Commentary: Mediation and moderation analyses: a novel approach to exploring the complex pathways between maternal medical conditions, preterm birth and associated newborn morbidity risk.

Whereas infants born at earlier gestational ages suffer the greatest morbidity and mortality, adverse health consequences of late preterm and early term births are also well documented. The aetiology of preterm birth is multifactorial and the pathways leading to it probably vary with gestational age. They include infection or inflammation, uteroplacental ischaemia or haemorrhage, uterine overdistension, stress and other immunologically mediated processes. Each of these pathways probably has its own initiating factors and mediators. How pre-existing or pregnancy-related medical conditions and complications interact with or result in preterm birth to increase risk of neonatal morbidity is not well understood. Regrettably, most studies were not designed to explore these complex and poorly understood pathways. In this issue of the International Journal of Epidemiology, Brown and colleagues make an important contribution to knowledge of how biological determinants of preterm birth may act through and with gestational age to increase the risk of adverse neonatal outcomes. Using a retrospective cohort study design and linking administrative databases, the authors use mediation and moderation analyses to explore associations, comparing infants born late preterm and early term with their term counterparts. Mediation analysis answered the question, ‘Does gestational age act as a partial mediator between biological determinants of preterm birth and poor neonatal outcomes? Moderation analysis answered the question, ‘Do biological determinants of preterm birth modify the effect of gestational age on poor neonatal outcomes?’ For the mediation analysis, the authors used general estimating equations to test the significance of differences in coefficients between full (with gestational age) and reduced (without gestational age) models. To infer an indirect effect of the biological determinants, they depended on differences in coefficients. For the moderation analyses, the authors determined the presence of additive interaction by calculating the relative excess risk due to interaction. They showed that the effect of gestational age on newborn morbidity is partially explained by biological components, and specifically that placental ischaemia and other hypoxia conditions exacerbate the effect of gestational age on adverse neonatal outcomes among infants born late preterm and early term. To my knowledge, this is the first study to use both mediation and moderation analyses to explore these complex relationships. The study is timely because rates of deliveries before 39 weeks of gestation remain a concern, as evidenced by new recommendations and campaigns focused on reducing non-medically indicated deliveries before 39 weeks of gestation. The study is clinically meaningful for several reasons. First, most studies comparing late preterm and/or early