Causes of congenital heart disease: an integrative narrative review

Congenital heart disease (CHD) is the most common congenital anomaly, with lifelong implications as survival into adulthood becomes the norm. Despite advances in prenatal detection, surgical care and long-term follow-up, the aetiology of CHD remains incompletely understood. This narrative review synthesises current evidence across genetic, epigenetic and environmental domains, with particular attention to their interplay.Growing evidence indicates that genetic susceptibility in combination with environmental exposures may shape CHD risk. While chromosomal anomalies and single-gene defects explain a minority of cases, polygenic contributions and emerging evidence on epigenetic programming suggest additional layers of complexity in CHD aetiology. Maternal health conditions, such as diabetes, autoimmune disease and infections together with medication use, play critical roles in determining fetal cardiac development and contribute to modifiable risk pathways. Lifestyle, reproductive and external environmental factors, including smoking, assisted reproductive technology and air pollution, further underscore the need for proactive counselling and early risk mitigation. Emerging evidence also points to gene-environment interactions as a key mechanism through which genetic susceptibility modulates the impact of external exposures, offering new avenues for precision prevention.Looking ahead, progress will depend on integrating multi-omic data with longitudinal cohorts, multinational registries and interoperable data infrastructures. Such efforts must be coupled with implementation research to translate mechanistic insights into predictive tools and scalable interventions. Framing CHD within this bench-to-bedside-to-policy continuum positions it as both a model for precision prevention and lifelong, multidisciplinary care and a test case for approaches that could be extended to other multifactorial conditions with major population-health impact.