Apnea of prematurity: What can observational studies tell us about pathophysiology?

Apnea of prematurity (AOP) is a developmental sleep disorder which is yet to be completely understood. Although there is some evidence of brainstem immaturity, there is nothing to suggest that infants with AOP have gross deficits in respiratory control. It appears, however, that the early (and frequent) occurrence of hypoxemia during apnea in preterm infants is related to their low expiratory lung volume, which falls even further during apnea, while the accompanying bradycardia results from this combination of apnea and hypoxemia. Feeding is an important trigger for AOP. While hypoxemia during feeding is most likely related to an immature coordination between sucking, swallowing and breathing and potentially also to an immature laryngeal chemoreflex, hypoxemia after feeding may be caused by diaphragmatic fatigue; gastro-esophageal reflux only rarely plays a role. The time course of AOP, i.e., its increased occurrence during the second and third rather than the first week of life, together with data from physiological studies, also suggests a role for diaphragmatic fatigue. Additional factors include upper airway obstruction, persistence of the fetal response to hypoxia, i.e., ventilatory depression, and the close proximity between the eupneic and apneic CO(2) thresholds in neonates. Observational data cannot provide definite answers on cause-and-effect issues but may provide a starting point for further studies into mechanisms involved in AOP and for the development of new therapeutic interventions. First, however, we need to better define how much AOP can be tolerated in an infant without endangering neurodevelopment.