Recent advances in understanding pathophysiology of non-nutritional stunting in very preterm infants

Abstract

Very preterm infants (VPIs) often experience extrauterine growth failure. Therefore, aggressive nutritional management of VPIs is recommended with the goal of achieving the postnatal growth of an equivalent fetus. However, VPIs frequently present postnatal length growth restriction at term-corrected age that remains lower than the standard weight and have greater fat mass and lower lean and bone mass than term-born infants. This condition differs from the classic pattern of infant undernutrition defined as a significantly lower weight for a given length. Moreover, it suggests that nonnutritional factors play a key role in length growth restriction. While weight faltering has been extensively studied, the significance of length growth failure in VPIs has only recently emerged. The nonnutritional factors underlying poor length growth in VPIs are currently not fully understood. In this review, we address recent advances in our understanding of the pathophysiology of length growth restriction, which has been identified as a major predictor of adverse neurodevelopmental and cognitive outcomes in VPIs. First, we review the shortand long-term consequences of poor length growth in VPIs; next, we highlight the effects of nonnutritional factors on postnatal length growth with focus on sustained neonatal inflammation; and finally, we discuss hypothesis and future lines of research attempting to understand the complex inflammatory-endocrine interactions and pathophysiological changes during early postnatal life, appropriately guide and apply clinical strategies aimed at optimizing length growth of VPIs, and identify evidence of the associations between sustained neonatal inflammation, stunting, and long-term health risks and the potential implications thereof.

Keywords: Failure to thrive; Growth disorders; Infant; Inflammation; Premature.

Fig. 1.

Complex risk profile and potential short- and long-term adverse outcomes of very preterm infants with length growth restriction due to sustained neonatal inflammation. This model describes that very preterm infants are at risk of sustained inflammation due to their severe immaturity and several aggressive environmental factors. The acute inflammatory process is often not properly resolved after clinical recovery, resulting in sustained inflammation.

Fig. 2.

Pathophysiology of nonnutritional stunting among very preterm infants. Sustained neonatal inflammation induces growth hormone (GH) resistance at the liver, resulting in a decreased expression of insulin-like growth factor-1 (IGF-1); this increases circulating GH levels due to loss of the negative feedback of IGF-1on GH release. IGF-1 is the key mediator of the effect of the GH axis on linear growth.

Fig. 3.

This model aims to elucidate the effects of sustained inflammation in early life on child and adult health. According to the hypothesis related to the early origins of adult disease, neonatal length growth restriction in very preterm infants could lead to epigenetic changes, which may subsequently affect child and adult health outcomes. The available data suggest that these changes may not be complete in early postnatal life but may be affected by persistent inflammation during infancy. However, the mechanistic basis for this phenomenon and the ultimate effect of stunting on adult health outcomes remain poorly understood.