Accounting for deaths in neonatal trials: is there a correct approach?

INTRODUCTION The Disability and Perinatal Care report published by the National Perinatal Epidemiology Unit and Oxford Regional Health Authority in 1994 emphasised that data on the neurodevelopmental outcomes of neonates requiring intensive care should be formally collected. Over the last 40 years, survival rates of high-risk infants have improved but these have not been matched with parallel improvements in neurodevelopmental outcomes. Consequently, the focus of neonatal care has shifted increasingly towards reducing long-term morbidity and neurodevelopmental impairment. 2 Improved long-term neurodevelopment is now considered the ‘Holy Grail’ in neonatology. 5 These developments have led to a change in focus of perinatal trials, which have moved away from survival as the primary outcome towards using long-term functional outcomes. This has raised the question of how to deal with deaths in those trials where neurodevelopmental impairment is of primary interest. In perinatal trials involving the recruitment of high-risk infants, it is inevitable that some will die and quantifying outcome for these infants has led to a range of approaches, none of which are without compromise. This issue has become even more pertinent since some interventions designed to improve neurodevelopmental outcomes may not necessarily have a biologically plausible effect on mortality. Nevertheless, mortality is significantly higher in neonatology compared with other fields of medicine, particularly among very preterm infants, which strongly influences both trial design and analysis. This review considers approaches that have been taken by trialists regarding the role of death in their outcome measures, the pros and cons of the various approaches, the effect on the outcomes measured and the subsequent interpretation of the findings.