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Lipid emulsions
Evidence review D4
NICE Guideline, No. 154
National Guideline Alliance (UK).
Safety and effectiveness of different lipid formulations in parenteral nutrition for preterm and term babies
Review question
What is the clinical effectiveness, efficacy and safety of lipid formulations from different sources (for example, soya, fish oil, or mixed sources)?
Introduction
Lipid emulsions are a vital part of neonatal parenteral nutrition (PN). However, soybean oil-based lipid emulsions (S-LE), which have been used conventionally, contain a high amount of polyunsaturated fatty acid (PUFA) and phytosterols which may contribute to adverse events in neonates, including PN associated liver disease (PNALD). There are newer lipid emulsions available from other lipid sources that decrease fatty acid content. Guidance on the effectiveness and safety of different lipid emulsions is required.
Summary of the protocol
Please see Table 1 for a summary of the Population, Intervention, Comparison and Outcome (PICO) characteristics of this review.
Table 1
Summary of the protocol (PICO table).
Clinical evidence
Included studies
In a collaboration with Cochrane Neonatal two Cochrane reviews were conducted specifically to address this topic for the guideline to be included in this review (Kapoor 2018a and Kapoor 2018b). This was initially planned as an update review by Cochrane Neonatal, but adjustments were made to address the needs of the current guideline (such as additional comparisons and a separate review for late-preterm and term babies).
For methodological considerations related to this collaboration see supplementary material C.
One review compared the safety and efficacy of different lipid emulsions in preterm (before 27 weeks’ gestation) babies (Kapoor 2018a).
One review compared the safety and efficacy of different lipid emulsions in term and late preterm (between 34 and 36+6 weeks’ gestation) babies (Kapoor 2018b).
Studies are summarised in Table 2 (with hyperlinks to the full reviews) and hyperlinks to study evidence tables are in appendix D.
Table 2
Summary of included studies.
See the Cochrane reviews for the literature search strategy, study selection flow chart, forest plots, and GRADE tables.
Excluded studies
See the Cochrane reviews for list of excluded studies with reasons for their exclusions.
Summary of clinical studies included in the evidence review
Summaries of the studies that were included in this review are presented Table 2.
See appendix D for the full evidence tables.
Quality assessment of clinical outcomes included in the evidence review
GRADE was conducted to assess the quality of outcomes. Evidence was identified for critical and important outcomes. The clinical evidence profiles can be found in the Cochrane reviews.
Economic evidence
Included studies
A systematic review of the economic literature was conducted but no economic studies were identified which were applicable to this review question. A single economic search was undertaken for all topics included in the scope of this guideline. Please see supplementary material D for details.
Excluded studies
No studies were identified which were applicable to this review question.
Economic evidence statements
No studies were identified which were applicable to this review question.
Summary of studies included in the economic evidence review
No economic evaluations were identified which were applicable to this review question.
Economic model
This question was medium priority for economic evaluation. However, the identified clinical data was insufficient to inform de-novo economic modelling in this area.
Evidence statements
Clinical evidence statements
Evidence statements were based on the GRADE analysis carried out by the authors of the Cochrane reviews.
Fish oil lipid emulsion (MOFS-LE) compared with non-fish oil lipid emulsion for preterm babies
Weight gain
Rate of weight gain
- Low quality evidence from 5 randomised controlled trials (RCTs) (n=347) showed no clinically important difference in rate of weight gain in babies who received MOFS-LE compared with S-LE. However, there was uncertainty around the effect: Mean difference (MD) 0.71g/kg/day (95% CI −0.17 to 1.60).
PNALD/cholestasis
Direct bilirubin ≥ 2mg/dl (equivalent to 34.2mmol/L)
- Low quality evidence from 4 RCTs (n=328) showed a clinically important difference in the rate of direct bilirubin ≥ 2mg/dl in babies who received fish oil lipid emulsions compared with non-fish oil lipid emulsions. Fewer babies receiving fish oil lipid emulsions had PNALD/cholestasis. However, there was high uncertainty around the effect: Relative risk (RR) 0.61 (95% CI 0.24 to 1.56).
Any definition
- Very low quality evidence from 11 RCTs (n=1154) showed a clinically important difference in the rate of PNALD/cholestasis (using any definition) in babies who received fish oil lipid emulsions compared with non-fish oil lipid emulsions. Fewer babies receiving fish oil lipid emulsions had PNALD/cholestasis. However, there was uncertainty around the effect: RR 0.63 (95% CI 0.43 to 0.91).
Death before discharge
- Low quality evidence from 9 RCTs (n=855) showed no clinically important difference in rate of death before discharge in babies who received MOFS-LE compared with S-LE. However, there was uncertainty around the effect: RR 1.24 (95% CI 0.81 to 1.90).
Sepsis
Culture positive
- Low quality evidence from 7 RCT (n=774) showed no clinically important difference in the rate of cultures positive for sepsis in babies who received fish oil lipid emulsions compared with non-fish oil lipid emulsions. However, there was uncertainty around the effect: RR 1.16 (95% CI 0.91 to 1.48).
Fish oil lipid emulsion (MOFS-LE) compared with another fish oil lipid emulsion (MFS-LE) for preterm babies
Weight gain
Rate of weight gain
- Low quality evidence from 1 RCT (n=55) showed no clinically important difference in rate of weight gain in babies who received MOFS-LE compared with MFS-LE. However, there was uncertainty around the effect: MD 4g/kg/day (95% CI −2.03 to 10.03).
PNALD/cholestasis
- Low quality evidence from 1 RCT (n=55) showed no clinically important difference in the rate of direct bilirubin ≥ 2mg/dl in babies who received MOFS-LE compared with MFS-LE. However, there was high uncertainty around the effect: RR 0.96 (95% CI 0.06 to 14.65).
Death before discharge
- Low quality evidence from 1 RCT (n=60) showed no clinically important difference in the rate of death before discharge in babies who received MOFS-LE compared with MFS-LE. However, there was high uncertainty around the effect: RR 1.00 (95% CI 0.15 to 6.64).
Sepsis
- Low quality evidence from 1 RCT (n=55) showed a clinically important difference in the rate of sepsis in babies who received MOFS-LE compared with MFS-LE. More babies receiving MOFS-LE had sepsis. However, there was high uncertainty around the effect: RR 1.69 (95% CI 0.56 to 5.11).
Alternative lipid emulsion compared with Soybean based emulsion (S-LE) for preterm babies
Weight gain
Rate of weight gain
- Low quality evidence from 1 RCT (n=60) showed no clinically important difference in rate of weight gain in babies who received MS-LE compared with S-LE. However, there was uncertainty around the effect: MD −2.67g/kg/day (95% CI −8.20 to 2.86).
- Low quality evidence from 2 RCTs (n=123) showed no clinically important difference in rate of weight gain in babies who received OS-LE compared with S-LE. However, there was uncertainty around the effect: MD −0.42 (95% CI −5.15 to 4.30).
Death before discharge
- Low quality evidence from 3 RCTs (n=224) showed no clinically important difference in the rate of death before discharge in babies who received OS-LE compared with S-LE. However, there was high uncertainty around the effect: RR 1.00 (95% CI 0.21 to 4.82).
Sepsis
Culture positive
- Low quality evidence from 2 RCTs (n=164) showed no clinically important difference in the rate of cultures positive for sepsis in babies who received OS-LE compared with S-LE. However, there was high uncertainty around the effect: RR 1.22 (95% CI 0.54 to 2.78).
Alternative lipid emulsion compared with another alternative lipid emulsion for preterm babies
Weight gain
Rate of weight gain
- Low quality evidence from 1 RCT (n=59) showed no clinically important difference in rate of weight gain in babies who received MS-LE compared with OS-LE. However, there was uncertainty around the effect: MD −1.33g/kg/day (95% CI −7.36 to 4.70).
PNALD/cholestasis
- Low quality evidence from 1 RCT (n=59) showed a clinically important difference in the rate of direct bilirubin ≥ 2mg/dl in babies who received MS-LE compared with OS-LE. More babies receiving MS-LE had PNALD/cholestasis. However, there was high uncertainty around the effect: RR 2.90 (95% CI 0.12 to 68.5).
Sepsis
- Low quality evidence from 1 RCT (n=59) showed a clinically important difference in the rate of sepsis in babies who received MS-LE compared with OS-LE. More babies receiving MS-LE had sepsis. However, there was high uncertainty around the effect: RR 1.93 (95% CI 0.65 to 5.73).
Fish oil lipid emulsion compared with non-fish oil lipid emulsion for preterm babies with surgical conditions
PNALD/cholestasis
- Very low quality evidence from 1 RCT (n=19) showed no clinically important difference in the rate of direct bilirubin ≥ 2mg/dl in babies who received pure fish oil compared with S-LE. However, there was high uncertainty around the effect: RR 1.11 (95% CI 0.08 to 15.28).
Sepsis
- Very low quality evidence from 1 RCT (n=19) showed no clinically important difference in the rate of cultures positive for sepsis in babies who received pure fish oil compared with S-LE. However, there was high uncertainty around the effect: RR 1.11 (95% CI 0.39 to 3.19).
Fish oil lipid emulsion compared with non-fish oil lipid emulsion for preterm babies with cholestasis
Weight gain
- Very low quality evidence from 1 RCT (n=16) showed a clinically important difference in rate of weight gain in babies who received pure fish oil compared with S-LE. Weight gain was greater in babies who received pure fish oil. However, there was uncertainty around the effect: MD 45g/week (95% CI 15 to 75).
Head growth
- Very low quality evidence from 1 RCT (n=16) showed a clinically important difference in rate of head growth in babies who received pure fish oil compared with S-LE. Head growth was greater in babies who received pure fish oil. However, there was uncertainty around the effect: MD 0.16cm/week (95% CI −0.01 to 0.33).
PNALD/cholestasis
- Very low quality evidence from 2 RCTs (n=40) showed a clinically important difference in the rate of PNALD/cholestasis (using any definition) in babies who received fish oil lipid emulsions compared with non-fish oil lipid emulsions. Fewer babies receiving fish oil had PNALD/cholestasis. However, there was uncertainty around the effect: RR 0.54 (95% CI 0.32 to 0.91).
- Very low quality evidence from 1 RCT (n=16) showed a clinically important difference in the rate of resolution of PNALD/cholestasis (direct bilirubin < 2 mg/dl) in babies who received pure fish oil compared with Intralipid. More babies receiving pure-fish oil had resolution of PNALD/cholestasis. However, there was high uncertainty around the effect: RR 5.60 (95% CI 0.34 to 93.35).
Death before discharge
- Very low quality evidence from 2 RCTs (n=40) showed a clinically important difference in the rate of death before discharge in babies who received fish oil lipid emulsions compared with non-fish oil lipid emulsions. Fewer babies receiving fish oil died before discharge. However, there was high uncertainty around the effect: RR 0.24 (95% CI 0.03 to 1.87).
Sepsis
- Very low quality evidence from 2 RCTs (n=40) showed no clinically important difference in the rate of sepsis in babies who received fish oil lipid emulsions compared with non-fish oil lipid emulsions. However, there was high uncertainty around the effect: RR 1.21 (95% CI 0.50 to 2.92).
Fish oil lipid emulsion compared with non-fish oil lipid emulsion for term and late preterm babies with surgical conditions
PNALD/cholestasis
- Very low quality evidence from 1 RCT (n=19) showed no clinically important difference in the rate of direct bilirubin ≥ 2mg/dl in babies who received pure fish oil compared with S-LE. However, there was high uncertainty around the effect: RR 1.11 (95% CI 0.08 to 15.28).
- Low quality evidence from 2 RCTs (n=68) showed no clinically important difference in the rate of PNALD/cholestasis (using any definition) in babies who received fish oil lipid emulsions compared with non-fish oil lipid emulsions. However, there was high uncertainty around the effect: RR 1.20 (95% CI 0.38 to 3.76).
Sepsis
Culture positive
- Very low quality evidence from 2 RCTs (n=51) showed no clinically important difference in the rate of cultures positive for sepsis in babies who received fish oil lipid emulsions compared with non-fish oil lipid emulsions. However, there was high uncertainty around the effect: RR 1.05 (95% CI 0.47 to 2.34).
Fish oil lipid emulsion compared with non-fish oil lipid emulsion for term and late preterm babies with cholestasis
Weight gain
- Very low quality evidence from 1 RCT (n=16) showed a clinically important difference in rate of weight gain in babies who received pure fish oil compared with S-LE. Weight gain was greater in babies who received pure fish oil. However, there was uncertainty around the effect: MD 45g/week (95% CI 15 to 75).
PNALD/cholestasis
- Very low quality evidence from 2 RCTs (n=40) showed a clinically important difference in the rate of PNALD/cholestasis (using any definition) in babies who received fish oil lipid emulsions compared with non-fish oil lipid emulsions. Fewer babies receiving fish oil had PNALD/cholestasis. However, there was uncertainty around the effect: RR 0.54 (95% CI 0.32 to 0.91).
- Very low quality evidence from 1 RCT (n=16) showed a clinically important difference in the rate of resolution of PNALD/cholestasis (direct bilirubin < 2 mg/dl) in babies who received pure fish oil compared with Intralipid. More babies receiving pure-fish oil had resolution of PNALD/cholestasis. However, there was high uncertainty around the effect: RR 5.60 (95% CI 0.34 to 93.35).
Death before discharge
- Very low quality evidence from 2 RCTs (n=40) showed a clinically important difference in the rate of death before discharge in babies who received fish oil lipid emulsions compared with non-fish oil lipid emulsions. Fewer babies receiving fish oil died before discharge. However, there was high uncertainty around the effect: RR 0.24 (95% CI 0.03 to 1.87).
Sepsis
- Very low quality evidence from 2 RCTs (n=40) showed no clinically important difference in the rate of sepsis in babies who received fish oil lipid emulsions compared with non-fish oil lipid emulsions. However, there was high uncertainty around the effect: RR 1.21 (95% CI 0.50 to 2.92).
Hypertriglyceridemia
- Very low quality evidence from 1 RCT (n=24) showed a clinically important difference in the rate of hypertriglyceridemia in babies who received MOFS-LE compared with S-LE. Fewer babies receiving MOFS-LE had hypertriglyceridemia. However, there was high uncertainty around the effect: RR 0.79 (95% CI 0.30 to 2.09).
Economic evidence statements
No economic evidence was identified which was applicable to this review question.
The committee’s discussion of the evidence
Interpreting the evidence
The outcomes that matter most
Lipids are an essential part of PN; therefore, growth and neurodevelopmental outcomes were prioritised as critical outcomes by the committee. PN associated liver disease (PNALD) was also selected as a critical outcome as different lipid emulsions contain varying amounts of polyunsaturated fatty acid and phytosterols which may contribute to PNALD.
Other adverse effects of intravenous lipid emulsions (infection including sepsis, hyperglycaemia, hypertriglyceridemia and hyperlipidaemia) were selected as important outcomes as they may vary according to the type of lipid emulsion used. Duration of hospital stay and mortality were selected as important outcomes as they may be affected by both the type of lipid emulsion used and the overall clinical condition of the baby. Nutritional intake was also selected as an important outcome as nutritional composition varies across different lipid emulsions.
The quality of the evidence
The quality of the Cochrane systematic reviews was assessed using the ROBIS tool. Both reviews were rated as having a low risk of bias. The Cochrane authors performed a GRADE analysis of the outcomes. The evidence was all very low and low quality and was downgraded due to risk of bias in included studies, small sample sizes, small number of events, and uncertainty around effects.
There was no evidence for neurodevelopmental outcomes, hyperglycaemia, hyperlipidaemia, duration of hospital stay or nutritional intake.
There was no evidence for late preterm or term babies that did not have pre-existing PNALD or surgical conditions.
Benefits and harms
There was limited evidence of greater weight gain and head growth, greater resolution of PNALD and less mortality and hypertriglyceridemia when babies with PNALD were given composite lipid emulsions, for example those containing fish oil, compared with pure soybean lipid emulsions. However, there was no evidence comparing different composite lipid emulsions to each other, or composite lipid emulsions not containing fish oil with pure soybean lipid emulsions, in babies with PNALD. Therefore, the committee could not conclude what composite lipid emulsions provided the most benefit over pure soybean lipid emulsions. The evidence was from preterm and late preterm babies; however, the committee agreed that late preterm and term babies are often treated the same in clinical practice and that term babies with PNALD would be likely to also benefit from using a composite lipid emulsion. Therefore, the committee recommended, that therapeutic use of composite lipid emulsions, rather than a pure soybean lipid emulsion, should be considered for preterm and term babies with PNALD.
For babies with surgical conditions, there was no evidence of advantage of any specific lipid formulation. Therefore, the committee agreed they could not make a recommendation for this population. They discussed that for babies with surgical conditions who are likely to be on long term PN, such as those with little or no remaining bowel, the duration of parental nutrition will be much longer than is covered by the scope of this guideline and these babies may require management by a multidisciplinary team, including a gastroenterologist.
There was some evidence of a benefit of fish oil containing lipid emulsions at reducing the rate of PNALD in preterm babies without surgical conditions or pre-existing PNALD. The committee discussed whether or not fish oil containing lipid emulsions should be considered in these babies and could not reach agreement as it was felt that there was no conclusive evidence of benefit, particularly as benefits of fish oil containing lipid emulsions were not seen for outcomes beyond PNALD. The committee also discussed that there is a risk of essential fatty acid deficiency with pure fish oil.
There was also no evidence comparing different lipid emulsions in late preterm or term babies without surgical conditions or pre-existing PNALD. The committee discussed that it might be more beneficial to use fish-oil containing lipid emulsions in babies that are likely to be on PN for a longer duration, as there will be a greater risk of developing PNALD; however, the committee did not think there was sufficient evidence to support this as a recommendation. Further, in the absence of surgical conditions, it might not always be possible to know how long babies are likely to need PN.
Cost effectiveness and resource use
No economic studies were identified which were applicable to this review question.
The committee note that in preterm and term babies with PNALD the use of fish oil containing lipid emulsions may result in avoiding the costs associated with poorer growth, worsening of PNALD and increased risk of hypertriglyceridemia. These are severe long-lasting complications which result in substantial costs to the NHS and also have a detrimental impact on the health-related quality of life of babies and also their parents or carers. Combined with an increased risk of mortality the use of lipid emulsions that do not contain fish oil would result in substantial losses in quality adjusted life years (QALYs). The committee explained that the use of fish oil containing lipid emulsions will have negligible, if any, impact on the unit cost of PN. As a result, the committee was of a view that the use of fish oil containing lipid emulsions would represent a cost effective use of NHS resources in pre-term and term babies with PNALD.
References
Kapoor 2018a
Kapoor, V., Malviya, M. N., Soll, R., Lipid emulsions for parenterally fed preterm infants. Cochrane Database of Systematic Reviews 2018, Issue 11Kapoor 2018b
Kapoor, V., Malviya, M. N., Soll, R., Lipid emulsions for parenterally-fed term and late preterm infants. Cochrane Database of Systematic Reviews 2018, Issue 11 [PMC free article: PMC6953354] [PubMed: 31158920]
Appendices
Appendix A. Review protocols
Review protocol for review question: What is the clinical effectiveness, efficacy and safety of lipid formulations from different sources (for example, soya, fish oil, or mixed sources)?
The protocol drafted by the committee is displayed below and formed the basis of discussion with Cochrane Neonatal. The two Cochrane protocols were then adapted in line with this protocol.
See Cochrane reviews for the review protocols:
Cochrane protocol for preterm babies: https://www.cochranelibrary.com/cdsr/doi/10.1002/14651858.CD013163/full
Cochrane protocol for term and late- preterm babies: https://www.cochranelibrary.com/cdsr/doi/10.1002/14651858.CD013171/full
Appendix B. Literature search strategies
Literature search strategy for review question: What is the clinical effectiveness, efficacy and safety of lipid formulations from different sources (for example, soya, fish oil, or mixed sources)?
See the Cochrane reviews for the literature search strategy:
Appendix C. Clinical evidence study selection
Clinical study selection for review question: What is the clinical effectiveness, efficacy and safety of lipid formulations from different sources (for example, soya, fish oil, or mixed sources)?
See the Cochrane reviews for the study selection flow charts:
Appendix D. Clinical evidence tables
Clinical evidence tables for review question: What is the clinical effectiveness, efficacy and safety of lipid formulations from different sources (for example, soya, fish oil, or mixed sources)?
Table 4. Clinical evidence tables for included studies (PDF, 247K)
Appendix E. Forest plots
Forest plots for review question: What is the clinical effectiveness, efficacy and safety of lipid formulations from different sources (for example, soya, fish oil, or mixed sources)?
See the Cochrane reviews for forest plots:
Appendix F. GRADE tables
GRADE tables for review question: What is the clinical effectiveness, efficacy and safety of lipid formulations from different sources (for example, soya, fish oil, or mixed sources)?
See the Cochrane reviews for GRADE tables:
Appendix G. Economic evidence study selection
Economic evidence study selection for review question: What is the clinical effectiveness, efficacy and safety of lipid formulations from different sources (for example, soya, fish oil, or mixed sources)?
One global search was conducted for all review questions. See supplementary material D for further information.
Appendix H. Economic evidence tables
Economic evidence study selection for review question: What is the clinical effectiveness, efficacy and safety of lipid formulations from different sources (for example, soya, fish oil, or mixed sources)?
No economic studies were identified which were applicable to this review question.
Appendix I. Economic evidence profiles
Economic evidence profiles for review question: What is the clinical effectiveness, efficacy and safety of lipid formulations from different sources (for example, soya, fish oil, or mixed sources)?
No economic studies were identified which were applicable to this review question.
Appendix J. Economic analysis
Economic analysis for review question: What is the clinical effectiveness, efficacy and safety of lipid formulations from different sources (for example, soya, fish oil, or mixed sources)?
No economic analysis was undertaken for this review question.
Appendix K. Excluded studies
Excluded studies for review question: What is the clinical effectiveness, efficacy and safety of lipid formulations from different sources (for example, soya, fish oil, or mixed sources)?
Clinical studies
See the Cochrane reviews for excluded studies:
Economic studies
No economic evidence was identified for this review question. See supplementary material D for further information.
Appendix L. Research recommendations
Research recommendations for review question: What is the clinical effectiveness, efficacy and safety of lipid formulations from different sources (for example, soya, fish oil, or mixed sources)?
No research recommendations were made for this review question.
Final
Evidence reviews
These evidence reviews were developed by the National Guideline Alliance which is part of the Royal College of Obstetricians and Gynaecologists
Disclaimer: The recommendations in this guideline represent the view of NICE, arrived at after careful consideration of the evidence available. When exercising their judgement, professionals are expected to take this guideline fully into account, alongside the individual needs, preferences and values of their patients or service users. The recommendations in this guideline are not mandatory and the guideline does not override the responsibility of healthcare professionals to make decisions appropriate to the circumstances of the individual patient, in consultation with the patient and/or their carer or guardian.
Local commissioners and/or providers have a responsibility to enable the guideline to be applied when individual health professionals and their patients or service users wish to use it. They should do so in the context of local and national priorities for funding and developing services, and in light of their duties to have due regard to the need to eliminate unlawful discrimination, to advance equality of opportunity and to reduce health inequalities. Nothing in this guideline should be interpreted in a way that would be inconsistent with compliance with those duties.
NICE guidelines cover health and care in England. Decisions on how they apply in other UK countries are made by ministers in the Welsh Government, Scottish Government, and Northern Ireland Executive. All NICE guidance is subject to regular review and may be updated or withdrawn.
- Supplementary material A - National Guideline Alliance technical team list (PDF)
- Supplementary material B - Glossary and abbreviations (PDF)
- Supplementary material C - Methods (PDF)
- Supplementary material D - Health economic literature (PDF)
- Equality impact assessment (PDF)
- Membership of Neonatal Parenteral Nutrition Guideline Committee (PDF)
- Declarations of interests register (PDF)
- Lipid emulsionsLipid emulsions
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