Fetuses-at-risk, to avoid paradoxical associations at early gestational ages: extension to preterm infant mortality

Background: Fetuses-at-risk denominators are commonly used in research on preterm stillbirth, but applications to postnatal outcomes such as preterm infant mortality are controversial. We evaluated whether biased associations between maternal risk factors and preterm infant mortality caused by stratification by preterm birth could be avoided using fetuses-at-risk risk ratios. Methods: Data included 3 277 570 births drawn from the linked live birth-death file for Canada from 1990 through 2005. We used maternal age as the risk factor, and estimated the association with stillbirth, early neonatal, late neonatal and postneonatal mortality by gestational interval (22-24, 25-27, 28-31, 32-36, >= 37 weeks). Models were run using (i) log-binomial regression stratified by preterm gestational age, and (ii) unstratified logbinomial regression using fetuses-at-risk denominators. Results: Extremes of maternal age were associated with higher mortality among term births. Among preterm births, the stratified model suggested a protective, null or attenuated association of extremes of maternal age with stillbirth, early, late and post neonatal mortality. The unstratified fetuses-at-risk model, however, resulted in the expected higher risk of mortality at extremes of maternal age for all outcomes. Conclusions: Fetuses-at-risk regression can avoid paradoxical associations between maternal exposures and mortality of infants born early in gestation, caused by preterm birth stratification bias. The fetuses-at-risk approach can be extended through the first year of life, or potentially beyond, depending on the outcome and presence of unmeasured confounders associated with preterm birth.