Placental abruption and perinatal mortality with preterm delivery as a mediator: disentangling direct and indirect effects

Abstract

The authors use recent methodology in causal inference to disentangle the direct and indirect effects that operate through a mediator in an exposure-response association paradigm. They demonstrate how total effects can be partitioned into direct and indirect effects even when the exposure and mediator interact. The impact of bias due to unmeasured confounding on the exposure-response association is assessed through a series of sensitivity analyses. These methods are applied to a problem in perinatal epidemiology to examine the extent to which the effect of abruption on perinatal mortality is mediated through preterm delivery. Data on over 26 million US singleton births (1995-2002) were utilized. Risks of mortality among abruption and nonabruption births were 102.7 and 6.2 per 1,000 births, respectively. Risk ratios of the natural direct and indirect (preterm delivery-mediated) effects of abruption on mortality were 10.18 (95% confidence interval: 9.80, 10.58) and 1.35 (95% confidence interval: 1.33, 1.38), respectively. The proportion of increased mortality risk mediated through preterm delivery was 28.1%, with even higher proportions associated with deliveries at earlier gestational ages. Sensitivity analyses underscore that the qualitative conclusions of some mediated effects and substantial direct effects are reasonably robust to unmeasured confounding of a fairly considerable magnitude.

Figure 1.

Gestational age-specific risk of perinatal mortality (per 1,000 births) among abruption and nonabruption births and risk ratio of mortality between placental abruption and nonabruption births, US singleton births, 1995–2002.

Figure 2.

Directed acyclic graph showing the relation between placental abruption (X) and perinatal mortality (Y) with preterm delivery as the intermediary (mediating) covariate (M), US singleton births, 1995–2002. “C” is a set of confounders observed at baseline (common causes for placental abruption, preterm delivery, and perinatal mortality), and “U” is a set of unobserved confounders. We represent the relation between X and U as a dashed line because we do not consider this confounding scenario; consequently, our sensitivity analysis assumes that this pathway does not exist, and that we believe this confounding is weak in comparison.