Syndromes and malformations associated with congenital heart disease in a population-based study

International Journal of Cardiology 68 (1999) 151–156

Syndromes and malformations associated with congenital heart disease in a population-based study a, b Victor Grech *, Miriam Gatt a

Paediatric Department, St. Luke’ s Hospital, Guardamangia, Malta b Department of Health Information, Guardamangia, Malta Received 28 October 1998; accepted 17 November 1998

Abstract Congenital cardiac malformations are frequently associated with non-cardiac malformations and chromosomal anomalies. Management is therefore influenced by interventional needs for all of the various anomalies. We have studied the association of congenital heart disease with extracardiac anomalies in the relatively closed population of Malta, where echocardiographic screening of all syndromic / multiply malformed infants is routinely carried out. Malformations were classified by using the EUROCAT method, for the first time. During 1990–1994, the birth prevalence of congenital heart disease was 8.8 / 1000 live births (n5231). Of these, 21 (9%) had recognised chromosomal anomalies (0.80 / 1000 live births; 95% CI: 0.51–1.25), four (2%) had recognised non-chromosomal syndromes and 14 (6%) had other, major, non-cardiac malformations (0.69 / 1000 live births; 95% CI: 0.42–1.11). The commonest non-cardiac anomalies were musculoskeletal anomalies. Down syndrome accounted for 95% of all syndromic congenital heart disease, with a birth prevalence of 0.73 / 1000 live births (95% CI: 0.45–1.16). Comparison of these results with earlier studies showed wide disparities between studies, and this was attributed to differences in methods. such as differing inclusion criteria for both congenital heart disease and syndromes and malformations. The commonest lesion found in association with Down syndrome was isolated ventricular septal defect, not atrioventricular septal defect, and this was attributed to our screening process which identifies small lesions which would otherwise have been clinically missed and / or closed spontaneously.  1999 Elsevier Science Ireland Ltd. All rights reserved. Keywords: Heart defects, congenital; Chromosomes, abnormalities; Syndrome; Abnormalities, multiple

1. Introduction Congenital cardiac malformations are frequently associated with other non-cardiac congenital malformations and chromosomal anomalies [1]. Conversely, syndromic infants constitute a substantial proportion of all babies with congenital heart disease [2]. Such patients may require intervention of a surgical or medical nature independently from the cardiac problem. Management of the heart lesion may *Corresponding author. Tel.: 1356-241251, ext. 1471; e-mail: [email protected]

therefore be influenced by the medical and / or surgical treatment needed for all of the various anomalies. For this reason, it is important to know how frequently one may expect to encounter congenital heart disease occurring in association with other anomalies. Malta is an ideal location for such epidemiological studies as the official religion is Roman-Catholic, termination of pregnancy is illegal, and there is no antenatal fetal anomaly screening programme. Furthermore, all new-borns in Malta suspected of having a chromosomal anomaly, or noted to have major or multiple abnormalities, are routinely referred for echocardiographic assessment in order to diagnose

0167-5273 / 99 / $ – see front matter  1999 Elsevier Science Ireland Ltd. All rights reserved. PII: S0167-5273( 98 )00354-4

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congenital heart disease as early as possible and form a treatment plan that deals with all of the patients’ problems. The aim of this study is to describe the prevalence of congenital heart disease in live births and the association with other, non-cardiac congenital anomalies in Malta, where active echocardiographic screening of such infants is routinely undertaken. This study also compares these results with other studies carried out elsewhere, and puts forward an explanation for the wide variations found between studies.

catheters and operations, lists of patients sent abroad for urgent cardiac catheterisation or intervention not available in Malta, clinic registers of patients seen at visiting consultant paediatric cardiologist clinics (held three to four times a year) and post-mortem reports [7]. Clinical diagnoses of congenital heart disease were not accepted. A Medline search yielded studies dealing with the association of congenital heart disease with syndromes and malformations.

2.2. Statistics 2. Materials and methods

2.1. Definitions, classification and patients For the purposes of this study, a syndrome was defined as ‘‘a recognised pattern of congenital abnormalities whose unique combination of features sets it apart from other patterns’’ [3]. Syndromes were subdivided into recognised chromosomal anomalies and recognised non-chromosomal syndromes or sequences. A malformation was defined as ‘‘a permanent change produced by an intrinsic abnormality of development in a body structure during prenatal life’’ [3]. Malformations were subdivided into major and minor malformations following guidelines set out by EUROCAT (European Registers of Congenital Anomalies and Twins) [4]. Congenital heart disease was defined as ‘‘a structural abnormality of the heart or intrathoracic great vessels that is actually or potentially of functional significance’’ [1]. Only infants born to Maltese residents were included in the study. A resident was considered to be anyone who had lived on the islands of Malta and Gozo for more than 6 months [5]. This study examines a previously defined cohort of patients with congenital heart disease [6] born between 1990 and 1994, who were diagnosed as having congenital heart disease by 1 year of age. Live-born patients with anomalies and / or syndromes were obtained from the Maltese Paediatric Cardiology Database. Database sources included: children being followed up for congenital heart disease at the only regional hospital in Malta, copies of all paediatric echocardiogram reports, lists of locally performed elective cardiac

Ninety-five percent confidence intervals for rates were calculated using the binomial distribution [8]. Official Maltese publications were used to obtain total live births from 1990 to 1994 [5].

3. Results During the period 1990–1994, 26 117 live births were born to Maltese residents. Of these, 231 infants were diagnosed as having congenital heart disease, giving a birth prevalence of 8.8 / 1000 live births [6]. Of these 231 infants, 21 (9%) had recognised chromosomal anomalies, four (2%) had recognised nonchromosomal syndromes and 14 (6%) had other, major, non-cardiac malformations (Table 1). Of those infants with associated non-cardiac anomalies, six (43%) had associated musculoskeletal anomalies. Minor anomalies were found in 2% (n55); three had undescended testicles: one had glandular hypospadias and one had postural unilateral talipes equinovarus. These individuals were classified as having isolated congenital heart disease and were excluded from further analysis. Cardiac lesions found associated with chromosomal anomalies and recognised syndromes or sequences are shown in Table 2 [9]. The prevalence at live birth of isolated congenital heart disease was 7.35 / 1000 live births (95% CI: 6.37–8.48 / 1000 live births). That of chromosomal syndromes associated with congenital heart disease for this period was 0.80 / 1000 live births (95% CI: 0.51–1.25 / 1000 live births). Down syndrome accounted for 95% of all

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153

Table 1 Congenital heart disease with associated malformations and syndromes in Malta 1990–1994 Type of anomaly

Number

%

Isolated congenital heart disease Associated with chromosomal anomalies Down Edward Killian–Pallister Associated with recognised non-chromosomal syndromes / sequences Noonan Holt–Oram VACTER* Other major non-cardiac malformations Cleft lip and palate Partial midline cleft palate and clinodactyly Spina bifida and hydrocephalus Unilateral microphthalmia, bilateral chorioretinal colobomas, tracheobronchomalacia and dysplastic ears Unilateral pulmonary sequestration Biliary atresia Tracheo-eosophageal fistula, bilateral hypoplastic auditory meatus and vertebral anomalies Moderate bilateral hydronephrosis Triphalangeal thumbs Syndactyly of toes and brachydactyly with hypoplastic nails of fingers Unilateral short and bowed femur Isolated syndactyly of toes Total

192 21 19 1 1 4 2 1 1 14 2 1 1 1 1 1 1 1 1 1 1 1 231

83 9

2

6

VACTER: vertebral, anal, cardiac, tracheal, esophageal, radial and renal anomalies (sequence).

syndromic congenital heart disease, with a birth prevalence of 0.73 / 1000 live births (95% CI: 0.45– 1.16 / 1000 live births). Major malformations occurring in association with congenital heart disease but not associated with chromosomal anomalies were present in 0.69 / 1000 live births (95% CI: 0.42–1.11 / 1000 live births).

Table 2 Cardiac lesions found associated with chromosomal anomalies and recognised syndromes / sequences Syndrome / sequence

Cardiac anomaly

n

Down

Ventricular septal defect Complete atrioventricular septal defect Partial atrioventricular septal defect Tetralogy of Fallot Atrial septal defect Double outlet right ventricle Pulmonary stenosis Tetralogy of Fallot Ventricular septal defect Ventricular septal defect

11 a 5 1 1 1 1 2 1 1 1

Edward Noonan Killian–Pallister Holt–Oram VACTER sequence a

Five of 11 defects were too small to require intervention, and two of these five defects closed spontaneously.

4. Discussion In this study we describe the occurrence of congenital heart disease associated with other anomalies in live births in Malta during the period 1990–1994. Since termination of pregnancy is illegal in Malta, the prevalence at birth is a true reflection of the natural live birth prevalence of infants with congenital heart disease, with and without associated anomalies. The true incidence of congenital heart disease, with or without associated anomalies, can only be determined if all live births, fetal deaths and spontaneous and induced abortions are examined. However, in this study, fetal deaths and spontaneous abortions were not studied. Furthermore, this is the first study which reports the association of extracardiac anomalies with congenital heart disease in a region where all infants with suspected syndromes and major or multiple extracardiac anomalies are screened for cardiac defects, to the best of our knowledge. Our results are compared with those reported in other studies in Table 3 [1,2,10–16]. Comparison

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Table 3 Comparison of rates of syndromes and malformations found in association with congenital heart disease between various studies Study

Methods

CHD: totals and prevalence when given

Breakdown

n

%

Mitchell et al. (1971) [1]

Collaborative study between 12 centres in the United States ? Period studied: 1958–1965 ? Includes patients diagnosed beyond infancy Infants included in the Liverpool Congenital Anomalies Register ? Period studied: 1960–1969 ? Includes both live births and fetal deaths ? Includes patients diagnosed beyond infancy Infants included in the New England Regional Infant Cardiac Program ? Period studied: 1968–1972 ? Includes live births only ? Includes patients diagnosed in infancy only

457

Isolated CHD

319

70

7.7/1000 Live births 1081

Extracardiac anomalies

138

30

Isolated CHD

856

80

6.6/1000 total births

Extracardiac anomalies

225

20

1566

Isolated CHD

1171

74

Child Health and Development Studies—Kaiser Foundation Health Plan ? Period studied: 1959–1966 ? Includes both live births and fetal deaths ? Includes patients diagnosed beyond infancy Infants included in the Baltimore Washington Infant Study ? Period studied: 1981–1986 ? Includes live births only ? Includes patients diagnosed in infancy only

163

Extracardiac anomalies: ? recognised chromosomal anomalies ? non-recognised chromosomal syndromes ? other extracardiac abnormalities Isolated CHD

395 89 43 263 85

25 6 3 17 52.1

Extracardiac anomalies ? Down syndrome ? other extracardiac abnormalities Isolated CHD

78 9 69 1539

47.9 5.5 42.3 73.2

Collaborative study between 11 maternity hospitals in Strasbourg ? Period studied: 1979–1986 ? Includes live births and stillbirths ? Includes patients diagnosed in infancy only

801

Extracardiac anomalies: ? recognised chromosomal anomalies ? recognised non-chromosomal syndromes ? suspect syndrome ? other extracardiac abnormalities Isolated CHD

563 271 98 20 174 595

26.8 12.9 4.6 1.0 8.3 74.3

Infants born alive to mothers resident in New South Wales or Australian Capital Territory ? Period studied: 1981–1984 ? Includes live births only ? Includes patients diagnosed in infancy only

1479

Extracardiac anomalies: ? recognised chromosomal anomalies ? recognised non-chromosomal syndromes ? other extracardiac abnormalities Isolated CHD

206 72 20 114 1116

25.7 8.9 2.5 14.2 75.4

Infants included in the MACDP ? Period studied: 1990–1994 ? Includes live births, fetal deaths and abortions .20 weeks ? Includes patients diagnosed in infancy only Swedish cardiology register and registry of congenital malformations ? Period studied: 1981–1990 ? Includes live births, fetal deaths and abortions .20 weeks ? Includes patients diagnosed in infancy only ? Only includes patients with major CHD (major CHD not defined in study) Maltese Paediatric Cardiology Database: Maltese residents ? Period studied: 1990–1994 ? Includes live births only ? Includes patients diagnosed in infancy only

1589 8.1/1000 live births

Extracardiac anomalies: ? recognised chromosomal anomalies ? recognised non-chromosomal syndromes ? other extracardiac abnormalities Isolated CHD Extracardiac anomalies: ? recognised chromosomal anomalies

363 141 33 189 823 766 206

25 9.5 2.2 12.8 51.8 48.2 13

2618

? other extracardiac abnormalities Isolated CHD

560 1898

35.2 72.5

2.8/1000 live births

Extracardiac anomalies: ? recognised chromosomal anomalies

720 323

27.5 44.9

? recognised non-chromosomal syndromes ? other extracardiac abnormalities

27 370

1.0 14.1

231

Isolated CHD

192

83.1

8.8/1000 live births

Extracardiac anomalies: ? recognised chromosomal anomalies ? recognised non-chromosomal syndromes ? other extracardiac abnormalities

39 21 4 14

16.9 1.1 1.7 6.1

Kenna et al. (1975) [10]

Greeenwood et al. (1975) [2]

Hoffman and Christianson (1978) [11]

Ferencz et al. (1987) [12]

Stoll et al. (1989) [13]

Kidd et al. (1993) [14]

Montana et al. (1996) [15]

Pradat (1997) [16]

This study

CHD, congenital heart disease; infancy, ,1 year of age.

8.8/1000 live births 2102 4/1000 live births

7.6/1000 total births

4.3/1000 live births

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between studies is difficult due to differences in methods. Some of the older studies failed to break down extracardiac anomalies at all, and syndromes, sequences and malformations were grouped together. Figures for recognised chromosomal anomalies ranged from 6 to 44% of patients with congenital heart disease in those studies which provided a breakdown of extracardiac anomalies. The high figure of 44% was from a study by Pradat [16] who only studied individuals with major congenital cardiac anomalies, without specifying the exact lesions included. If this study is not included, the range then becomes 6.0–12.9%. Although testing for 22q11 microdeletion is not widely available in Malta, the local figure for recognised chromosomal anomalies of 9.1% falls well within the range. Our series was too small to allow meaningful analyses of the more common types of congenital heart disease associated with specific non-cardiac anomalies (Table 2). However, several authors [2,16] have shown that the more common extracardiac anomalies associated with congenital heart disease are musculoskeletal defects, as was found in this study. In Table 3, recognised non-chromosomal syndromes comprised 1.0–4.6% of patients with congenital heart disease, and isolated extracardiac anomalies were found in 8.3–42.3% of patients with congenital heart disease. This wide range is almost certainly due to different inclusion criteria for malformations. Some studies only included major malformations, and arbitrarily defined these in different ways, with studies variously including lesions that were potentially life-threatening, or required intervention, or produced significant morbidity. Other studies included minor anomalies, thereby inflating the percentage of patients reported as having extracardiac anomalies in addition to congenital heart disease. It was not possible to confirm this as studies tended not to specify the exact anomalies found. In our study, we are the first to use the internationally accepted EUROCAT classification [4], to the best of our knowledge. The use of this classification will allow comparison with other studies which also use this method. Yet another factor that may influence the proportion of patients with anomalies are the inclusion criteria for patients with congenital heart disease itself. Older studies included patients diagnosed

155

beyond infancy, and were hampered by lack of echocardiography, a non-invasive diagnostic technique which is ideally suited for screening purposes. Furthermore, a substantial proportion of minor cardiac lesions, such as atrial and ventricular septal defects, tend to resolve spontaneously [17,18]. In Malta, a higher prevalence at birth of congenital heart disease has been reported [6] when compared with recent studies with similar methods [19,20]. This was attributed to easy access to echocardiography in the neonatal period, which results in a high ascertainment of all lesions, and particularly of minor lesions. The classical teaching is that the commonest cardiac anomaly associated with Down syndrome is atrioventricular septal defect [21–23]. However, in this study, the commonest cardiac anomaly found in association with Down syndrome was ventricular septal defect (Table 2). It has been shown that 5% of all live births have small ventricular septal defects [24]. Our results are attributed to active echocardiographic screening of all syndromic babies in Malta, which leads to the detection of small defects which may otherwise have been missed clinically, or defects which would otherwise have undergone spontaneous resolution. Other factors which may truly influence the prevalence at birth of syndromic children with congenital heart disease are changes in demography and screening practices. In Malta, as in Europe, there is an ongoing trend towards increasing maternal age at conception [5], and older mothers are known to have a higher risk for conceptions with chromosomal anomalies, including trisomies [25]. Antenatal screening [26] and termination of pregnancy may limit the number of children born with chromosomal anomalies, but no such limiting factor is possible in Malta where termination of pregnancy is illegal and antenatal screening is not available. A rise in Down syndrome deliveries will result in a significant increase in resources required for the management of cardiac defects as the modern trend is to treat these children in the same way as non-syndromic individuals [27]. Resources would also have to be allocated for the management of other anomalies as well as other problems related to the ongoing care of these children. In conclusion, about one-fifth of individuals with congenital heart disease will have extracardiac

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anomalies which consist of syndromes, sequences or major extracardiac malformations, providing that individuals with extracardiac anomalies are screened for cardiac malformations.

Acknowledgements We thank Dr Grech’s Ph.D. supervisors, Dr Chris Wren (Freeman Hospital Newcastle) and Mr Martin Elliott (Great Ormond Street Hospital, London); the Paediatric Department; the Department of Health Information; the Cardiac Laboratory and the Almoner’s Office and Medical Records, St. Luke’s Hospital, Malta; the Registry of the Health Division, Valletta, Malta; and the Cardiothoracic Unit, Great Ormond Street Hospital for Children, London, UK. Sponsorship: Health Division, Malta Paediatric Department, St. Luke’s Hospital, Malta and Centre for Clinical Coding & Classification Loughborough, Leicester, UK.

References [1] Mitchell SC, Korones SB, Berendes HW. Congenital heart disease in 56109 births. Incidence and natural history. Circulation 1971;43:323–32. [2] Greenwood RD, Rosenthal A, Parisi L, Fyler DC, Nadas AS. Extracardiac abnormalities in infants with congenital heart disease. Pediatrics 1975;55:485–92. [3] Jones KL. Smith’s Recognisable Patterns of Human Malformations, 4th ed. Pennsylvania, PA: WB Saunders 1988:1–9. [4] A EURO CAT Working Group. 15 years of surveillance of congenital anomalies in Europe 1980–1994. EUROCAT Report 7. Belgium: Scientific Institute of Public Health Louis Pasteur, 1997:10–149. [5] Central Office of Statistics. Demographic review for the Maltese Islands. Malta: Central Office of Statistics (Annual publications). [6] Grech V. Spectrum of congenital heart disease in Malta: an excess of lesions causing right ventricular outflow tract obstruction in a population based study. Eur Heart J 1998;19:521–5. [7] Grech V. Congenital Heart Disease in Malta (PhD thesis). London: University of London, 1998. [8] Fleiss JL. Statistical Methods for Rates and Proportions, 2nd ed. New York: John Wiley, 1981:14–15.

[9] Grech V, Parascandolo R, Cuschieri A. Tetralogy of Fallot in a patient with Killian-Pallister syndrome. Pediatr Cardiol (in press). [10] Kenna AP, Smithells RW, Fielding DW. Congenital heart disease in Liverpool: 1960–69. Q J Med 1975;173:17–44. [11] Hoffman JI, Christianson MA. Congenital heart disease in a cohort of 19,502 births with long-term follow-up. Am J Cardiol 1978;42:641–7. [12] Ferencz C, Rubin JD, McCarter RJ. Cardiac and noncardiac malformations in a population-based study. Teratology 1987;35:367–78. [13] Stoll C, Alembik Y, Roth MP, Doff B, De Geeter B. Risk factors in congenital heart disease. Eur J Epidemiol 1989;5:382–91. [14] Kidd SA, Lancaster PAL, McCredie RM. The incidence of congenital heart defects in the first year of life. J Paediatr Child Health 1993;29:344–9. [15] Montana E, Khoury MJ, Cragan JD, Sharma S, Dhar P, Fyfe D. Rates of chromosome abnormalities at different maternal ages. Obstet Gynecol 1981;58:282–5. [16] Pradat P. Noncardiac malformations at major congenital heart defects. Pediatr Cardiol 1997;18:11–8. [17] Timmis GC, Gordon S, Reed JO. Spontaneous closure of an atrial septal defect. J Am Med Assoc 1966;196:137–9. [18] Evans JR, Rowe RD, Keith JD. Spontaneous closure of ventricular septal defects. Circulation 1960;22:1044–54. [19] Samanek M, Slavik Z, Zborilova B, Hrobonova V, Voriskova M, Skovranek J. Prevalence, treatment and outcome of heart disease in live-born children: a prospective analysis of 91,823 live-born children. Pediatr Cardiol 1989;10:205–11. [20] Jackson M, Walsh KP, Peart I, Arnold R. Epidemiology of congenital heart disease in Merseyside—1978–1988. Cardiol Young 1996;6:272–80. [21] Rowe RD, Uchida IA. Cardiac malformations in mongolism. A prospective study of 184 mongoloid children. Am Med J 1961;31:726–35. [22] Warkany J, Passarge E, Smith LB. Congenital malformations in autosomal trisomy syndromes. Am J Dis Child 1966;112:502–17. [23] Park SC, Mathews RA, Zuberbuhler JR, Rowe RD, Neches WH, Lenox CC. Down syndrome with congenital heart malformation. Am J Dis Child 1977;131:29–33. [24] Hiraishi S, Agata Y, Nowatari M, Oguchi K, Misawa H, Hirota H, Nobuyuki F, Horiguchi Y, Yashiro K, Nakae S. Incidence and natural history of trabecular ventricular septal defect: two-dimensional echocardiography and colour Doppler flow imaging study. J Pediatr 1992;120:409–15. [25] Hook EB. Trends and outcomes after prenatal diagnosis of congenital cardiac malformations by fetal echocardiography in a well defined birth population, Atlanta, Georgia, 1990–1994. J Am Coll Cardiol 1996;28:1805–9. [26] Haddow JE, Palomaki GE, Knight GJ, Williams J, Pulkkinen A, Canick JA. Prenatal screening for Down’s syndrome with use of maternal serum markers. New Engl J Med 1992;327:588–93. [27] Scheider DS, Zahka KG, Clark EB, Neill CA. Patterns of cardiac care in infants with Down syndrome. Am J Dis Child 1989;143:363–5.