Apnoea of Prematurity and Neurodevelopmental Outcomes: Current Understanding and Future Prospects for Research

Abstract

Infants who are born prematurely are at significant risk of apnoea. In addition to the short-term consequences such as hypoxia, apnoea of prematurity has been associated with long-term morbidity, including poor neurodevelopmental outcomes. Clinical trials have illustrated the importance of methylxanthine drugs, in particular caffeine, in reducing the risk of long term adverse neurodevelopmental outcomes. However, the extent to which apnoea is causative of this secondary neurodevelopmental delay or is just associated in a background of other sequelae of prematurity remains unclear. In this review, we first discuss the pathophysiology of apnoea of prematurity, previous studies investigating the relationship between apnoea and neurodevelopmental delay, and treatment of apnoea with caffeine therapy. We propose a need for better methods of measuring apnoea, along with improved understanding of the neonatal brain's response to consequent hypoxia. Only then can we start to disentangle the effects of apnoea on neurodevelopment in preterm infants. Moreover, by better identifying those infants who are at risk of apnoea, and neurodevelopmental delay, we can work toward a risk stratification system for these infants that is clinically actionable, for example, with doses of caffeine tailored to the individual. Optimising treatment of apnoea for individual infants will improve neonatal care and long-term outcomes for this population.

Keywords: apnoea of prematurity; brain; caffeine; neonate; neurodevelopment; preterm.

Figure 1

Respiratory control mechanisms and the differences in infancy. Blue arrow: positive stimulation (encourages ventilation). Red lines: negative stimulation (depresses ventilation). In the brain: the yellow shape indicates pontine respiratory centre, the green circle indicates the dorsal respiratory group, the blue circle indicates the ventral respiratory group, and the red dot illustrates the pre-Bötzinger Complex. SLN is the Superior Laryngeal Nerve. This figure was created using BioRender (https://Biorender.com).

Figure 2

Which comes first, the immaturity or the apnoea? A model of the interplay between the causes (top) and consequences (bottom) of apnoea of prematurity and respiratory immaturity in neonates, and how this might lead to neurodevelopmental impairment. DCD, developmental coordination disorder. Dashed lines indicate mixed causes between the sequelae of AOP and prematurity itself on neurological damage in these infants. This figure was created using BioRender (https://Biorender.com).