Might Rare Factors Account for Most of the Mortality of Preterm Babies?

Background: Preterm delivery has a variety of causes, with each of these presumably carrying its own mortality risk. To the extent that they add to the risk of mortality, the various pathologic factors triggering preterm delivery will confound the causal contribution of gestational age to mortality, inflating the observed rates of gestational-age-specific mortality. We have previously estimated that about half of the mortality of US preterm singletons may be due to unmeasured pathologies that increase mortality risk and also cause preterm birth. In this paper, we examine the impact that rare factors may have, at least in theory, on preterm mortality. Methods: We constructed a simple model of gestational-age-specific mortality, in which we arbitrarily selected a function to represent the mortality due to immaturity alone (baseline risk). We then added unmeasured confounding factors that cause mortality and also cause preterm birth. This construct allowed us to calculate, in simple scenarios, the proportion of preterm mortality that could be caused by unmeasured confounding. Results: We found that rare pathologies with moderate-to-strong effects can substantially contribute to preterm mortality. The presence of such rare factors can also produce an intersection of gestational-age-specific mortality curves when stratifying by known risk factors. Conclusions: It is possible that a few relatively rare factors may account for a large fraction of preterm mortality. The search for such factors should be a primary focus of future research on preterm delivery.