Abstract
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°C 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.