Newborn screening for beta-ketothiolase deficiency: evidence from a systematic review

Background

Newborn screening aims to reduce morbidity and mortality through early detection of treatable conditions. Beta-ketothiolase deficiency (βKT) is a rare metabolic disorder associated with severe ketoacidotic crises, but its inclusion in screening programmes remains uncertain due to limited evidence on effectiveness.

Methods

A systematic review was conducted to assess the clinical effectiveness of newborn screening for βKT using tandem mass spectrometry (MS/MS) compared with no screening. Searches included systematic reviews, health technology assessments, and primary studies (2019–2026). Study selection followed PRISMA guidelines. Evidence was synthesised using an Evidence-to-Decision framework. A national survey of screening programmes was also performed.

Results

Seventeen studies were included, mainly observational and retrospective, with no comparative studies identified. Screening programmes covered over 26 million newborns internationally, with high participation rates (>90%). MS/MS is widely implemented, but evidence on diagnostic accuracy is limited, with uncertain sensitivity and low predictive value due to low disease prevalence. Clinical effectiveness remains unclear, as no studies directly compare screened and unscreened populations. Observational data suggest earlier diagnosis may reduce severity, but findings are inconsistent and non-causal.

Conclusions

Evidence supporting newborn screening for βKT is limited and of low quality, preventing robust conclusions on its impact on health outcomes. While screening is technically feasible and widely implemented, key uncertainties remain regarding effectiveness and test performance. Further research is needed to support evidence-based decision-making.

Key messages

• Evidence on newborn screening for beta-ketothiolase deficiency is limited and insufficient to demonstrate clinical effectiveness

• Despite high feasibility, key uncertainties in test performance and outcomes hinder evidence-based screening decisions.