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Meta-Analysis
. 2019 Jun 4;6(6):CD013163.
doi: 10.1002/14651858.CD013163.pub2.

Lipid emulsions for parenterally fed preterm infants

Vishal Kapoor  1 , Manoj N Malviya, Roger Soll
Affiliations
Meta-Analysis

Lipid emulsions for parenterally fed preterm infants

Vishal Kapoor et al. Cochrane Database Syst Rev. .

Abstract

Background: 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.

Objectives: 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.

Search methods: 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.

Selection criteria: 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: 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.

Main 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).

Authors' conclusions: 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.

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Conflict of interest statement

VK: none.

MM: none.

RS: none.

Figures

1
1
PRISMA flow diagram.
2
2
Risk of bias summary: review authors' judgements about each risk of bias item for each included study.
3
3
Forest plot of comparison: 1 Fish oil lipid emulsion (LE) versus non‐fish oil LE, outcome: 1.4 Parenteral nutrition‐associated liver disease (PNALD)/cholestasis (conjugated bilirubin ≥ 2 mg/dL): combined subgroups.
4
4
Forest plot of comparison: 1 Fish oil lipid emulsion (LE) versus non‐fish oil LE, outcome: 1.6 Parenteral nutrition‐associated liver disease (PNALD)/cholestasis (any definition): analysis stratified by low and unclear risk of bias studies versus high risk of bias studies (risk ratios).
5
5
Funnel plot of comparison: 1 Fish oil lipid emulsion (LE) versus non‐fish oil LE, outcome: 1.5 Parenteral nutrition‐associated liver disease (PNALD)/cholestasis (any definition).
6
6
Forest plot of comparison: 1 Fish oil lipid emulsion (LE) versus non‐fish oil LE, outcome: 1.31 Conjugated bilirubin levels (µmol/L): all subgroups combined.
7
7
Forest plot of comparison: 3 Alternative lipid emulsion (LE) versus S‐LE, outcome: 3.6 Parenteral nutrition‐associated liver disease (PNALD)/cholestasis (any definition): all subgroups combined.
8
8
Forest plot of comparison: 1 Fish oil lipid emulsion (LE) versus non‐fish oil LE, outcome: 1.6 Parenteral nutrition‐associated liver disease (PNALD)/cholestasis (any definition): analysis stratified by low and unclear risk of bias studies versus high risk of bias studies (risk differences).
1.1
1.1. Analysis
Comparison 1 Fish oil lipid emulsion (LE) versus non‐fish oil LE (see Appendix 3), Outcome 1 Days to regain birth weight.
1.2
1.2. Analysis
Comparison 1 Fish oil lipid emulsion (LE) versus non‐fish oil LE (see Appendix 3), Outcome 2 Growth rate (g/kg/day).
1.3
1.3. Analysis
Comparison 1 Fish oil lipid emulsion (LE) versus non‐fish oil LE (see Appendix 3), Outcome 3 Parenteral nutrition‐associated liver disease (PNALD)/cholestasis (conjugated bilirubin ≥ 2 mg/dL).
1.4
1.4. Analysis
Comparison 1 Fish oil lipid emulsion (LE) versus non‐fish oil LE (see Appendix 3), Outcome 4 PNALD/cholestasis (conjugated bilirubin ≥ 2 mg/dL): combined subgroups.
1.5
1.5. Analysis
Comparison 1 Fish oil lipid emulsion (LE) versus non‐fish oil LE (see Appendix 3), Outcome 5 PNALD/cholestasis (any definition).
1.6
1.6. Analysis
Comparison 1 Fish oil lipid emulsion (LE) versus non‐fish oil LE (see Appendix 3), Outcome 6 PNALD/cholestasis (any definition): combined subgroups (all studies) and sensitivity analysis.
1.7
1.7. Analysis
Comparison 1 Fish oil lipid emulsion (LE) versus non‐fish oil LE (see Appendix 3), Outcome 7 Death before discharge.
1.8
1.8. Analysis
Comparison 1 Fish oil lipid emulsion (LE) versus non‐fish oil LE (see Appendix 3), Outcome 8 Any ROP.
1.9
1.9. Analysis
Comparison 1 Fish oil lipid emulsion (LE) versus non‐fish oil LE (see Appendix 3), Outcome 9 Retinopathy of prematurity (ROP) (≥ stage 3) or requiring surgery.
1.10
1.10. Analysis
Comparison 1 Fish oil lipid emulsion (LE) versus non‐fish oil LE (see Appendix 3), Outcome 10 ROP (≥ stage 3) or requiring surgery (sensitivity analysis).
1.11
1.11. Analysis
Comparison 1 Fish oil lipid emulsion (LE) versus non‐fish oil LE (see Appendix 3), Outcome 11 Any bronchopulmonary dysplasia (BPD).
1.12
1.12. Analysis
Comparison 1 Fish oil lipid emulsion (LE) versus non‐fish oil LE (see Appendix 3), Outcome 12 Chronic lung disease (oxygen requirement at 36 weeks).
1.13
1.13. Analysis
Comparison 1 Fish oil lipid emulsion (LE) versus non‐fish oil LE (see Appendix 3), Outcome 13 Duration of ventilation (days).
1.14
1.14. Analysis
Comparison 1 Fish oil lipid emulsion (LE) versus non‐fish oil LE (see Appendix 3), Outcome 14 Duration of supplemental oxygen (days).
1.15
1.15. Analysis
Comparison 1 Fish oil lipid emulsion (LE) versus non‐fish oil LE (see Appendix 3), Outcome 15 Duration of hospital stay (days).
1.16
1.16. Analysis
Comparison 1 Fish oil lipid emulsion (LE) versus non‐fish oil LE (see Appendix 3), Outcome 16 Culture‐positive sepsis.
1.17
1.17. Analysis
Comparison 1 Fish oil lipid emulsion (LE) versus non‐fish oil LE (see Appendix 3), Outcome 17 Any sepsis (clinical or culture positive (or both)).
1.18
1.18. Analysis
Comparison 1 Fish oil lipid emulsion (LE) versus non‐fish oil LE (see Appendix 3), Outcome 18 Necrotising enterocolitis (≥ stage 2).
1.19
1.19. Analysis
Comparison 1 Fish oil lipid emulsion (LE) versus non‐fish oil LE (see Appendix 3), Outcome 19 Intraventricular haemorrhage (grade III‐IV).
1.20
1.20. Analysis
Comparison 1 Fish oil lipid emulsion (LE) versus non‐fish oil LE (see Appendix 3), Outcome 20 Periventricular leukomalacia.
1.21
1.21. Analysis
Comparison 1 Fish oil lipid emulsion (LE) versus non‐fish oil LE (see Appendix 3), Outcome 21 Any patent ductus arteriosus.
1.22
1.22. Analysis
Comparison 1 Fish oil lipid emulsion (LE) versus non‐fish oil LE (see Appendix 3), Outcome 22 Significant patent ductus arteriosus requiring treatment.
1.23
1.23. Analysis
Comparison 1 Fish oil lipid emulsion (LE) versus non‐fish oil LE (see Appendix 3), Outcome 23 Duration of phototherapy (days).
1.24
1.24. Analysis
Comparison 1 Fish oil lipid emulsion (LE) versus non‐fish oil LE (see Appendix 3), Outcome 24 Hypertriglyceridaemia.
1.25
1.25. Analysis
Comparison 1 Fish oil lipid emulsion (LE) versus non‐fish oil LE (see Appendix 3), Outcome 25 Hyperglycaemia.
1.26
1.26. Analysis
Comparison 1 Fish oil lipid emulsion (LE) versus non‐fish oil LE (see Appendix 3), Outcome 26 Hypoglycaemia.
1.27
1.27. Analysis
Comparison 1 Fish oil lipid emulsion (LE) versus non‐fish oil LE (see Appendix 3), Outcome 27 Head growth velocity (cm/week).
1.28
1.28. Analysis
Comparison 1 Fish oil lipid emulsion (LE) versus non‐fish oil LE (see Appendix 3), Outcome 28 Length velocity (cm/week).
1.29
1.29. Analysis
Comparison 1 Fish oil lipid emulsion (LE) versus non‐fish oil LE (see Appendix 3), Outcome 29 Intrahepatocellular lipid.
1.30
1.30. Analysis
Comparison 1 Fish oil lipid emulsion (LE) versus non‐fish oil LE (see Appendix 3), Outcome 30 Non‐adipose tissue mass.
1.31
1.31. Analysis
Comparison 1 Fish oil lipid emulsion (LE) versus non‐fish oil LE (see Appendix 3), Outcome 31 Conjugated bilirubin levels (µmol/L).
2.1
2.1. Analysis
Comparison 2 Fish oil lipid emulsion (LE) vs another fish oil LE (see Appendix 3), Outcome 1 Days to regain birth weight.
2.2
2.2. Analysis
Comparison 2 Fish oil lipid emulsion (LE) vs another fish oil LE (see Appendix 3), Outcome 2 Growth rate (g/kg/day).
2.3
2.3. Analysis
Comparison 2 Fish oil lipid emulsion (LE) vs another fish oil LE (see Appendix 3), Outcome 3 Parenteral nutrition‐associated liver disease (PNALD)/cholestasis (conjugated bilirubin ≥ 2 mg/dL).
2.4
2.4. Analysis
Comparison 2 Fish oil lipid emulsion (LE) vs another fish oil LE (see Appendix 3), Outcome 4 PNALD/cholestasis (any definition).
2.5
2.5. Analysis
Comparison 2 Fish oil lipid emulsion (LE) vs another fish oil LE (see Appendix 3), Outcome 5 Death before discharge.
2.6
2.6. Analysis
Comparison 2 Fish oil lipid emulsion (LE) vs another fish oil LE (see Appendix 3), Outcome 6 Chronic lung disease (oxygen requirement at 36 weeks).
2.7
2.7. Analysis
Comparison 2 Fish oil lipid emulsion (LE) vs another fish oil LE (see Appendix 3), Outcome 7 Any sepsis (clinical or culture positive (or both)).
2.8
2.8. Analysis
Comparison 2 Fish oil lipid emulsion (LE) vs another fish oil LE (see Appendix 3), Outcome 8 Necrotising enterocolitis (≥ stage 2).
2.9
2.9. Analysis
Comparison 2 Fish oil lipid emulsion (LE) vs another fish oil LE (see Appendix 3), Outcome 9 Any patent ductus arteriosus.
2.10
2.10. Analysis
Comparison 2 Fish oil lipid emulsion (LE) vs another fish oil LE (see Appendix 3), Outcome 10 Conjugated bilirubin levels (µmol/L).
3.1
3.1. Analysis
Comparison 3 Alternative lipid emulsion (LE) versus soybean oil‐based lipid emulsion (S‐LE) (see Appendix 3), Outcome 1 Days to regain birth weight.
3.2
3.2. Analysis
Comparison 3 Alternative lipid emulsion (LE) versus soybean oil‐based lipid emulsion (S‐LE) (see Appendix 3), Outcome 2 Growth rate (g/kg/day).
3.3
3.3. Analysis
Comparison 3 Alternative lipid emulsion (LE) versus soybean oil‐based lipid emulsion (S‐LE) (see Appendix 3), Outcome 3 Parenteral nutrition‐associated liver disease (PNALD)/cholestasis (conjugated bilirubin ≥ 2 mg/dL).
3.4
3.4. Analysis
Comparison 3 Alternative lipid emulsion (LE) versus soybean oil‐based lipid emulsion (S‐LE) (see Appendix 3), Outcome 4 PNALD/cholestasis (conjugated bilirubin ≥ 2 mg/dL): Combined subgroups.
3.5
3.5. Analysis
Comparison 3 Alternative lipid emulsion (LE) versus soybean oil‐based lipid emulsion (S‐LE) (see Appendix 3), Outcome 5 PNALD/cholestasis (any definition).
3.6
3.6. Analysis
Comparison 3 Alternative lipid emulsion (LE) versus soybean oil‐based lipid emulsion (S‐LE) (see Appendix 3), Outcome 6 PNALD/cholestasis (any definition): Combined subgroups.
3.7
3.7. Analysis
Comparison 3 Alternative lipid emulsion (LE) versus soybean oil‐based lipid emulsion (S‐LE) (see Appendix 3), Outcome 7 Death before discharge.
3.8
3.8. Analysis
Comparison 3 Alternative lipid emulsion (LE) versus soybean oil‐based lipid emulsion (S‐LE) (see Appendix 3), Outcome 8 Any retinopathy of prematurity.
3.9
3.9. Analysis
Comparison 3 Alternative lipid emulsion (LE) versus soybean oil‐based lipid emulsion (S‐LE) (see Appendix 3), Outcome 9 Any bronchopulmonary dysplasia.
3.10
3.10. Analysis
Comparison 3 Alternative lipid emulsion (LE) versus soybean oil‐based lipid emulsion (S‐LE) (see Appendix 3), Outcome 10 Chronic lung disease (oxygen requirement at 36 weeks).
3.11
3.11. Analysis
Comparison 3 Alternative lipid emulsion (LE) versus soybean oil‐based lipid emulsion (S‐LE) (see Appendix 3), Outcome 11 Duration of ventilation (days).
3.12
3.12. Analysis
Comparison 3 Alternative lipid emulsion (LE) versus soybean oil‐based lipid emulsion (S‐LE) (see Appendix 3), Outcome 12 Duration of supplemental oxygen (days).
3.13
3.13. Analysis
Comparison 3 Alternative lipid emulsion (LE) versus soybean oil‐based lipid emulsion (S‐LE) (see Appendix 3), Outcome 13 Duration of hospital stay (days).
3.14
3.14. Analysis
Comparison 3 Alternative lipid emulsion (LE) versus soybean oil‐based lipid emulsion (S‐LE) (see Appendix 3), Outcome 14 Need for home oxygen therapy.
3.15
3.15. Analysis
Comparison 3 Alternative lipid emulsion (LE) versus soybean oil‐based lipid emulsion (S‐LE) (see Appendix 3), Outcome 15 Any sepsis (clinical or culture positive (or both)).
3.16
3.16. Analysis
Comparison 3 Alternative lipid emulsion (LE) versus soybean oil‐based lipid emulsion (S‐LE) (see Appendix 3), Outcome 16 Culture‐positive sepsis.
3.17
3.17. Analysis
Comparison 3 Alternative lipid emulsion (LE) versus soybean oil‐based lipid emulsion (S‐LE) (see Appendix 3), Outcome 17 Necrotising enterocolitis (≥ stage 2).
3.18
3.18. Analysis
Comparison 3 Alternative lipid emulsion (LE) versus soybean oil‐based lipid emulsion (S‐LE) (see Appendix 3), Outcome 18 Intraventricular haemorrhage (grade III‐IV).
3.19
3.19. Analysis
Comparison 3 Alternative lipid emulsion (LE) versus soybean oil‐based lipid emulsion (S‐LE) (see Appendix 3), Outcome 19 Periventricular leukomalacia.
3.20
3.20. Analysis
Comparison 3 Alternative lipid emulsion (LE) versus soybean oil‐based lipid emulsion (S‐LE) (see Appendix 3), Outcome 20 Any patent ductus arteriosus.
3.21
3.21. Analysis
Comparison 3 Alternative lipid emulsion (LE) versus soybean oil‐based lipid emulsion (S‐LE) (see Appendix 3), Outcome 21 Air leaks.
3.22
3.22. Analysis
Comparison 3 Alternative lipid emulsion (LE) versus soybean oil‐based lipid emulsion (S‐LE) (see Appendix 3), Outcome 22 Significant jaundice requiring treatment.
3.23
3.23. Analysis
Comparison 3 Alternative lipid emulsion (LE) versus soybean oil‐based lipid emulsion (S‐LE) (see Appendix 3), Outcome 23 Duration of phototherapy (days).
3.24
3.24. Analysis
Comparison 3 Alternative lipid emulsion (LE) versus soybean oil‐based lipid emulsion (S‐LE) (see Appendix 3), Outcome 24 Hypertriglyceridaemia.
3.25
3.25. Analysis
Comparison 3 Alternative lipid emulsion (LE) versus soybean oil‐based lipid emulsion (S‐LE) (see Appendix 3), Outcome 25 Hyperglycaemia.
3.26
3.26. Analysis
Comparison 3 Alternative lipid emulsion (LE) versus soybean oil‐based lipid emulsion (S‐LE) (see Appendix 3), Outcome 26 Head growth velocity (cm/week).
3.27
3.27. Analysis
Comparison 3 Alternative lipid emulsion (LE) versus soybean oil‐based lipid emulsion (S‐LE) (see Appendix 3), Outcome 27 Conjugated bilirubin levels (µmol/L).
4.1
4.1. Analysis
Comparison 4 Alternative lipid emulsion (LE) vs another alternative‐LE (see Appendix 3), Outcome 1 Days to regain birth weight.
4.2
4.2. Analysis
Comparison 4 Alternative lipid emulsion (LE) vs another alternative‐LE (see Appendix 3), Outcome 2 Growth rate (g/kg/day).
4.3
4.3. Analysis
Comparison 4 Alternative lipid emulsion (LE) vs another alternative‐LE (see Appendix 3), Outcome 3 Parenteral nutrition‐associated liver disease (PNALD)/cholestasis (conjugated bilirubin ≥ 2 mg/dL).
4.4
4.4. Analysis
Comparison 4 Alternative lipid emulsion (LE) vs another alternative‐LE (see Appendix 3), Outcome 4 PNALD/cholestasis (any definition).
4.5
4.5. Analysis
Comparison 4 Alternative lipid emulsion (LE) vs another alternative‐LE (see Appendix 3), Outcome 5 Death before discharge.
4.6
4.6. Analysis
Comparison 4 Alternative lipid emulsion (LE) vs another alternative‐LE (see Appendix 3), Outcome 6 Chronic lung disease (oxygen requirement at 36 weeks).
4.7
4.7. Analysis
Comparison 4 Alternative lipid emulsion (LE) vs another alternative‐LE (see Appendix 3), Outcome 7 Any sepsis (clinical or culture positive (or both)).
4.8
4.8. Analysis
Comparison 4 Alternative lipid emulsion (LE) vs another alternative‐LE (see Appendix 3), Outcome 8 Necrotising enterocolitis (≥ stage 2).
4.9
4.9. Analysis
Comparison 4 Alternative lipid emulsion (LE) vs another alternative‐LE (see Appendix 3), Outcome 9 Any patent ductus arteriosus.
4.10
4.10. Analysis
Comparison 4 Alternative lipid emulsion (LE) vs another alternative‐LE (see Appendix 3), Outcome 10 Conjugated bilirubin levels (µmol/L).
5.1
5.1. Analysis
Comparison 5 Fish oil lipid emulsion (LE) vs non‐fish oil LE in preterm infants with surgical conditions (see Appendix 3), Outcome 1 Parenteral nutrition‐associated liver disease (PNALD)/cholestasis (conjugated bilirubin ≥ 2 mg/dL).
5.2
5.2. Analysis
Comparison 5 Fish oil lipid emulsion (LE) vs non‐fish oil LE in preterm infants with surgical conditions (see Appendix 3), Outcome 2 Death before discharge.
5.3
5.3. Analysis
Comparison 5 Fish oil lipid emulsion (LE) vs non‐fish oil LE in preterm infants with surgical conditions (see Appendix 3), Outcome 3 Culture‐positive sepsis.
5.4
5.4. Analysis
Comparison 5 Fish oil lipid emulsion (LE) vs non‐fish oil LE in preterm infants with surgical conditions (see Appendix 3), Outcome 4 Hypertriglyceridemia.
5.5
5.5. Analysis
Comparison 5 Fish oil lipid emulsion (LE) vs non‐fish oil LE in preterm infants with surgical conditions (see Appendix 3), Outcome 5 Conjugated bilirubin levels (µmol/L).
6.1
6.1. Analysis
Comparison 6 Fish oil lipid emulsion (LE) vs non‐fish oil LE in preterm infants with cholestasis (see Appendix 3), Outcome 1 Growth rate (g/week).
6.2
6.2. Analysis
Comparison 6 Fish oil lipid emulsion (LE) vs non‐fish oil LE in preterm infants with cholestasis (see Appendix 3), Outcome 2 Resolution of parenteral nutrition‐associated liver disease (PNALD)/cholestasis (conjugated bilirubin < 2 mg/dL).
6.3
6.3. Analysis
Comparison 6 Fish oil lipid emulsion (LE) vs non‐fish oil LE in preterm infants with cholestasis (see Appendix 3), Outcome 3 PNALD/cholestasis (any definition).
6.4
6.4. Analysis
Comparison 6 Fish oil lipid emulsion (LE) vs non‐fish oil LE in preterm infants with cholestasis (see Appendix 3), Outcome 4 Death before discharge.
6.5
6.5. Analysis
Comparison 6 Fish oil lipid emulsion (LE) vs non‐fish oil LE in preterm infants with cholestasis (see Appendix 3), Outcome 5 Any sepsis.
6.6
6.6. Analysis
Comparison 6 Fish oil lipid emulsion (LE) vs non‐fish oil LE in preterm infants with cholestasis (see Appendix 3), Outcome 6 Hyperglycaemia.
6.7
6.7. Analysis
Comparison 6 Fish oil lipid emulsion (LE) vs non‐fish oil LE in preterm infants with cholestasis (see Appendix 3), Outcome 7 Head growth velocity (cm/week).
6.8
6.8. Analysis
Comparison 6 Fish oil lipid emulsion (LE) vs non‐fish oil LE in preterm infants with cholestasis (see Appendix 3), Outcome 8 Conjugated bilirubin levels (µmol/L).
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References

References to studies included in this review

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Lam 2014 {published data only}
    1. Lam HS, Tam YH, Poon TC, Cheung HM, Yu X, Chan BP, et al. A double‐blind randomised controlled trial of fish oil‐based versus soy‐based lipid preparations in the treatment of infants with parenteral nutrition‐associated cholestasis. Neonatology 2014;4(105):290‐6. [DOI: 10.1159/000358267; PUBMED: 24576844] - DOI - PubMed
Lehner 2006 {published data only (unpublished sought but not used)}
    1. Lehner F, Demmelmair H, Röschinger W, Decsi T, Szász M, Adamovich K, et al. Metabolic effects of intravenous LCT or MCT/LCT lipid emulsions in preterm infants. Journal of Lipid Research 2006;47(2):404‐11. [DOI: 10.1194/jlr.M500423-JLR200; PUBMED: 16299352] - DOI - PubMed
Najm 2017 {published data only}
    1. Najm S, Löfqvist C, Hellgren G, Engström E, Lundgrenb P, Hård AL, et al. Effects of a lipid emulsion containing fish oil on polyunsaturated fatty acid profiles, growth and morbidities in extremely premature infants: a randomised controlled trial. Clinical Nutrition ESPEN 2017;20:17‐23. [DOI: 10.1016/j.clnesp.2017.04.004; PUBMED: 29072164] - DOI - PMC - PubMed
Nehra 2014 {published data only}
    1. Nehra D, Fallon EM, Potemkin AK, Voss SD, Mitchell PD, Valim C, et al. A comparison of 2 intravenous lipid emulsions: interim analysis of a randomised controlled trial. JPEN. Journal of Parenteral and Enteral Nutrition 2014;38(6):693‐701. [DOI: 10.1177/0148607113492549; PUBMED: 23770843] - DOI - PMC - PubMed
Pawlik 2014 {published data only}
    1. Pawlik D, Lauterbach R, Walczak M, Hurkala J, Sherman MP. Fish‐oil fat emulsion supplementation reduces the risk of retinopathy in very low birth weight infants: a prospective, randomised study. JPEN. Journal of Parenteral and Enteral Nutrition 2014;38(6):711‐6. [DOI: 10.1177/0148607113499373; PUBMED: 23963690] - DOI - PubMed
Rayyan 2012 {published data only (unpublished sought but not used)}
    1. Rayyan M, Devlieger H, Jochum F, Allegaert K. Short‐term use of parenteral nutrition with a lipid emulsion containing a mixture of soybean oil, olive oil, medium‐chain triglycerides, and fish oil: a randomised double‐blind study in preterm infants. Journal of Parenteral and Enteral Nutrition 2012;36(1 Suppl):81S‐94S. [DOI: 10.1177/0148607111424411; PUBMED: 22237883] - DOI - PMC - PubMed
Repa 2018 {published data only}
    1. Repa A, Binder C, Thanhaeuser M, Kreissl A, Pablik E, Huber‐Dangl M, et al. A mixed lipid emulsion for prevention of parenteral nutrition associated cholestasis in extremely low birth weight infants: a randomized clinical trial. Journal of Pediatrics 2018;194:87‐93. [DOI: 10.1016/j.jpeds.2017.11.012; PUBMED: 29269199] - DOI - PMC - PubMed
Roggero 2010 {published data only}
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Rubin 1994 {published data only}
    1. Rubin M, Moser A, Naor N, Merlob P, Pakula R, Sirota L. Effect of three intravenously administered fat emulsions containing different concentrations of fatty acids on the plasma fatty acid composition of premature infants. Journal of Pediatrics 1994;125(4):596‐602. [PUBMED: 7931881] - PubMed
Savini 2013 {published data only (unpublished sought but not used)}
    1. Savini S, D'Ascenzo R, Biagetti C, Serpentini G, Pompilio A, Bartoli A, et al. The effect of 5 intravenous lipid emulsions on plasma phytosterols in preterm infants receiving parenteral nutrition: a randomised clinical trial. American Journal of Clinical Nutrition 2013;98(2):312‐8. [DOI: 10.3945/ajcn.112.056556; PUBMED: 23761482] - DOI - PubMed
Skouroliakou 2010 {published data only (unpublished sought but not used)}
    1. Skouroliakou M, Konstantinou D, Koutri K, Kakavelaki C, Stathopoulou M, Antoniadi M, et al. A double‐blind, randomised clinical trial of the effect of omega‐3 fatty acids on the oxidative stress of preterm neonates fed through parenteral nutrition. European Journal of Clinical Nutrition 2010;64(9):940‐7. [DOI: 10.1038/ejcn.2010.98; PUBMED: 20551967] - DOI - PubMed
Skouroliakou 2016 {published data only}
    1. Skouroliakou M, Konstantinou D, Agakidis C, Kaliora A, Kalogeropoulos N, Massara P, et al. Parenteral MCT/omega‐3 polyunsaturated fatty acid‐enriched intravenous fat emulsion is associated with cytokine and fatty acid profiles consistent with attenuated inflammatory response in preterm neonates: a randomized, double‐blind clinical trial. Nutrition in Clinical Practice 2016;31(2):235‐44. - PubMed
Techasatid 2017 {published data only}
    1. Techasatid W, Sapsaprang S, Tantiyavarong P, Luvira A. Effectiveness of multicomponent lipid emulsion in preterm infants requiring parenteral nutrition: a two‐center, double‐blind randomized clinical trial. Journal of the Medical Association of Thai 2017;100(9):972‐9.
Tomsits 2010 {published data only (unpublished sought but not used)}
    1. Tomsits E, Pataki M, Tölgyesi A, Fekete G, Rischak K, Szollár L. Safety and efficacy of a lipid emulsion containing a mixture of soybean oil, medium‐chain triglycerides, olive oil, and fish oil: a randomised, double‐blind clinical trial in premature infants requiring parenteral nutrition. Journal of Pediatric Gastroenterology and Nutrition 2010;51(4):514‐21. [DOI: 10.1097/MPG.0b013e3181de210c; PUBMED: 20531018] - DOI - PubMed
Uthaya 2016 {published data only}
    1. Uthaya S, Liu X, Babalis D, Dore C, Warwick J, Bell J, et al. Nutritional evaluation and optimisation in neonates: a randomised, double‐blind controlled trial of amino acid regimen and intravenous lipid composition in preterm parenteral nutrition. American Journal of Clinical Nutrition 2016;103:1443‐52. [PUBMED: 27030860] - PMC - PubMed
Vlaardingerbroek 2014 {published data only}
    1. Vlaardingerbroek H, Vermeulen MJ, Carnielli VP, Vaz FM, Akker CH, Goudoever JB. Growth and fatty acid profiles of VLBW infants receiving a multicomponent lipid emulsion from birth. Journal of Pediatric Gastroenterology and Nutrition 2014;58(4):417‐27. [DOI: 10.1097/MPG.0000000000000280; PUBMED: 24667866] - DOI - PubMed
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Wang 2016 {published data only}
    1. Wang Y, Zhou KJ, Tang QY, Hong L, Feng Y, Lu LN, et al. Effect of an olive oil‐based lipid emulsion compared with a soybean oil‐based lipid emulsion on liver chemistry and bile acid composition in preterm infants receiving parenteral nutrition: a double‐blind, randomized trial. Journal of Parenteral and Enteral Nutrition 2016;40(6):842‐50. [DOI: 10.1177/0148607114566853; PUBMED: 25560678] - DOI - PubMed

References to studies excluded from this review

Angsten 2002 {published data only}
    1. Angsten G, Boberg M, Cederblad G, Meurling S, Stiernström H. Metabolic effects in neonates receiving intravenous medium‐chain triglycerides. Acta Paediatrica 2002;91(2):188‐97. [PUBMED: 11952008] - PubMed
Ariyawangso 2014 {published data only}
    1. Ariyawangso U, Puttilerpong C, Ratanachuek S, Anuntkosol M. Short‐term safety and efficacy of fish‐oil emulsions on the prevention of parenteral nutrition‐associated liver disease in surgical neonates: a randomised controlled trial. Thai Journal of Pharmaceutical Sciences 2014;38(4):202‐9.
Lima 1988 {published data only}
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Magnusson 1997 {published data only}
    1. Magnusson G, Boberg M, Cederblad G, Meurling S. Plasma and tissue levels of lipids, fatty acids and plasma carnitine in neonates receiving a new fat emulsion. Acta Paediatrica 1997;86(6):638‐44. [PUBMED: 9202801] - PubMed
Webb 2008 {published data only}
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Wilson 1997 {published data only}
    1. Wilson DC, Cairns P, Halliday HL, Reid M, McClure G, Dodge JA. Randomised controlled trial of an aggressive nutritional regimen in sick very low birthweight infants. Archives of Disease in Childhood. Fetal and Neonatal Edition 1997;77(1):F4‐11. [PUBMED: 9279175] - PMC - PubMed

References to studies awaiting assessment

Karagiozoglou‐Lampoudi 2012 {published data only (unpublished sought but not used)}
    1. Karagiozoglou‐Lampoudi T, Skouroliakou M, Konstantinou D, Agakidis C, Delikou N, Koutri K, et al. Omega‐3‐polyunsaturated fatty acid – enriched parenteral lipid emulsion and prevention of cholestasis in preterm infants. Comparison with soybean‐based lipid emulsion. European Journal of Hospital Pharmacy: Science and Practice 2012;19(2):221‐2. [DOI: ]
NCT03275090 {unpublished data only}
    1. Wahba Y, Abdelkareem M, Shouman B, Mesbah A. The effects of two different intravenous lipid emulsions on the outcomes of preterm infants with sepsis: a randomised controlled trial. Journal of Pediatric Care 2018;4. [DOI: 10.21767/2471-805X-C2-009] - DOI
Wang 2016b {published data only}
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References to other published versions of this review

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