Correcting for Exposure Misclassification Using Survival Analysis With a Time-Varying Exposure

Purpose: Survival analysis is increasingly being used in perinatal epidemiology to assess time-varying risk factors for various pregnancy outcomes. Here we show how quantitative correction for exposure misclassification can be applied to a Cox regression model with a time-varying dichotomous exposure. Methods: We evaluated influenza vaccination during pregnancy in relation to preterm birth among 2267 non-malformed infants whose mothers were interviewed as part of the Slone Birth Defects Study during 2006 through 2011. The hazard of preterm birth was modeled using a time-varying exposure Cox regression model with gestational age as the time-scale. The effect of exposure misclassification was then modeled using a probabilistic bias analysis that incorporated vaccination date assignment. The parameters for the bias analysis were derived from both internal and external validation data. Results: Correction for misclassification of prenatal influenza vaccination resulted in an adjusted hazard ratio (AHR) slightly higher and less precise than the conventional analysis: Bias-corrected AHR 1.04 (95% simulation interval, 0.70-1.52); conventional AHR, 1.00 (95% confidence interval, 0.71-1.41). Conclusions: Probabilistic bias analysis allows epidemiologists to assess quantitatively the possible confounder-adjusted effect of misclassification of a time-varying exposure, in contrast with a speculative approach to understanding information bias

Risks and Safety of Pandemic H1N1 Influenza Vaccine in Pregnancy: Birth Defects, Spontaneous Abortion, Preterm Delivery, and Small for Gestational Age Infants

Introduction: There is a need for additional information on the fetal risks and relative safety of the pandemic H1N1 monovalent or trivalent influenza (pH1N1)-containing vaccines in women exposed during pregnancy. Methods: To assess risks and relative safety of the pH1N1-containing vaccines, we conducted a prospective cohort study of pH1N1-vaccine-exposed and unexposed comparison women residing in the U.S. or Canada who were recruited during pregnancy and followed to outcome between October 2009 and August 2012. For exposure to the pH1N1 vaccine, adjusted relative risks (RRs) and 95% confidence intervals (CIs) were estimated for major birth defects and infants small for gestational age. Adjusted hazard ratios (HRs) and 95% CIs were estimated for spontaneous abortion and preterm delivery for time-varying exposure. Results: There were 1032 subjects available for analysis; 841 women were exposed to a pH1N1-containing vaccine in pregnancy, and 191 women were unexposed to any influenza vaccine in pregnancy. Nine of 328 (2.7%) first-trimester-exposed pregnancies resulted in an infant with a major birth defect compared to 6/188 (3.2%) in the unexposed (adjusted RR 0.79, 95% CI 0.26-2.42). The HR for spontaneous abortion was not elevated (adjusted HR 0.92, 95% CI 0.31-2.72). Adjusted HRs for preterm delivery were elevated for exposure anytime in pregnancy (3.28, 95% CI 1.25-8.63), specifically with exposure in the 1st or 2nd trimester. However, the mean decrease in gestational age in the exposed pregnancies was approximately three days. Adjusted RRs for small for gestational age infants on weight and length approximated 1.0. Conclusions: For the 2009-12 influenza seasons combined, we found no meaningful evidence of increased RR or HR for major birth defects, spontaneous abortion, or small for gestational age infants. There was some evidence of an increased HR for preterm delivery following pH1N1-influenza vaccine exposure; however the decrease in gestational age on average was approximately three days