Accounting for multiple births in neonatal and perinatal trials: systematic review and case study

Abstract

Objectives: To determine the prevalence in the neonatal literature of statistical approaches accounting for the unique clustering patterns of multiple births and to explore the sensitivity of an actual trial to several analytic approaches to multiples.

Study design: A systematic review of recent perinatal trials assessed the prevalence of studies accounting for clustering of multiples. The Nitric Oxide to Prevent Chronic Lung Disease (NO CLD) trial served as a case study of the sensitivity of the outcome to several statistical strategies. We calculated odds ratios using nonclustered (logistic regression) and clustered (generalized estimating equations, multiple outputation) analyses.

Results: In the systematic review, most studies did not describe the random assignment of twins and did not account for clustering. Of those studies that did, exclusion of multiples and generalized estimating equations were the most common strategies. The NO CLD study included 84 infants with a sibling enrolled in the study. Multiples were more likely than singletons to be white and were born to older mothers (P < .01). Analyses that accounted for clustering were statistically significant; analyses assuming independence were not.

Conclusions: The statistical approach to multiples can influence the odds ratio and width of confidence intervals, thereby affecting the interpretation of a study outcome. A minority of perinatal studies address this issue.

Figure 1. Results of systematic review

The majority of studies excluded multiples or did not specify whether they were enrolled. Only the minority of studies enrolling multiples used statistics that accounted for the non-independence of their outcomes. *Of the postnatal intervention trials that excluded multiples, two excluded all infants from a multiple gestation,, and one only included the first-born multiple.