Bias due to selection on live births in studies of environmental exposures during pregnancy: A simulation study

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 (NO₂ ) and autism spectrum disorder (ASD) that found an odds ratio (OR) of 0.77 per 5:85 ppb NO₂ 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 NO₂ 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 NO₂ and U independently influenced pregnancy loss (collider-stratification without interaction), was stronger when NO₂-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 NO₂-loss, U-loss, U-ASD, and U prevalence = 0:75 yielded NO₂-ASD ORs per 5:85 ppb NO₂ 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.