Accounting for Twins and Other Multiple Births in Perinatal Studies of Live Births Conducted Using Healthcare...

The analysis of perinatal studies is complicated by twins and other multiple births even when multiples are not the exposure, outcome, or a confounder of interest. In analyses of infant outcomes restricted to live births, common approaches to handling multiples include restriction to singletons, counting outcomes at the pregnancy level (i.e., by counting if at least one twin experienced a binary outcome), or infant-level analysis including all infants and accounting for clustering of outcomes, such as by using generalized estimating equations or mixed effects models. Several healthcare administration databases only support restriction to singletons or pregnancy-level approaches. For example, in MarketScan insurance claims data, diagnoses in twins are often assigned to a single infant identifier, thereby preventing ascertainment of infant-level outcomes among multiples. Different approaches correspond to different questions, produce different estimands, and often rely on different assumptions. We demonstrate the differences that can arise from these different approaches using Monte Carlo simulations, algebraic formulas, and an applied example.