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

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

The objective of this review was to compare the efficacy and safety of early versus late administration of intravenous AA in neonates born at < 37 weeks of gestation.

We searched CENTRAL, MEDLINE, Embase, and trial registries in March 2023. We checked the reference lists of included studies and studies/systematic reviews where subject matter related to the intervention or population examined in this review.

We included randomised controlled trials (RCTs) comparing early administration of AA with late administration in premature newborn infants. We defined early administration of AA solution as the administration of AA in isolation or with total parenteral nutrition within the first 24 hours of birth, and late administration as the administration of AA in isolation or with total parenteral nutrition after the first 24 hours of birth.

We used standard Cochrane methodological procedures. We used the GRADE approach to assess the certainty of the evidence.

Nine studies (383 participants) were eligible for inclusion in the review. All study participants were born at < 37 weeks of gestation and were inpatients in neonatal intensive care units. No studies reported growth during the first months of life as assessed by difference in weight. Early administration of AA may have little or no effect on growth in the first month of life as measured by length (mean difference (MD) 0.00, 95% confidence interval (CI) -0.41 to 0.41; 1 study; 21 participants; low-certainty evidence) and head circumference (MD 0.05, 95% CI -0.03 to 0.14; 2 studies; 87 participants; low-certainty evidence). No studies reported the discharge weight outcome. Early administration of AA may result in little to no difference in neurodevelopmental outcome assessed by Mental Developmental Index (MDI) of < 70 at two years of age (odds ratio 0.83, 95% CI 0.21 to 3.28; 1 study; 111 participants; low-certainty evidence). No studies reported all-cause mortality at 28 days and before discharge. Early administration of AA may result in a large increase in positive nitrogen balance in the first three days of life (MD 250.42, 95% CI 224.91 to 275.93; 4 studies; 93 participants; low-certainty evidence).

Low-certainty evidence suggests that there may be little to no difference between early and late administration of AA in growth (measured by length and head circumference during the first month after birth) and neurodevelopmental outcome (assessed by MDI of < 70). No RCTs reported on weight in the first month of life, mortality (all-cause mortality at 28 days and before discharge), or discharge weight. Low-certainty evidence suggests a large increase in positive nitrogen balance in preterm infants who received AA within 24 hours of birth. The clinical relevance of this observation is unknown. The number of infants in the RCTs included in the review was small, and there was clinical heterogeneity amongst trials. Adequately powered trials in infants < 37 weeks' gestation are required to determine optimal timing of initiation of AA. We identified two ongoing studies. Both studies will be recruiting infants ≥ 34 weeks of gestation and may or may not add to the outcome data for this review.