Elsevier

The Lancet

Volume 351, Issue 9099, 31 January 1998, Pages 311-316
The Lancet

Articles
Recurrence risks in offspring of adults with major heart defects: results from first cohort of British collaborative study

https://doi.org/10.1016/S0140-6736(97)06486-6Get rights and content

Summary

Background

Congenital heart defects are generally assumed to have a multifactorial aetiology. We have tested this hypothesis by studying adults with heart defects and their families.

Methods

We identified 1094 patients who survived surgery for major cardiac defects before 1970. We chose individuals with disturbance of situs or segmental connection, with atrioventricular septal defect or with tetralogy of Fallot. After exclusion and non-participation, 727 individuals were traced. Each was visited by an investigator and completed a detailed questionnaire. If possible, all “normal” offspring were examined by a paediatric cardiologist.

Findings

The 727 individuals had 393 live offspring. There were 71 miscarriages and five terminated pregnancies. Overall, we found recurrent heart defects in 16 liveborn offspring—a recurrence risk of 4·1%. This result differed significantly from sibling risk (2,1%; p=0·021). More congenital heart defects occurred in the offspring of affected women than in those of affected men (p=0·047); when all malformations (cardiac and non-cardiac) in the offspring were taken into account the excess was more significant (p=0·032). We found an excess of miscarriages in the offspring of affected women (p=0·001). In tetralogy of Fallot, heart defects occured in seven (3·1%) of 223 offspring, 12 (2·2%) of 539 siblings, five (0·3%) of 1575 second-degree relatives, and eight (0·3%) of 2728 third-degree relatives.

Interpretation

Our findings do not support a polygenic basis for all heart defects. Atrioventricular septal defect seems to be a single-gene defect and tetralogy of Fallot a polygenic disorder with a small number of interacting genes. Our data suggest that isolated transposition of the great arteries is a sporadic defect.

Introduction

An increasing number of patients with major congenital cardiac defects survive to adulthood and parenthood. Data on the frequency of recurrent congenital malformation—both cardiac and non-cardiac—in the offspring of such individuals can therefore provide valuable clues about the aetiology of congenital heart diseases, as well as empirical data for counselling purposes. Many investigators have produced recurrence data in an attempt to clarify this aetiology.1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 There are several sources of bias in the published research, relating in particular to methods and recruitment, which undermine the validity of the data. In many instances the data are conflicting and of limited application.

In this study, we attempted to provide unbiased recurrence data on major cardiac malformations by drawing together the resources of the UK paediatric cardiology services. The study is prospective in that the cohort was identified from paediatric surgical records and traced through the National Health Service; personal contact ensured maximum recruitment, and clinical examination of offspring made possible the accurate assessment of clinical status.

Section snippets

Patients and methods

The study began in 1985. Inclusion and exclusion criteria are shown in the panel. A major defect was defined as an abnormality of situs (eg, right isomerism sequence), atrioventricular connection (eg, tricuspid atresia), ventriculoarterial connection (eg, transposition of the great arteries), anomalous pulmonary venous drainage, atrioventricular septal defect, or tetralogy of Fallot. Patients who met the entry criteria, and who underwent palliative or corrective paediatric cardiac surgery in

Cohort characteristics

1094 individuals with surgically modified major structural heart defects were identified from paediatric records in participating centres. This cohort was reduced to 943 patients by exclusion of 108 who died in childhood, 31 who had emigrated, and 12 who were mentally retarded. 62 (6·6%) of the 943 cases could not be traced by available methods. Of the 881 traceable probands, 29 (3·3%) declined to participate; in 125 (14·2%) cases, either the family practitioner or the proband did not respond

Discussion

Nora16 introduced the “multifactorial” model for the aetiology of isolated congenital heart defects (excluding malformations associated with chromosomal defects, syndromes, and known teratogenic exposure as well as Mendelian traits) in which several genetic loci interact together, with or without environmental factors. Persistent patency of the arterial duct in human beings supports this model: well-recognised environmental insults are known to cause persistent patency of the arterial duct

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