EBNEO Commentary: Early Amino Acids in Extremely Preterm Infants and Neurodisability at 2 Years

March 21, 2023

Early Amino Acids in Extremely Preterm Infants and Neurodisability at 2 Years


Bloomfield FH, Jiang Y, Harding JE, Crowther CA, Cormack BE, ProVIDe Trial Group. Early Amino Acids in Extremely Preterm Infants and Neurodisability at 2 Years. N Engl J Med 2022; 387(18):1661-1672. PMID 36322845.


Jane Stremming, MD
Assistant Professor of Pediatrics
University of Colorado Anschutz Medical Campus

Laura Brown, MD
Professor of Pediatrics
University of Colorado Anschutz Medical Campus




In neonates born at <1000 grams (P), does higher protein intake in the first 5 days of life (I) improve rates of survival without neurodevelopmental disability at 2 years of age (O, T) compared to neonates who receive standard protein intake (C)?


  • Design: Multi-center, double-blind, randomized control trial
  • Allocation: Infants were randomized to the intervention or placebo group in a 1:1 ratio by a Web-based interface. Randomization was stratified by recruitment site, sex, and small for gestational age
  • Blinding: Double blinded
  • Follow-up period: 2 years corrected gestational age
  • Setting: 6 neonatal units in New Zealand and 2 neonatal units in Australia with patients recruited between April 2014-October 2018
  • Patients:
    • Inclusion criteria: Infants who were <24 hours old and weighing <1000 grams at birth with an umbilical arterial catheter (UAC)
    • Exclusion criteria: >24 hours old at the time of NICU admission, multiple births with >2 infants, known chromosomal anomaly, congenital disorder that might affect growth, inborn error of metabolism, danger of imminent death
  • Intervention: Starting within 24 hours of birth, infants received either 8.5% TrophAmine containing 1 gram of amino acids (intervention) or 0.45% saline (placebo) at a rate of 0.5 ml/hr via UAC for 120 hours or until the UAC was removed
  • Outcomes:
    • Primary outcome: Survival without neurodisability at 2 years corrected gestational age. Neurodisability was assessed by the Bayley Scales of Infant and Toddler Development third edition (Bayley-III), neurological examination, evaluation of executive function, the Behavior Rating Inventory of Executive Function-Preschool Version and Child Behavior Checklist, and presence of cerebral palsy, blindness or deafness.
    • Secondary outcomes: Infant growth (weight, length, and head circumference at 28 days, 8 weeks postmenstrual age, 36 weeks postmenstrual age, NICU discharge, and 2 years corrected gestational age); body composition by air-displacement plethysmography at 36 weeks postmenstrual age; intraventricular or cerebellar hemorrhage; periventricular leukomalacia; patent ductus arteriosus requiring treatment; necrotizing enterocolitis; chronic lung disase; retinopathy of prematurity; sepsis (early or late onset); serum urea, calcium, phosphate, ammonia concentrations, and evidence for refeeding syndrome (post hoc) at the end of the intervention; length of stay in the neonatal unit
  • Analysis and Sample Size:
    • Assuming an incidence of 50% of infants with neurodisability in the placebo group and a 10% loss to follow up rate, 430 infants (215 per group) were needed to detect a difference of 15 percentage points for the primary outcome using a power of 85% and alpha of 5%
    • An intention to treat analysis was used
    • Linear models were used to compare groups; adjustments were made for stratification factors such as hospital site, sex, and small for gestational age. Linear regression was used to assess continuous variables, and Poisson regression models with a log link were used to compare binary outcomes
  • Patient follow-up: % included in analysis
    • 981 infants were assessed for eligibility, and 499 were found to be eligible. 65 of these infants were excluded due to parental preference, parental denial of consent, death, or randomization error
    • 217 infants were recruited to each group
      • 39 infants in the intervention group and 42 in the placebo group died before 2 years corrected gestational age
    • In the intervention group, 203 infants were included in the primary analysis; 165 infants were assessed at 2 years (93% of surviving patients)
    • In the placebo group, 205 infants were included in the primary analysis; 165 infants were assessed at 2 years (94% of surviving patients)


The intervention and placebo groups were similar for maternal factors (age, socioeconomic status, race/ethnicity, education, antenatal steroid use, diabetes, and cesarean delivery). Infant characteristics were also similar between groups, including gestational age, size at birth (including weight, length, and head circumference), percent small for gestational age, sex, and singleton gestation. 73% percent of infants in each group received at least 80% of the prescribed fluid regimen. Infants in the intervention group received higher parental amino acid intake in the first 7 days of life than the placebo group (intervention: 3.4±0.6 grams/kg/day versus placebo: 2.6±0.6 grams/kg/day).

For the primary outcome, 47.8% of infants in the intervention group and 49.8% in the placebo group survived without neurodisability at 2 years of age, which was not statistically different.

For the secondary outcomes, more infants in the intervention group had moderate to severe neurodisability compared to placebo (16.5% versus 8.6%, respectively, adjusted relative risk 1.95; 95% confidence interval 1.09-3.48), and more infants in the intervention group had moderate to severe cognitive delay compared to placebo (6.9% versus 1.9%, respectively, adjusted relative risk 3.81; 95% confidence interval 1.09-13.31). Infants in the intervention group had a lesser decrease in z scores for weight between birth and 4 weeks than those in the placebo group and thus were heavier at 4 weeks of age (adjusted mean difference 0.13; 95% confidence interval 0.05-0.22). Growth parameters were otherwise similar between groups, and in a preplanned subgroup analysis, small for gestational age status did not impact growth outcomes. Infants in the intervention group were more likely to require treatment for patent ductus arteriosus than placebo (54% versus 42%, respectively, adjusted relative risk 1.3; 95% confidence interval 1.05-1.60). Infants in the intervention group had higher serum urea concentrations (adjusted mean difference 36.6 mg/dl; 95% confidence interval 31.2 to 42.0). Infants in the intervention group had a higher incidence of refeeding syndrome (24.4% versus 15.7% respectively, adjusted relative risk 1.64; 95% confidence interval 1.09 to 2.45), which was defined by serum phosphate and calcium concentrations on day of life 5.


In extremely preterm infants, higher parenteral protein administration in the first 5 days of life did not improve neurodevelopmental outcomes at 2 years of age.


Preterm infants require nutritional support immediately after birth to prevent catabolism and support normal growth, often in the setting of increased energy requirements due to postnatal environmental conditions and critical illness. Observational studies in preterm infants have shown that there is a positive association between protein intake in the first month of life, short term growth outcomes at NICU discharge (1), and long term neurodevelopmental outcomes (2, 3). However, a meta-analysis of randomized controlled trials found that preterm infants with higher intake of parenteral amino acids demonstrated improved postnatal growth but did not show improvement in neurodevelopmental outcomes compared to infants who received lower intake of amino acids (4).

Despite evidence for the benefit of early protein delivery on growth in the preterm infant, there are still many questions about the optimal dosing regimen of parenteral amino acids, including starting dose, maximal intake dose, timing, and speed of increase in delivery. For example, there have been small, randomized controlled trials that have raised concerns for adverse effects from high dose (>3 grams/kg/day) parenteral amino acids advanced rapidly in the first week of life, including smaller head circumference at NICU discharge (5, 6) and reduced growth through the first 2 years of life (7).

In this multi-center, double-blind, randomized control trial, extremely low birth weight infants who received higher parenteral amino acid intake in the first 5 days of life (3.4±0.6 versus 2.6±0.6 grams/kg/day) did not have improved survival without neurodevelopmental impairment at 2 years corrected gestational age. In fact, higher amino acid intake was associated with higher rates of moderate to severe neurodisability compared to neonates who received lower amino acid intake. Although increased protein intake was associated with improved growth in the first month of life, there were no differences in growth at 2 years old.

This study was adequately powered and is the largest study to date to test for differences in neurodevelopmental outcome as a result of amino acid dose in the first week of life. The investigators provided a difference of 0.8 grams/kg of protein between groups, thus isolating its effect over other components of parenteral nutrition. Limitations included that additional amino acids were only administered for 5 days; it is unclear if prolonged supplementation would change outcomes. Outcomes at 2 years old weakly predict outcomes in school aged children. Plasma amino acid concentrations were not reported, but are critical to determine if current pediatric amino acid solutions are adequate for preterm infants.

In summary, increasing parenteral amino acid intake via the UAC for 5 days after birth does not improve neurodevelopmental outcomes or growth at 2 years in preterm infants; higher protein intake may be associated with worse neurodevelopmental outcomes. The European Society for Paediatric Gastroenterology, Hepatology, and Nutrition recommends that preterm infants should not receive more than 3.5 grams/kg/day of parenteral amino acids unless administered in a clinical trial (8). This study supports that recommendation; clinicians should be cautious of excessive parenteral protein administration to preterm infants especially in the first week of life.


  1. Ramel SE, Haapala J, Super J, Boys C, Demerath EW. Nutrition, Illness and Body Composition in Very Low Birth Weight Preterm Infants: Implications for Nutritional Management and Neurocognitive Outcomes. Nutrients 2020; 12(1):145.

  2. Stephens BE, Walden RV, Gargus RA, Tucker R, McKinley L, Mance M, et al. First-week protein and energy intakes are associated with 18-month developmental outcomes in extremely low birth weight infants. Pediatrics 2009; 123(5):1337-1343.

  3. Yang J, Chang SS, Poon WB. Relationship Between Amino Acid and Energy Intake and Long-Term Growth and Neurodevelopmental Outcomes in Very Low Birth Weight Infants. JPEN J Parenter Enteral Nutr 2016; 40(6):820-826.

  4. Osborn DA, Schindler T, Jones LJ, Sinn JK, Bolisetty S. Higher versus lower amino acid intake in parenteral nutrition for newborn infants. Cochrane Database Syst Rev 2018; 3(3).

  5. Uthaya S, Liu X, Babalis D, Doré CJ, Warwick J, Bell J, et al. Nutritional Evaluation and Optimisation in Neonates: a randomized, double-blind controlled trial of amino acid regimen and intravenous lipid composition in preterm parenteral nutrition. Am J Clin Nutr 2016; 103(6):1443-1452.

  6. Balakrishnan M, Jennings A, Przystac L, Phornphutkul C, Tucker R, Vohr B, et al. Growth and Neurodevelopmental Outcomes of Early, High-Dose Parenteral Amino Acid Intake in Very Low Birth Weight Infants: A Randomized Controlled Trial. JPEN J Parenter Enteral Nutr 2018; 42(3):597-606.

  7. Blanco CL, Gong AK, Schoolfield J, Green BK, Daniels W, Liechty EA, et al. Impact of early and high amino acid supplementation on ELBW infants at 2 years. J Pediatr Gastroenterol Nutr 2012; 54(5):601-607.

  8. van Goudoever JB, Carnielli V, Darmaun D, Sainz de Pipaon M. ESPGHAN/ESPEN/ESPR/CSPEN working group on pediatric parenteral nutrition. ESPGHAN/ESPEN/ESPR/CSPEN guidelines on pediatric parenteral nutrition: Amino acids. Clin Nutr 2018; 37(6 Pt B):2315-2323.

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