Bias due to Selection on Live Births in Studies of Environmental Exposures during Pregnancy: A Simulation Study

Abstract

Background: Studies of the effects of prenatal environmental exposures on postnatal outcomes are particularly vulnerable to live birth bias; i.e., the bias that arises from the necessary restriction of the analysis to live births when that is influenced by both the exposure under study $A$ and unmeasured factors $U$ that also affect the outcome.

Objectives: In the context of a recent publication of nitrogen dioxide (${\mathrm{NO}}_2$) and autism spectrum disorder (ASD) that found an odds ratio (OR) of 0.77 per $5.85\text{ppb}$ ${\mathrm{NO}}_2$ during pregnancy, we aimed to examine what parameters would be needed to account for this protective association through live birth bias.

Methods: We simulated the magnitude of bias under two selection mechanisms and when both mechanisms co-occur, assuming a true null effect. Simulation input parameters were based on characteristics of the original study and a range of plausible values for the prevalence of unmeasured factor $U$ and the ORs for the selection effects (i.e., the effects of ${\mathrm{NO}}_2$ and $U$ on loss and of $U$ on ASD). Each scenario was simulated 1,000 times.

Results: We found that the magnitude of bias was small when ${\mathrm{NO}}_2$ and $U$ independently influenced pregnancy loss (collider-stratification without interaction), was stronger when ${\mathrm{NO}}_2\text{-induced}$ loss preferentially occurred in $U=1$ (depletion of susceptibles), and was strongest when both mechanisms worked together. For example, ORs of 3.0 for ${\mathrm{NO}}_2\text{-loss}$, $U$-loss, $U$-ASD, and U $\text{prevalence}=0.75$ yielded ${\mathrm{NO}}_2\text{-ASD}$ ORs per $5.85\text{ppb}$ ${\mathrm{NO}}_2$ of 0.95, 0.89, and 0.75 for the three scenarios, respectively. The bias is amplified with multiple $Us$, yielding ORs as low as 0.51.

Discussion: Our simulations illustrate that live birth bias may lead to exposure-outcome associations that are biased downward, where the extent of the bias depends on the fetal selection mechanism, the strength of that selection, and the prevalence of U. https://doi.org/10.1289/EHP7961.