Congenital heart disease prevalence: what does the future hold?

This editorial refers to ‘Congenital heart disease: changes in recorded birth prevalence and cardiac interventions over the past half-century in Sweden’, by K.W. Giang et al., https://doi.org/10.1093/eurjpc/zwac227. In the current issue of the European Journal of Preventive Cardiology, Giang et al.1 present the changes in birth prevalence of congenital heart disease (CHD) in Sweden between 1970 and 2017. The authors report an increase in prevalence which may be attributed to improvements in the diagnostic accuracy of echocardiogram that became widely available after the mid-eighties. Prior to this era, mild or even moderate CHD could go undetected. In contrast, the diagnosis of a severe cyanotic congenital cardiac lesion CHD would be difficult to miss due to its potential life-threatening nature and its clinical presentation. Through the period of the study, there was a statistically significant, but small, increase in the complex CHD prevalence, in the Swedish cohort.1 The authors report a decline in cardiac interventions from 40.7% of the CHD population in 1970 to <17% during the period 2014–6 while the absolute number of cardiac interventions increased. Cardiac interventions also increased for patients with the most complex lesions. Unfortunately, the authors were unable to report on the specific types of interventions, and the differences in performance over the study period were not available in the registries. It would have been informative to discover the changing nature of interventional procedures from 1970 to 2017. In Figure 1, a timeline of CHD transcatheter and surgical interventions underlines the tremendous progress in the interventional management of CHD.2 Developments over the years in cardiac surgery and interventional cardiology. ASD, atrial septal defect; AV, aortic valve; AVSD, atrioventricular septal defect; BT, Blalock–Taussig; CPB, cardiac pulmonary bypass; HLTx, heart–lung transplantation; MRI, magnetic resonance imaging; PA, pulmonary artery; PDA, patent ductus arteriosus; PV, pulmonary valve; TAPVD, total anomalous pulmonary venous drainage; TAVI, transcatheter aortic valve implantation; TOF, tetralogy of Fallot; Tx, cardiac transplantation; VSD, ventricular septal defect. From Reference 2. As foetal echocardiogram became widely available, prenatal diagnosis of critical CHD became possible.3 This resulted in the ability to individualize care and to improve outcomes. Despite these advances, not all CHDs are diagnosed before birth. In a recent study, prevalence of CHD determined by echocardiography screening at birth was higher and more accurate that obtained from birth defect registries.4 There is no doubt that CHD diagnosis is the first step in medical and interventional management, thus improving significantly the survival of young patients. A recent meta-analysis of 260 studies that incorporated global data concluded that the reported prevalence of CHD continued to increase.5 The prevalence of mild lesions increased at the same period as in the Swedish study.1 There were significant regional discrepancies, with prevalence reported from Africa being the lowest (overall and mild lesions) and Asia the highest (mild lesions). Geographical and socioeconomic factors have been shown to influence the birth prevalence in China, underlying the importance of environment and health resources in diagnosis and adequate management of CHD.6 Congenital anomalies like CHD, cleft lip, and palate are associated with environmental risk factors (maternal exposure to air pollution, toxic chemicals, etc.), parental smoking, maternal health (infectious diseases during pregnancy, pregestational and gestational diabetes mellitus, maternal obesity, maternal drug intake), artificial reproductive technologies, as well as socioeconomic factors.7 In this light, identification of risk factors leading to congenital anomalies is fundamental for future preventative strategies. Genetics plays a central role in CHD pathogenesis, a discovery that has benefited from considerable technical advances in examining the human genome. In earlier studies, karyotyping patients with syndromic CHD uncovered aneuploidies, most commonly Trisomy 13, 18, or 21 (Down syndrome) and monosomy × (Turner syndrome). These occur in ∼12% of patients with CHD. Genes linked to CHD provide new insights into the crucial molecules and pathways involved in cardiogenesis. They complement and extend the considerable information derived from experimental models exploring heart development. Studies of spontaneous (de novo) gene variants in sporadic CHD can identify new genes involved in cardiogenesis. At the same time, detailed clinical evaluations allow the definition of a broader spectrum of cardiac and extracardiac phenotypes compared with studies based on experimental models. Given that most human variants are heterozygous, studies based on experimental models often explore homozygous variants. For this reason, human CHD data had the potential to be more informative about subtler influences on heart formation.8 Why is CHD the most common congenital anomaly? One hypothesis is that complex developmental processes of heart formation are exquisitely sensitive to changes in gene dosage among many essential genes and pathways. When gene dosage is altered, developmental errors can occur—many of which are readily detected by contemporary screening foetal echocardiogram during the second trimester of pregnancy. Genes linked to CHD are increasingly identified through analyses of CHD cohorts, carried out in single centres or by national and international collaborations. Most studies have enrolled patients with severe or critical CHD, while they under-represent patients with simple lesions and exclude patients with clinically established genetic syndromes. The discovery of genes and variants with a potential causal link to CHD combined with analyses of gene expression during development and functional studies in model systems provides crucial evidence for assigning causality in the clinical setting. The identification of definitive causal CHD variants influences patient care. Both the family of a newborn baby with CHD and adults with repaired or palliated CHD, benefit when genotyping can accurately inform the risk of recurrence thus giving increased opportunity for prenatal genetic counselling and pre-implantation genotyping. The genotype may lead to identifying associated extracardiac anomalies or comorbidities such as neurodevelopmental delay and underlines the need for surveillance for unfavourable postoperative outcomes and future cancer development. Variants are typically discovered by whole-exome sequencing and analyses of case–control comparisons. These studies show that patients with CHD have the same rates of total de novo variants but significantly more rare damaging variants compared with the general population, including 9% excess of de novo damaging variants, 7% excess of dominant inherited variants, and 1% recessive inherited variants. In conclusion, as the CHD birth prevalence is increasing, there is need for maternal risk factor modification in the general population, as well as genetic assessment in selected cohorts. These components emphasize the multifactorial aetiology of CHD and highlight it as part of a genetic-based disruption of human cardiac morphogenesis. Even if improvements in CHD diagnosis and management (including catheter-based intervention, cardiac surgery, medical management, and psychological support) have secured a longer life of higher quality for even the most complex cases it is clear that the prevalence of CHD could be modified by lifestyle and further advances in genetic counselling. The author thanks Dr Lorna Swan Consultant Cardiologist, Scottish Adult Congenital Cardiac Service, Golden Jubilee Hospital, Glasgow, UK for her help with English language.