On optimal timing of antenatal corticosteroids: time to reformulate the question

Administration of antenatal corticosteroids (ACS) for accelerating foetal lung maturation in threatened preterm birth is one of the cornerstones of prevention of neonatal mortality and morbidity. To identify the optimal timing of ACS administration, most studies have compared subgroups based on treatment-to-delivery intervals. Such subgroup analysis of the first placebo-controlled randomised controlled trial indicated that a one to seven day interval between ACS administration and birth resulted in the lowest rates of neonatal respiratory distress syndrome. This efficacy window was largely confirmed by a series of subgroup analyses of subsequent trials and observational studies and strongly influenced obstetric management. However, these subgroup analyses suffer from a methodological flaw that often seems to be overlooked and potentially has important consequences for drawing valid conclusions. In this commentary, we point out that studies comparing treatment outcomes between subgroups that are retrospectively identified at birth (i.e. after randomisation) may not only be plagued by post-randomisation confounding bias but, more importantly, may not adequately inform decision making before birth, when the projected duration of the interval is still unknown. We suggest two more formal interpretations of these subgroup analyses, using a counterfactual framework for causal inference, and demonstrate that each of these interpretations can be linked to a different hypothetical trial. However, given the infeasibility of these trials, we argue that none of these rescue interpretations are helpful for clinical decision making. As a result, guidelines based on these subgroup analyses may have led to suboptimal clinical practice. As an alternative to these flawed subgroup analyses, we suggest a more principled approach that clearly formulates the question about optimal timing of ACS treatment in terms of the protocol of a future randomised study. Even if this 'target trial' would never be conducted, its protocol may still provide important guidance to avoid repeating common design flaws when conducting observational 'real world' studies using statistical methods for causal inference.