Invited Commentary: Influenza, Influenza Immunization, and Pregnancy-It's About Time

Immunization of pregnant women against influenza has the potential to reduce adverse fetal outcomes by reducing prenatal exposure to influenza illness. However, as touched on by Fell et al. (Am J Epidemiol. 2016;184(3):163-175) and Vazquez-Benitez et al. (Am J Epidemiol. 2016;184(3):176-186) in this issue of the Journal, observational studies in which the causal effect of maternal influenza illness and influenza immunization on fetal health are evaluated are prone to bias because of the complex temporal nature of influenza illness seasonality, influenza immunization schedules, and gestation itself. Immortal time bias is introduced by an "anytime-in-pregnancy" exposure definition because the shortened pregnancy duration associated with many adverse fetal outcomes limits the opportunity to become exposed, whereas including follow-up time during which pregnancies are no longer at risk of an adverse outcome (e.g., gestational time after 37 weeks in studies of preterm birth) can lead to overestimation of any true benefits of immunization (or harms from influenza illness). We present a framework to avoid time-related biases in the study of influenza illness and immunization in pregnancy and advise that investigations of fetal benefit from maternal influenza immunization should only be undertaken when information is available on the calendar time of influenza virus circulation and the gestational age at which maternal influenza immunization occurred.