We should do better in accounting for multiple births in neonatal randomised trials: a methodological systematic review

OBJECTIVE: To conduct a methodological systematic review of multicentre trials of premature infants to (1) determine if and how multiple births have been considered in the design, analysis and reporting of recent trials and (2) assess whether there has been an improvement since the last review was conducted 10 years ago. DESIGN: A systematic search was conducted in PubMed on 28 June 2023 for articles published between June 2018 and June 2023. Articles were eligible for inclusion if they were a multicentre randomised trial of infants born preterm and reported the results of a primary outcome that was measured on an infant or could be attributed to an infant. RESULTS: We reviewed 62/74 trials (80%), after determining it was unclear if multiple births were present in the other 20%. 87% of trials (54/62) did not account for multiple births in their sample size calculations and 48% (30/62) did not account for clustering due to multiple births in their analyses. Problems were not limited to lower-ranked journals. No trials reported the intraclass correlation coefficient for any outcomes, indicating the degree of clustering present. CONCLUSIONS: Persistent problems remain with the design and analysis of multicentre trials of premature infants due to ignoring the complexity that comes with the inclusion of multiple births, despite methods available to address this. Trialists should consider the impact of multiple births in their trial design and analysis. Readers of neonatal trials should be aware of these issues, particularly those who peer review papers.