Tandem mass spectrometry in newborn screening for inherited metabolic diseases: A comprehensive review

Newborn screening represents a critical public health strategy for preventing childhood morbidity and mortality. The introduction of tandem mass spectrometry (MS/MS) has revolutionized the screening landscape for inherited metabolic diseases, shifting the paradigm from single-disease assays to a high-throughput, integrated platform capable of detecting dozens of disorders in a single run. This review systematically outlines the applications and challenges of MS/MS in newborn screening. It begins by outlining the technical principles underlying MS/MS, highlighting its unique capacity to simultaneously quantify multiple amino acids, organic acids, and fatty acid oxidation metabolites. Then, it summarizes global implementation experiences and overviews evidence to demonstrate that MS/MS significantly enhances disease detection rates, enables early intervention, and substantially improves clinical outcomes. However, its widespread adoption introduces new challenges, such as the interpretation of false-positive results, confirmation of clinical relevance for newly screened conditions, and accompanying ethical concerns. Future directions include leveraging artificial intelligence to refine interpretive workflows, expanding the screening panel, and integrating genomic technologies with MS/MS to achieve more precise diagnosis and personalized management. This review aims to offer public health policymakers, clinicians, and laboratory specialists a comprehensive interdisciplinary overview to advance the next developmental phase of newborn screening systems.