Measurement of birth outcomes in analyses of the impact of maternal influenza vaccination

Background The estimated association of maternal influenza vaccination and birth outcomes may be sensitive to methods used to define preterm birth or small-for-gestational age (SGA). Methods In a cohort of pregnant women in Lao People's Democratic Republic, we estimated gestational age from: (a) date of last menstrual period (LMP), (b) any prenatal ultrasound, (c) first trimester ultrasound, (d) Ballard Score at delivery, and (e) an algorithm combining LMP and ultrasound. Infants were classified as SGA at birth using a Canadian, global, and equation-based growth reference. We estimated the association of maternal influenza vaccination and birth outcomes, by influenza activity, using multivariable log-binomial regression and Cox proportional hazards regression with vaccination as a time-varying exposure. Results The frequency of preterm birth in the cohort varied by method to estimate gestational age, from 5% using Ballard Score to 15% using any ultrasound. Using LMP, any ultrasound, or the algorithm, we found statistically significant reductions in preterm birth among vaccinated women during periods of high influenza activity and statistically significant increases in SGA, using a Canadian growth reference. We did not find statistically significant associations with SGA when using global or equation-based growth references. Conclusions The association of maternal influenza vaccination and birth outcomes was most affected by the choice of a growth reference used to define SGA at birth. The association with pre-term birth was present and consistent across multiple statistical approaches. Future studies of birth outcomes, specifically SGA, should carefully consider the potential for bias introduced by measurement choice.