**10. Challenges in supporting healthy neonatal growth during PN**

The ultimate goal of NICU physicians is to support optimal infant growth and maturation until the child is stable for discharge. This goal is complicated by increased metabolic needs in infants who commonly have infectious stresses and underdeveloped GI and immune organs function. Preterm infants do not require the same nutrition intake as weight-matched term infants; they often require greater caloric intake due to weight loss after birth and high metabolic rates [120]. Despite the years of research and clinical trial and error that have gone into creating the PN formulas used in NICUs today, several developmental delays are still noted in neonates during PN. Among these are neurodevelopmental delays, which have been widely observed, but the underlying mechanisms remain poorly characterized [121]. There are also delays in development of the immune system and the closely related enteric nervous system in the intestine. PN infants also show slowing of intestinal and hepatic development.

Developmental outcomes for preterm infants have mostly only been studied during the NICU stay. What is less clear is the longer-term effects of neonatal growth delay. Several studies have examined the effects of too little growth and/ or the deficiency of certain nutrients during infancy on height, BMI z-scores, and other developmental factors measured later in life. In a cohort study of preterm infants receiving either standard or energy-enhanced PN (meaning an increased calorie:protein ratio), no significant difference in growth was found at 24 months of life. Both types of PN did, however, cause PN-related complications in 98% of patients [122]. Other studies have shown little or no significant difference in the effects of different protein or fat compositions of neonatal formula on height or BMI after 1 year of age [123]. It has, however, been found that breast feeding reproducibly leads to a higher IQ in childhood compared to formula feeding, and by extension PN. As discussed in Section 12, supplementation of PN with DHA may help alleviate some detriments of neurological development [123].

Though most of the focus is on supporting adequate growth in the neonate, some researchers have questioned the effect of overcompensation and accelerated growth on later life. It has been observed that overly accelerated growth in infants may lead to increased incidence of obesity and other related diseases later in life. This appears to be true whether the infants are term or premature [124]. These longterm effects are thought to occur through "nutritional programming"; that is, the nutrients received in certain key developmental periods can lastingly alter endocrine function, immune function, and other health indices via epigenetic responses to early life nutrients [123]. A cohort study in the UK identified several risk factors in children who were obese at 7 years of age. In that study, neonatal "catch up" growth was identified as an independent risk factor for obesity. However, large birth weight was also an independent risk factor, suggesting a trade-off between these two variables [125]. The clinical goal is to strike a balance between providing enough nutrition to prevent neurodevelopmental delays and prevent hyperalimentation associated with long term obesity risk. It is also important to note that most of these studies have focused on accelerated growth with enteral feeding (either breast milk or formula), so little is known about the compound effects of overaccelerated growth on PN.
