Confounding by Conception Seasonality in Studies of Temperature and Preterm Birth: A Simulation Study

Background: Seasonal patterns of conception may confound acute associations between birth outcomes and seasonally varying exposures. We aim to evaluate four epidemiologic designs (time-stratified case-crossover, time-series, pair-matched case-control, and time-to-event) commonly used to study acute associations between ambient temperature and preterm births.Methods: We conducted simulations assuming no effect of temperature on preterm birth. We generated pseudo-birth data from the observed seasonal patterns of birth in the United States and analyzed them in relation to observed temperatures using design-specific seasonality adjustments.Results: Using the case-crossover approach (time-stratified by calendar month), we observed a bias (among 1,000 replicates) = 0.016 (Monte-Carlo standard error 95% CI: 0.015-0.018) in the regression coefficient for every 10? increase in mean temperature in the warm season (May-September). Unbiased estimates obtained using the time-series approach required accounting for both the pregnancies-at-risk and their weighted probability of birth. Notably, adding the daily weighted probability of birth from the time-series models to the case-crossover models corrected the bias in the case-crossover approach. In the pair-matched case-control design, where the exposure period was matched on gestational window, we observed no bias. The time-to-event approach was also unbiased but was more computationally intensive than others.Conclusions: Most designs can be implemented in a way that yields estimates unbiased by conception seasonality. The time-stratified case-crossover design exhibited a small positive bias, which could contribute to, but not fully explain, previously reported associations.

Automated summary

This study evaluates four epidemiologic designs commonly used to study acute associations between ambient temperature and preterm births. The results show that most designs can yield estimates unbiased by conception seasonality, but the time-stratified case-crossover design exhibits a small bias.