Early versus late administration of amino acids in preterm infants receiving parenteral nutrition

Cochrane Database Syst Rev. 2013 Jul 23;(7):CD008771. doi: 10.1002/14651858.CD008771.pub2.


Background: Observational studies in preterm newborns suggest that delay in administering amino acids could result in a protein catabolic state and could impact on growth and development.

Objectives: To determine the effect of early administration of amino acids in premature newborns on growth, neurodevelopmental outcome, mortality and clinically important side effects.

Search methods: The standard search strategy of the Neonatal Review Group as outlined in The Cochrane Library was used. Relevant randomised controlled trials were identified by searching the Cochrane Central Register of Controlled Trials (CENTRAL, The Cochrane Library 2012 I ssue 9 ), MEDLINE, EMBASE and CINAHL from their earliest dates to September 2012. The trial registry portal of the World Health Organization's International Cilinical Trial Registry Platform and ClinicalTrials.gov (US National Institute of Health) was searched to identify ongoing and completed but unpublished studies.

Selection criteria: Randomised controlled trials comparing early administration of amino acids with late administration in premature newborn infants were included. Early administration of amino acid solution was defined as the administration of amino acids in isolation or with total parenteral nutrition within the first 24 hours of birth; late initiation was defined as the administration of amino acids in isolation or with total parenteral nutrition after the first 24 hours of birth. The primary outcome measures were growth, neurodevelopmental outcome and mortality at 28 days. The secondary outcomes were biochemical abnormalities, sepsis and mortality.

Data collection and analysis: Both review authors independently selected trials, assessed trial quality and extracted data from the included studies. We contacted authors for further information. Fixed-effect analyses were performed. The treatment effect was expressed as mean difference for continuous variables and as risk difference and risk ratio for dichotomous variables. All results included 95% confidence intervals (CIs).

Main results: Seven randomised controlled trials were included in this review. One randomised controlled trial reported no difference in crown-heel length and occipitofrontal head circumference by day 10. Four trials that enrolled 93 premature infants showed positive nitrogen balance (The mean difference with 95% CI was 250.42 (224.91 to 275.93 P value < 0.00001). Four trials showed a significant difference in the level of blood urea nitrogen (BUN) in the first 48 hours (P value < 0.00001). Early administration of amino acids did not result in metabolic acidosis in the first 24 hours.

Authors' conclusions: There is no available evidence of the benefits of early administration of amino acids on mortality, early and late growth and neurodevelopment. There is evidence from four randomised controlled trials included in this review that early administration of amino acids is associated with a positive nitrogen balance. The clinical relevance of this finding is not known. Acid-base status and ammonia levels were normal in the infants who received amino acids early. Given the small number of infants in the randomised controlled trials included in this review, the clinical heterogeneity among them, and the lack of data on important clinical outcomes, there is insufficient evidence to guide practice regarding the early versus late administration of amino acids to infants less than 37 weeks gestation.

Publication types

  • Meta-Analysis
  • Research Support, N.I.H., Extramural
  • Review
  • Systematic Review

MeSH terms

  • Amino Acids / administration & dosage*
  • Blood Urea Nitrogen
  • Cephalometry
  • Drug Administration Schedule
  • Humans
  • Infant, Newborn
  • Infant, Premature / blood
  • Infant, Premature / growth & development*
  • Nitrogen / metabolism
  • Parenteral Nutrition*
  • Randomized Controlled Trials as Topic
  • Time Factors


  • Amino Acids
  • Nitrogen