The Effect of Prenatal Treatments on Offspring Events in the Presence of Competing Events: An Application to a Randomized Trial of Fertility Therapies

Abstract

When studying the effect of a prenatal treatment on events in the offspring, failure to produce a live birth is a competing event for events in the offspring. A common approach to handle this competing event is reporting both the treatment-specific probabilities of live births and of the event of interest among live births. However, when the treatment affects the competing event, the latter probability cannot be interpreted as the causal effect among live births. Here we provide guidance for researchers interested in the effects of prenatal treatments on events in the offspring in the presence of the competing event "no live birth." We review the total effect of treatment on a composite event and the total effect of treatment on the event of interest. These causal effects are helpful for decision making but are agnostic about the pathways through which treatment affects the event of interest. Therefore, based on recent work, we also review three causal effects that explicitly consider the pathways through which treatment may affect the event of interest in the presence of competing events: the direct effect of treatment on the event of interest under an intervention to eliminate the competing event, the separable direct and indirect effects of treatment on the event of interest, and the effect of treatment in the principal stratum of those who would have had a live birth irrespective of treatment choice. As an illustrative example, we use a randomized trial of fertility treatments and risk of neonatal complications.

Figure 1.. Causal directed acyclic graphs (DAGs) showing the effect of fertility treatments on neonatal complications.

A denotes the treatment (1 for letrozole, 0 for gonadotropin), D the competing event (1 if no livebirth occurs, 0 otherwise), Y the outcome (1 if neonatal complications occur, 0 otherwise), U a set of unmeasured factors that affect both the probability of live birth and of neonatal complications, e.g., partner’s semen quality, maternal health status, or a genetic factor, A_Y is the component of A that directly affects neonatal complications, and A_D is the component of A that directly affects live birth. Graph ii is an extended version of the graph i, in which the treatment components A_Y and A_D are deterministic functions (bold arrows) of A.

Figure 2.. Pregnancy and neonatal outcomes by treatment group, AMIGOS trial (2010–2014)

Treatment failure was defined as no live birth due to any of the following: conception failure, miscarriage, termination, and stillbirth. Neonatal complications were defined as any of the following: jaundice, respiratory distress, neonatal hospitalization > 3 days, and neonatal intensive care unit (NICU) admission. When a multiple birth occurred, a neonatal complication was defined to be present if any of the infants experienced it.