Might rare factors account for most of the mortality of preterm babies?

Abstract

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.

Figure 1

The relation between gestational age at birth, mortality, and Factors 1 (or 3) and Factor 2. Arrows represent the gestational age by which approximately 99% of babies affected by that factor (or with no factor) have been born.

Figure 2

Gestational-age-specific mortality among babies with no pathological factor (baseline), with only Factor 1, only Factor 2, and only Factor 3. Arrows indicate the (approximate) gestational age by which 99% of babies are born. (Babies with more than one factor are not represented).

Figure 3

Baseline mortality and mortality in the presence of Factor 1 and Factor 2 (solid line) and in the presence of Factor 2 and Factor 3 (dotted line). In this representation, the pathological factors are unmeasured and babies with and without factors are mixed in the same curve.

Figure 4

Distribution of “target” gestations and baseline mortality for non-T and T babies. A. T has no direct effect on mortality B. T increases mortality with an OR of 1.7

Figure 5

Week-specific mortality of T and non-T babies in the presence of two unmeasured factors (Factors 2 and 3), when T increases baseline mortality by an OR of 1.7 at each gestational age.