Simultaneous Genomic and Metagenomic Analysis for Miscarriage and Stillbirth Further Increases the Diagnostic Utility of Genome Sequencing

Abstract Congenital abnormalities and infections are the predominant cause of perinatal death in developed countries. While standard-of-care autopsy investigations can ascertain the event that caused the death, the aetiology cannot always be established. Genetic approaches have demonstrated utility in identifying the underlying causes of congenital anomalies and infectious diseases, but the feasibility of simultaneous metagenomic and genomic analyses has not been examined. To determine the potential of this consolidated approach, genome sequencing was performed on DNA from lung in 20 cases of fetal death. Causative microbes were correctly identified in 4/7 known infection cases and plausible causative microbes identified for 2/5 cases unresolved from standard investigations. No significant microbial load was identified in 8/8 cases due to congenital abnormality. While methods for concurrent human and microbial genome analyses still require optimisation, this dual approach should improve the diagnostic yield compared to current standard-of-care investigations, enabling more accurate counselling and appropriate care in subsequent pregnancies.