1. Compared to unaffected children, children with inborn errors of metabolism have significantly elevated risk of mortality (21.2 times risk) before 14 years of age.
2. Of causes of death, children with inborn errors of metabolism are most significantly affected by respiratory, infectious, and gastrointestinal causes of death.
Evidence Rating Level: 2 (Good)
Study Rundown: Inborn errors in metabolism are rare genetic disorders of enzymes required for critical metabolic pathways. Although these genetic disorders result in significant morbidity and mortality in the newborn period, the long-term risk of mortality has not been well-elucidated. To address this knowledge gap, this study reviewed records of children with inborn errors of metabolism between 2006-2019. Among the deaths occurring in children during this timeframe, children with errors of metabolism had more than 21.2 times the risk of death before 14 years of age compared with unaffected children. Some factors associated with increased risk of death for children with inborn errors of metabolism included increasing age, preterm birth, and children with birth defects. Of causes of death, children with inborn errors of metabolism had the most elevated risk of death by respiratory causes, hepatic and digestive causes, and infectious causes compared to unaffected children. In addition, the risk of death from cancer, circulatory causes, and nervous system disorders was also elevated to a lesser extent. Although this provides compelling evidence of mortality risk, further studies are required to assess long-term mortality beyond 14 years of age. This study may have underestimated overall mortality, as it did not did capture children who died outside of the hospital. Overall, this study is the largest of its kind to describe the mortality risk of children with inborn errors of metabolism outside of the newborn period.
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In Depth [retrospective cohort]: This retrospective cohort study used the Maintenance and Exploitation of Data for the Study of Hospital Clientele repository, which included 1,750 children with inborn errors of metabolism and 1,036,668 children without errors of metabolism born in Quebec, Canada between 2006-2019. Follow up began on the patient’s birth date and was completed on the date of death or March 31, 2020, at the end of the study period. The mortality rate for inborn errors of metabolism was significantly higher than unaffected children, with mortality rate of 69.1 per 10,000 person-years (95% CI 56.4-84.7) compared with 3.2 per 10,000 persons-years (95% CI 3.0-3.3), respectively, representing 21.2 times the risk of death compared with unaffected children (95% CI 17.23-26.11). Factors that were associated with additional increase in risk of mortality included increasing age, preterm birth (HR 140.38, 95% CI 96.88-203.42), children with birth defects (HR 58.79, 95% CI 40.63-85.08). In terms of causes of mortality, children with inborn errors were 116.6 times more likely to die from respiratory causes (95% CI 71.06-191.23), 208.2 times more likely to die from gastrointestinal causes (95% CI 90.28-480.22), and 119.8 times more likely to die from infectious causes (95% CI 40.56-354.04), compared with unaffected children. There were also moderate increases in risk of death from cancer (HR 73.60, 95% CI 35.16-154.06), circulatory causes (HR 38.38, 95% CI 18.72-78.67), and nervous system disorders (HR 47.35, 95% CI 22.95-97.67).
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