp://www.eurocat-network.eu/ABOUTUS/MemberRegistries/MembersAndRegistryDescriptions/AllMembers.

DisclosuresNone.

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CLINICAL PERSPECTIVEInformation on prevalence and fetal and perinatal mortality associated with Congenital Heart Defects (CHD) in Europe isneeded as a baseline from which to monitor future progress in primary prevention, to monitor the impact of terminationof pregnancy for fetal anomaly (TOPFA) on prevalence, to plan for high-quality services, and to allow individual regionsto compare their rates with the European average and range. We analyzed data from 29 population-based congenitalanomaly registries in 16 European countries covering 3.3 million births from 2000 to 2005. The total prevalence of CHDwas 8.0 per 1000 births, and live birth prevalence was 7.2 per 1000 births, varying between countries. The total prevalenceof nonchromosomal CHD was 7.0 per 1000 births, of which 3.6% were perinatal deaths and 5.6% TOPFA. Severenonchromosomal CHD (ie, excluding ventricular septal defects, atrial septal defects, and pulmonary valve stenosis)occurred in 2.0 per 1000 births, of which 8.1% were perinatal deaths, 40% were prenatally diagnosed, and 14% wereTOPFA. The TOPFA proportion for severe CHD varied from 0 to 32% between countries. The live-birth prevalence ofDown syndrome with CHD (average 0.5 per 1000) varied �4-fold between countries because of differences in maternalage profile of births and differences in TOPFA rates for Down syndrome. There are an estimated 36 000 children live bornwith CHD in the European Union each year and 3000 TOPFA, stillbirth, or early neonatal deaths with CHD. Investing inprimary prevention and in cardiac services from in utero to adulthood is essential.




Supplemental Material

Supplemental Table 1(basis for Figure 2): Perinatal mortality and TOPFA associated with non-chromosomal CHD by country, 2000-2005

Non-chromosomal CHD

Perinatal Mortality * TOPFA†

No Prevalence per 1,000 births (95% CI)

No Prevalence per 1,000 births (95% CI)

Austria 21 0.34 (0.21-0.51) 8 0.13 (0.06-0.25)Belgium 49 0.27 (0.20-0.36) 48 0.26 (0.19-0.35)Croatia 7 0.21 (0.08-0.43) 0 0.00Denmark 10 0.31 (0.15-0.58) 8 0.25 (0.11-0.49)France 96 0.28 (0.23-0.34) 366 1.06 (0.96-1.18)Germany 34 0.27 (0.19-0.38) 62 0.50 (0.38-0.64)Ireland 82 0.38 (0.30-0.47) 0 0.00Italy 31 0.07 (0.05-0.10) 151 0.35 (0.30-0.41)Malta 9 0.38 (0.17-0.72) 0 0.00Netherlands 44 0.37 (0.27-0.50) 9 0.08 (0.04-0.14)Norway 69 0.20 (0.16-0.25) 97 0.28 (0.23-0.34)Poland 69 0.33 (0.26-0.42) 0 0.00Spain 42 0.22 (0.16-0.29) 85 0.44 (0.35-0.54)Switzerland 10 0.23 (0.11-0.43) 22 0.51 (0.32-0.78)Ukraine 24 0.93 (0.60-1.38) 2 0.08 (0.01-0.28)UK 248 0.26 (0.23-0.30) 450 0.47 (0.43-0.52)

Total 845 0.25 (0.24-0.27) 1308 0.39 (0.37-0.41)

* Perinatal mortality=fetal deaths from 20 weeks gestation and 1st week deaths†TOPFA = termination of pregnancy for fetal anomaly following prenatal diagnosis



Supplemental Figure 1: Proportion of cases resulting in mortality by severity, type of non-chromosomal CHD and type of mortality, 2000-2005



Health & Medicine

Prevalência e MI por CC na Europa de 2000 a 2005