Adding arginine to prevent necrotising enterocolitis in preterm infants

What is the issue? Necrotising enterocolitis (NEC) is a condition in which inflammation damages an infant's gastrointestinal (GI) tract. The rate of NEC ranges from 4% to 22% in very low birth weight infants. Necrotising enterocolitis may be caused by an infant's immaturity, lack of blood flow to the GI tract and surface (mucosa) breakdown resulting from infection or feeding with formula. To protect the GI tract, the body makes a natural substance - nitric oxide - from the amino acid arginine. Plasma arginine concentrations are reported to be low in very low birth weight infants and preterm infants who develop NEC. Adding extra arginine to the feeding solution may prevent NEC.

Why is this important? NEC can result in permanent damage to the intestine, the need for multiple surgeries, prolonged hospital stay, death and increased cost to the healthcare system.

What evidence did we find? Review authors searched the literature for controlled studies evaluating the efficacy and safety of arginine supplementation. Adding extra arginine to a preterm infant's feed reduced the risk of NEC in three good quality studies that included 285 infants born at less than 34 weeks' gestation. Six infants had to be treated, for one to benefit from treatment. Researchers reported no significant side effects directly attributable to too much arginine in the first 28 days, and one study reported no long-term (36 months) developmental delays. Possible effects of supplementing arginine include lower blood pressure and changes in blood glucose control.

What does this mean? Arginine supplementation may reduce the incidence and severity of NEC in preterm infants. Results are limited, as studies included only a few patients. A large study that includes infants from multiple centres is needed to verify these findings.

Authors' conclusions: 

Administration of arginine to preterm infants may prevent development of NEC. Because information was provided by three small trials that included 285 participants, the data are insufficient at present to support a practice recommendation. A multi-centre randomised controlled study that is focused on the incidence of NEC, particularly at more severe stages (2 and 3), is needed.

Read the full abstract...

Decreased concentration of nitric oxide has been proposed as one of the possible cellular mechanisms of necrotising enterocolitis (NEC). Arginine can act as a substrate for production of nitric oxide in the tissues, and arginine supplementation may help to prevent NEC.


To examine the effect of arginine supplementation (administered by any route) on the incidence of NEC in preterm neonates. To conduct subgroup analyses based on the dose of arginine and the gestational age of participants (≤ 32 weeks, > 32 weeks).

Search strategy: 

We used the standard search strategy of the Cochrane Neonatal Review Group to search the Cochrane Central Register of Controlled Trials (CENTRAL; 2016, Issue 4), MEDLINE via PubMed (from 1966 to 12 May 2016), Embase (from 1980 to 12 May 2016) and the Cumulative Index to Nursing and Allied Health Literature (CINAHL; from 1982 to 12 May 2016). We also searched clinical trials databases, conference proceedings and reference lists of retrieved articles for randomised controlled trials and quasi-randomised trials.

Selection criteria: 

Randomised and quasi-randomised controlled trials of arginine supplementation (administered orally or parenterally for at least seven days, in addition to what an infant may be receiving from an enteral or parenteral source) compared with placebo or no treatment.

Data collection and analysis: 

We assessed the methodological quality of trials by using information obtained from study reports and through personal communication with study authors. We extracted data on relevant outcomes and estimated and reported the effect size as risk ratio (RR), risk difference (RD) and mean difference (MD), as appropriate. We used the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach to assess the quality of evidence.

Main results: 

We identified three eligible studies that included a total of 285 neonates (140 received arginine) from three countries. We assessed the overall methodological quality of the included studies as good. We noted a statistically significant reduction in risk of development of NEC (any stage) among preterm neonates in the arginine group compared with the placebo group (RR 0.38, 95% confidence interval (CI) 0.23 to 0.64; I2 = 27%) (RD -0.19, 95% CI -0.28 to -0.10; I2 = 0%) and rated the quality of evidence as moderate. The number needed to treat for an additional beneficial outcome (NNTB) as required to prevent the development of NEC (any stage) was 6 (95% CI 4 to 10). Study results showed a statistically significant reduction in risk of development of NEC stage 1 (RR 0.37, 95% CI 0.15 to 0.90; I2 = 52%) (RD -0.07, 95% CI -0.14 to -0.01; I2 = 0%) and NEC stage 3 (RR 0.13, 95% CI 0.02 to 1.03; I2 = 0%) (RD -0.05, 95% CI -0.09 to -0.01; I2 = 89%) in the arginine group compared with the control group; the quality of evidence was moderate.

Arginine supplementation was associated with a significant reduction in death related to NEC (RR 0.18, 95% CI 0.03 to 1.00; I2 = 0%) (RD -0.05, 95% CI -0.09 to -0.01; I2 = 87%). Results showed clinical heterogeneity in mortality rates. Mortality due to any cause was not significantly different between arginine and control or no treatment groups (RR 0.77, 95% CI 0.41 to 1.45; I2 = 42%) (RD -0.03, 95% CI -0.10 to 0.04; I2 = 79%). Investigators noted no significant side effects directly attributable to arginine, including hypotension or alterations in glucose homeostasis. Follow-up data from one trial revealed no statistically significant differences in adverse outcomes (cerebral palsy, cognitive delay, bilateral blindness or hearing loss requiring hearing aids) at 36 months. Limitations of the present findings include a relatively small overall sample size.