Understanding Etiologic Pathways Through Multiple Sequential Mediators: An Application in Perinatal Epidemiology

Background: Causal mediation analysis facilitates decomposing the total effect into a direct effect and an indirect effect that operates through an intermediate variable. Recent developments in causal mediation analysis have clarified the process of evaluating how—and to what extent—different pathways via multiple causally ordered mediators link the exposure to the outcome. Methods: Through an application of natural effect models for multiple mediators, we show how placental abruption might affect perinatal mortality using small for gestational age (SGA) birth and preterm delivery as two sequential mediators. We describe methods to disentangle the total effect into the proportions mediated via each of the sequential mediators, when evaluating natural direct and natural indirect effects. Results: Under the assumption that SGA births causally precedes preterm delivery, an analysis of 16.7 million singleton pregnancies is consistent with the hypothesis that abruption exerts powerful effects on perinatal mortality (adjusted risk ratio = 11.9; 95% confidence interval = 11.6, 12.1). The proportions of the estimated total effect mediated through SGA birth and preterm delivery were 2% and 58%, respectively. The proportion unmediated via either SGA or preterm delivery was 41%. Conclusions: Through an application of causal mediation analysis with sequential mediators, we uncovered new insights into the pathways along which abruption impacts perinatal mortality.