The Role of Early Parenteral Amino Acid Supplementation in ELBW Infants on School-Age Outcomes

Extremely preterm infants experience a nutritional emergency after early delivery from the tightly regulated in utero environment and receipt of placental-derived nutrients. Early delivery results in nutritional deficits that are difficult to prevent with current nutritional practices, and although improved over time, weight faltering, as defined by extrauterine growth restriction, remains a common concern. Compounding this concern is the link between growth attainment and the increased risk of short- and long-term morbidities and altered neurodevelopment. Decades of research have been conducted to understand best practices in protein delivery to optimize growth and health outcomes.1 Recent studies in parenteral protein delivery have studied the question of whether providing higher amounts of protein benefits infants with low birth weight who require parenteral nutrition.In 2022, the investigators of the Protein Intravenous Nutrition on Development (ProVIDe) Trial published their 2-year neurodevelopmental findings in preterm infants with birth weights less than 1000 g (extremely low birth weight [ELBW]) randomized to receive an additional 1 g of parental amino acids per day in the first 5 days after birth compared with controls.2 There were no differences in the percentage of infants with survival free of neurodisability in the intervention and placebo groups (47.8% vs 49.8%; P = .56). This finding not only confirmed no advantage to targeting higher parenteral protein intake in the first 5 days after birth but also sounded a potential alarm with secondary findings of a higher proportion of moderate or severe neurodisability in the intervention group vs controls (16.5% vs 8.6%; adjusted relative risk, 1.95; 95% CI, 1.09–3.48) and higher rates of refeeding syndrome and metabolic disturbances.1,2In this issue of Pediatrics, Nyakotey et al report the school-aged follow-up of the same cohort at 6 to 7 years’ corrected age.3 Consistent with the 2-year results, there was no significant difference in the primary outcome of survival free of neurocognitive impairment between groups (20.9% vs 23.3%, P = .21). The difference in moderate to severe neurodisability that was observed at 2 years was also no longer evident at school age, with similarly high rates in both groups (40.9% vs 38.6%; adjusted risk ratio, 1.01; 95% CI, 0.91–1.12). This convergence is clinically important to acknowledge and has been shown in other studies of long-term neurodevelopmental outcomes. Early signals of neurodevelopmental concerns are not good predictors of later neurodevelopmental assessments, while new findings may emerge as higher cortical functions emerge with age. Highly concerning is that approximately 70% of children in both groups had low educational achievement regardless of protein assignment. This finding speaks to the profound developmental burden of extremely preterm birth that extends well beyond the neonatal period and underscores the urgency of comprehensive developmental surveillance and educational support for all survivors with ELBW.Although the difference in rates of moderate to severe neurodisability was no longer evident between the intervention and treatment groups, other differences emerged. Children randomized to additional amino acids had significantly lower relative handgrip strength z scores (−0.73 vs −0.33; adjusted mean difference, −0.39; 95% CI, −0.65 to −0.13) and a greater risk of low psychosocial functioning (26.0% vs 17.9%; adjusted risk difference, 1.82; 95% CI, 1.07–3.09). A sex-specific finding of worse global motion perception in boys but not girls receiving additional amino acids further suggests that the neurodevelopmental effects of excess early parenteral protein may not be uniform across the population, consistent with the recognized greater vulnerability of preterm male infants to neurological injury.The findings need to be weighed against the study’s limitations, including those raised with the initial publication. The positive secondary outcomes of lower muscle strength and worse psychosocial functioning among 15 prespecified secondary outcomes increase the risk of a type I error. The observation of a muscle strength difference without a difference in the lean mass index raises the possibility of a chance finding. The CI for psychosocial functioning is very wide, limiting precision in the true estimate. Follow-up was restricted to only the New Zealand participants (although the overall follow-up rate was outstanding at >90%). Finally, the original intervention required an absolute difference in protein of 1 g/d, which led to a range of different protein exposures when normalized to weight, further limiting an interpretation of a relationship between protein delivered and the outcomes observed.Despite these limitations, there remains no evidence to recommend parenteral protein delivery beyond the current maximum goal of 3.5 g/k/d,4,5 but there is enough potential concern to actively guard against providing more.Further investigations are needed to determine optimal protein delivery in preterm infants. Questions remain about the type or quality of protein currently used, including the overall composition of the amino acids, and whether individual amino acids confer distinct physiologic effects.6 Questions remain on the mechanisms that explain the outcome differences between parenteral vs enteral protein delivery.7 And questions remain on whether these findings or our current practices specifically address the needs of the most immature infants (<25 weeks of gestation)—a population of infants yet to be well represented in our current neonatal scientific literature.In parallel, the most important clinical outcomes to be measured also need to be determined. The battery of tools at one developmental stage may not reflect functional outcomes later. Defining clinically meaningful outcome measures that inform both physiology and functional outcomes important to children and parents alike will be a critical step forward.8