Review question: which lipid (fat) emulsions (LE) have the best outcomes in preterm infants with and without liver disease and surgical conditions?
Background: preterm infants who need nutrition (feeding) through intravenous (into a vein; called parenteral nutrition) lines have been conventionally given pure soybean oil-based fat emulsions. However, high polyunsaturated fatty acid (PUFA) content and phytosterols in pure soybean oil-based emulsions may be harmful and contribute to parenteral nutrition-associated liver disease (PNALD). The newer lipid emulsions (LE) from alternative lipid sources, including fish oil, may potentially improve clinical outcomes in preterm infants by decreasing PUFA content and providing lipid source-specific benefits.
Study characteristics: we searched the medical literature and identified 29 studies (including 2037 preterm infants). The evidence is up to date as of 18 June 2018.
Key findings: in the population of preterm infants, without liver disease or surgical conditions, no particular LE was better than another for growth, liver disease, death, retinopathy (eye disease), infection and chronic lung disease.
While there was very low quality and limited evidence to suggest that fish oil-based LE may improve liver disease-related outcomes in infants with pre-existing liver disease, this evidence was based on a limited number of infants from two small studies, one of which was terminated early, and no certain conclusions can be drawn.
Conclusions: based on this review, no particular LE is better than another for intravenous nutrition in preterm infants. There currently exists insufficient evidence from well-designed studies about the benefit of fish oil-LE for improving liver disease-related outcomes in infants with pre-existing liver disease or surgical conditions. Further research is required to establish the role of fish oil-LE for liver disease outcomes in preterm infants and the ideal composition of LE for preterm infants.
In the current review, we did not find any particular LE with or without fish oil to be better than another LE in preterm infants for prevention of PNALD/cholestasis, growth, mortality, ROP, BPD and other neonatal outcomes.
In preterm infants with surgical conditions or cholestasis, there is currently insufficient evidence from randomised studies to determine with any certainty if fish oil LEs offer advantage in prevention or resolution of cholestasis or in any other clinical outcome.
Further research, with larger well-designed trials, is warranted to evaluate the ideal composition of LE in preterm infants and the role of fish oil-containing and other LEs in the prevention and resolution of PNALD, ROP and other clinical outcomes.
Conventionally used soybean oil-based lipid emulsion (S-LE) have high polyunsaturated fatty acid (PUFA) content and phytosterols that may contribute to adverse effects in preterm infants. The newer lipid emulsions (LE) from different lipid sources are currently available for use in preterm infants.
To compare the safety and efficacy of all LE for parenteral nutrition (PN) in preterm infants (less than 37 weeks' gestation) including preterm infants with surgical conditions or parenteral nutrition-associated liver disease (PNALD)/cholestasis using direct comparisons and pair-wise meta-analyses.
We used the standard search strategy of Cochrane Neonatal to search the Cochrane Central Register of Controlled Trials (CENTRAL 2018, Issue 5), MEDLINE (1946 to 18 June 2018), Embase (1974 to 18 July 2018), CINAHL (1982 to 18 June 2018), MIDRIS (1971 to 31 May 2018), conference proceedings, trial registries (ClinicalTrials.gov and WHO's Trials Registry and Platform), and reference lists of retrieved articles.
Randomised or quasi-randomised controlled studies in preterm infants with or without surgical conditions or PNALD within the first six months of life.
Data collection and analysis conformed to the methods of Cochrane Neonatal. We used the GRADE approach to assess the quality of evidence for important outcomes in addition to reporting statistical significance of results.
We included 29 studies (n = 2037) in this review. LE were classified in three broad groups: 1. all fish oil-containing LE including pure fish oil-LE (F-LE) and multisource LE (e.g. medium-chain triglycerides (MCT)-olive-fish-soybean oil-LE (MOFS-LE), MCT-fish-soybean oil-LE (MFS-LE) and olive-fish-soybean oil-LE (OFS-LE); 2. conventional S-LE; 3. alternative-LE (e.g. MCT-soybean oil-LE (MS-LE), olive-soybean oil-LE and borage oil-based LE).
We considered the following broad comparisons: fish oil LE versus non-fish oil LE; fish oil LE versus another fish oil LE; alternative-LE versus S-LE; alternative-LE versus another alternative-LE in preterm infants less than 37 weeks' gestation, preterm infants with surgical conditions and preterm infants with PNALD/cholestasis. Separate subgroup comparisons of each LE preparation were included within these broader groups.
Most studies in preterm infants used PN for mean duration of four weeks or less and for longer duration in infants with cholestasis or surgical conditions.
We defined the primary outcome of PNALD/cholestasis as conjugated bilirubin (Cbil) 2 mg/dL or greater and resolution of PNALD/cholestasis as Cbil less than 2 mg/dL. There was heterogeneity in definitions used by the included studies with Cbil cut-offs ranging from 17.1 μmol/L (1 mg/dL) up to 50 μmol/L (about 3 mg/dL).
In preterm infants, meta-analysis found no evidence of a difference in the incidence of PNALD/cholestasis (Cbil cut-off: 2 mg/dl) between fish oil-LEs and all non-fish oil LEs (typical risk ratio (RR) 0.61, 95% confidence interval (CI) 0.24 to 1.56; typical risk difference (RD) –0.03, 95% CI –0.08 to 0.02; 4 studies; n = 328; low-quality evidence).
We also considered an outcome allowing for any definition of PNALD (different Cbil cutoffs). In the meta-analysis for PNALD/cholestasis, using any definition and restricted to low or unclear risk of bias studies, there was no evidence of a difference between fish oil LE and all non-fish oil LE for incidence of cholestasis (typical RR 0.80, 95% CI 0.53 to 1.21; typical RD –0.02, 95% CI –0.05 to 0.02; 10 studies; n = 1024; low-quality evidence). There was no evidence of difference in subgroup meta-analyses of individual LE types in any comparison.
In preterm infants with surgical conditions or cholestasis, there was only one small study each reporting no evidence of a difference in incidence or resolution of cholestasis respectively with use of a pure F-LE versus S-LE (using a Cbil cut-off of 2 mg/dL).
In preterm infants with PNALD/cholestasis (using any definition), the meta-analysis showed significantly less cholestasis with the use of fish oil-LE compared to S-LE (typical RR 0.54, 95% CI 0.32 to 0.91; typical RD –0.39, 95% CI –0.65 to –0.12; number needed to treat for an additional beneficial outcome (NNTB) 3, 95% CI 2 to 9; 2 studies; n = 40; very low-quality evidence). However, this outcome had a very low number of participants from two small studies with methodological differences, one of which was terminated early, increasing the uncertainty about effect estimates.
There were no differences between LE types in pair-wise meta-analyses for growth in preterm infants. There was paucity of studies in preterm infants with surgical conditions or cholestasis to perform meta-analyses for growth and most other outcomes.
In the secondary outcomes for preterm infants, there was no difference between fish-oil LE and non-fish oil LE in meta-analysis for severe retinopathy of prematurity (ROP) (stage 3 or greater, or requiring surgery: typical RR 0.80, 95% CI 0.55 to 1.16; typical RD –0.03, 95% CI –0.07 to 0.02; 7 studies; n = 731; very low-quality evidence). There were no differences in the LE types in pair-wise meta-analyses for death, bronchopulmonary dysplasia (BPD), ventilation duration, patent ductus arteriosus, sepsis, necrotising enterocolitis, intraventricular haemorrhage, periventricular leukomalacia, jaundice, hyperglycaemia, hypertriglyceridaemia, intrahepatocellular lipid content and conjugated bilirubin levels in any comparison.
In surgical infants, one study (n = 19) reported no differences in death, sepsis rates, Cbil and neurodevelopmental outcomes with pure F-LE versus S-LE.
In infants with cholestasis, there were no evidence of differences in death or sepsis in meta-analyses between fish oil-LE and S-LE; (2 studies; n = 40; very low-quality evidence).