Enteral lipid supplements for the prevention and treatment of parenteral nutrition-associated liver disease in infants.

rationaleEnteral lipid formulations may offer benefits according to preclinical studies, but their effectiveness and safety in preventing and treating parenteral nutrition-associated liver disease (PNALD) in infants remains unknown.

objectivesTo evaluate the benefits and harms of enteral lipid supplementation for the prevention and treatment of PNALD in infants. SEARCH

methodsWe searched CENTRAL, MEDLINE, Embase and trial registers, together with reference checking and contact with study authors. The latest search was in December 2024. ELIGIBILITY CRITERIA: We included parallel, randomized control trials (RCTs) in infants comparing enteral lipid supplements with either a placebo or no intervention in infants who were either at risk or who had PNALD. We excluded studies involving infants receiving enteral feeds without the need for parenteral nutrition, as they were neither at risk for PNALD, nor diagnosed with PNALD, and infants with cholestasis secondary to primary liver disease, inborn errors of metabolism, or congenital infection. OUTCOMES: Our primary outcomes were the prevention of PNALD during hospital stay and the first year of life; and resolution of PNALD during hospital stay and the first year of life. Other outcomes included feeding intolerance during the hospital stay, time to full feeds measured in days during the hospital stay, length of hospital stay in days, need for liver transplantation in the first year of life and all-cause mortality up to hospital discharge and in the first year of life. RISK OF BIAS: We used the Cochrane risk of bias 1 (RoB 1) tool to assess bias in the RCTs. SYNTHESIS

methodsWe synthesized results for each outcome using meta-analyses where possible, using random-effect models to calculate risk ratios (RRs) and risk difference (RD) with 95% confidence intervals (CIs) for dichotomous outcomes. For continuous outcomes, we calculated mean differences (MDs). If combining the data was not feasible, we summarized data narratively using Synthesis without Metaanalysis (SWiM). We summarized the certainty of evidence according to GRADE methods. INCLUDED STUDIES: We included 11 studies (2192 infants). A variety of enteral lipids were used as interventions, including algal oil, fungal oil, and fish oil, either alone or in combination. The intervention groups received: - Fish oil alone or in combination with other oils (three studies; n = 1328); - Algal oil alone or in combination with other oils (eight studies; n = 864). The comparison groups received either no intervention or other oils, such as sunflower oil, safflower oil, olive oil, or medium-chain triglyceride (MCT) oil. Most studies included preterm infants who received enteral lipid supplements while primarily on parenteral nutrition and minimal enteral nutrition, thus being considered at risk for PNALD. No studies examined enteral lipid supplementation in infants with established PNALD. SYNTHESIS OF

resultsAny enteral lipids compared to placebo or no treatment in infants at risk or with PNALD Enteral lipids may have little to no effect on the prevention of PNALD as measured by incidence of cholestasis during the hospital stay and in the first year of life; however, the evidence is very uncertain (RR 0.65, 95% CI 0.13 to 3.14; 3 studies, 265 participants; very low-certainty evidence). Enteral lipids may have little to no effect on feeding intolerance, but the evidence is very uncertain (RR 0.14, 95% CI 0.02 to 1.12; 4 studies, 236 participants; very low-certainty evidence). The evidence suggests that enteral lipids result in little to no difference in time taken to achieve full enteral feeds, but the evidence is very uncertain (MD -1.10, 95% CI -2.98 to 0.78; 1 study, 1273 participants; very low-certainty evidence). Enteral lipid supplementation may decrease the length of hospital stay, but the evidence is very uncertain (MD -3.44, 95% CI -6.20 to -0.68; I² not applicable; 1 study, 67 participants; very low-certainty evidence). Enteral lipids may have little to no effect on mortality up to discharge and the first year of life, but the evidence is very uncertain (RR 1.19, 95% CI 0.90 to 1.57; I² = 0%; 11 studies, 2200 participants; very low-certainty evidence). No studies reported on the resolution of PNALD during the hospital stay and in the first year of life, or the need for liver transplantation. Limitations of evidence: a wide variety of enteral lipids in both intervention and control groups made it challenging to make comparisons between the studies. Overall, the risk of selection bias was unclear to high and the certainty of evidence very low. The certainty of evidence was downgraded due to several methodological limitations, including risk of bias (allocation, blinding, and performance/detection issues), indirectness from the exclusion of high-risk infants, inconsistency in outcome definitions, and imprecision from small samples and wide confidence intervals. Incomplete reporting across studies also raised concerns about publication bias. AUTHORS'

conclusionsThe evidence is very uncertain about the effect of enteral lipids on the prevention of PNALD during the hospital stay and in the first year of life. There may be little to no difference in feeding intolerance or time to achieve full enteral feeds. They may decrease the length of stay and likely do not reduce or increase mortality up to discharge or during the first year of life in infants at risk for PNALD. Due to small samples, inconsistency, and risk of bias, the available data are of very low certainty, and so we are not able to draw conclusions about the effects of enteral lipids in infants who are at risk of PNALD. No studies evaluated resolution of PNALD during the hospital stay and in the first year of life, or the need for liver transplantation. Well-designed studies are needed to evaluate the short-term and long-term effects of different enteral lipids in infants who are at risk for PNALD or have PNALD. Future studies should focus on addressing the heterogeneity of enteral lipid preparations and the inconsistency in assessment of outcomes.

fundingThis Cochrane Review had no dedicated funding. REGISTRATION: Protocol (2021) DOI: 10.1002/14651858.CD014353.