Relevance of the Antenatal Corticosteroids-to-Delivery Interval in the Prevention of Neonatal Respiratory Distress Syndrome Through the Eyes of Causal Inference: A Review and Target Trial

Abstract

Purpose - To critically analyse the literature on the antenatal corticosteroids (ACS)-to-birth interval from a causal point of view and to present a solution to the problem of bias caused by post-hoc analysis. Methods - Due to the post-hoc nature of the ACS-to-birth interval, a randomised controlled trial (RCT) of ACS versus placebo is not able to examine the importance of the interval. When an RCT is not feasible, for whatsoever reason, a target trial can be set up and an attempt can be made to answer the causal question of interest using observational data. An attempt was made to set up a target trial which could enable to examine the causal effect of the ACS-to-birth interval on neonatal outcomes. An analysis of current literature on the ACS-to-birth interval was done.Results - The majority of studies aimed to examine the causal effect of the interval, but their study design only permitted to find associations between the interval and neonatal outcomes. Barriers for setting up a target trial are highlighted.Conclusion - Evidence on the superiority of any ACS-to-birth interval is lacking and the question can only be addressed causally and become clinically relevant if baseline randomisation to ACS-to-birth intervals is made possible.