Non-Invasive Prenatal Diagnosis of Haemoglobinopathies: From Concept to Clinical Reality

Haemoglobinopathies are the most prevalent monogenic disorders worldwide, contributing significantly to childhood morbidity and mortality. Preventive strategies, including carrier screening and prenatal diagnosis, have successfully reduced disease incidence in regions with established programmes. However, definitive prenatal diagnosis currently relies on invasive procedures, such as chorionic villus sampling and amniocentesis, which carry a small but significant risk of pregnancy loss. Non-invasive prenatal diagnosis (NIPD) offers a potential alternative that enables earlier diagnosis and eliminates procedure-related miscarriage risk. This narrative review explores the genetic basis and global burden of haemoglobinopathies, current screening strategies and the established invasive diagnostic approaches before critically evaluating the emergence of NIPD for sickle cell disease and thalassaemias. We summarise the principal methodological approaches, including relative haplotype dosage and relative mutation dosage, reviewing evidence from published studies and clinical trials. While multiple NIPD strategies demonstrate promising results, challenges remain including variable fetal fraction, technical complexity, cost and accuracy. Additionally, substantial global inequities persist regarding access to screening and diagnostic services, particularly in regions suffering from higher disease burden. Although NIPD could potentially improve the acceptability and uptake of prenatal diagnosis, routine clinical adoption for haemoglobinopathies requires further validation to demonstrate consistently high diagnostic accuracy, alongside standardised methodologies and reduced costs.