Energy needs

National Guideline Alliance (UK)

Energy needs

Neonatal parenteral nutrition

Evidence review C

NICE Guideline, No. 154

Authors

National Guideline Alliance (UK).

London: National Institute for Health and Care Excellence (NICE); 2020 Feb.

ISBN-13: 978-1-4731-3673-1

Energy needs of preterm and term babies

Review question

How many kcal/kg/day should be given to preterm and term babies receiving parenteral nutrition?

Introduction

Providing the optimal level of energy for babies receiving parenteral nutrition (PN) is very important. If nutritional deficits occur during early postnatal life, there is an increased risk of mortality and respiratory conditions, and detrimental effects on growth and neurodevelopment. Conversely, providing energy in excess of needs has been associated with impaired liver function, and increased adiposity. Determining the optimal energy needs of preterm and term babies receiving PN as their main source of nutrition is therefore important for optimal outcomes.

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).

For full details see the review protocol in appendix A.

Clinical evidence

Included studies

As limited RCT evidence was available, we also included observational studies. Six studies were identified for inclusion in this review (Duffy 1981, Forsyth 1995, Morgan 2014, Pineault 1988, Tan 2008, Zlotkin 1981).

Two Randomised controlled trials (RCTs) and 1 cross-over RCT compared high versus low energy intake (Forsyth 1995, Morgan 2014, Tan 2008).

Three studies had multiple groups within the high versus low energy comparison. One RCT compared high versus low energy intake for 2 different sources of amino acids (Duffy 1981). One observational study compared high versus low energy intake for 2 different energy sources (low fat and high fat; Pineault 1988). One observational study compared high versus low energy intake at different levels of nitrogen intake (Zlotkin 1981). For these studies, groups within high energy intake and low energy intake were combined for the purpose of analysis.

Although the actual energy intake differed across included studies, all studies were combined into one comparison of high versus low energy intake. This meant that for each individual study, the arm with the higher intake was included in the high energy arm and the arm with the lower intake was included in the low energy arm, even if the low energy arm of some studies was higher than the high energy arm of other studies. However, if there was significant heterogeneity on any outcome, the energy intakes of individual studies were examined to see if this might explain the difference between studies. RCT and observational evidence was analysed separately.

The included studies are summarised in Table 2.

Table 2

Summary of included studies.

See the literature search strategy in appendix B, study selection flow chart in appendix C, study evidence tables in appendix D, and GRADE tables in appendix F.

Excluded studies

Studies not included in this review are listed, and reasons for their exclusions are provided, in appendix K.

Summary of clinical studies included in the evidence review

Summaries of the studies that were included in this review are presented in Table 2.

See appendix D for 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 appendix F.

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.

Summary of studies included in the economic evidence review

No economic evaluations were identified which were applicable to this review question.

Economic model

No economic modelling was undertaken for this review because the committee agreed that other topics were higher priorities for economic evaluation

Evidence statements

Clinical Evidence statements

Nitrogen accretion

Nitrogen retention (%)

Low quality evidence from 1 RCT (n=24) showed a clinically important difference in nitrogen retention between babies who received high energy intake compared with low energy intake, with increased nitrogen retention in the group of babies receiving high energy intake. However, there was uncertainty around the effect: Mean difference (MD) 14.00% (95% CI 4.52 to 23.48).
Very low quality evidence from 2 observational studies (n=66) showed a clinically important difference in nitrogen retention between babies who received high energy intake compared with low energy intake, with increased nitrogen retention in the group of babies receiving high energy intake. However, there was uncertainty around the effect: MD 12.16% (95% CI 1.73 to 22.58).

Nitrogen balance (mg/kg/day)

Low quality evidence from 1 RCT (n=24) showed a clinically important difference in nitrogen balance between babies who received high energy intake compared with low energy intake, with higher nitrogen balance in the group of babies receiving high energy intake. However, there was uncertainty around the effect: MD 66.00mg/kg/day (95% CI 14.98 to 117.02).
Very low quality evidence from 2 observational studies (n=62) showed a clinically important difference in nitrogen balance between babies who received high energy intake compared with low energy intake, with higher nitrogen balance in the group of babies receiving high energy intake. However, there was uncertainty around the effect: MD 33.59mg/kg/day (95% CI 5.65 to 61.52).

Head circumference

Head circumference (mm) at 7, 14, 21 and 28 days and 36 weeks’ corrected gestational age (CGA)

High quality evidence from 1 RCT (n=135) showed no clinically important difference in head circumference at 7 days (MD 1.00mm [95% CI −3.39 to 5.39]) and 14 days (MD 2.00mm [95% CI −2.39 to 6.39]) between babies who received high energy intake compared with low energy intake.
Moderate quality evidence from the 1 RCT (n=135) showed no clinically important difference between head circumference at 21 days (MD 4.00mm [95% CI −1.07 to 9.07]) and at 28 days (MD 6.00mm [95% CI 0.43 to 11.57]) between babies who received high energy intake compared with low energy intake. However, there was uncertainty around the effects.
Very low quality evidence from 2 RCTs (n=240) showed no clinically important difference in head circumference at 36 weeks’ CGA in babies who received high energy intake compared with low energy intake. However, there was uncertainty around the effect: MD 1.04mm (95% CI −6.80 to 8.88).

Head circumference z-score at 36 weeks’ CGA

Low quality evidence from 1 RCT (n=114) showed no clinically important difference in head circumference z-score at 36 weeks’ CGA in babies who received high energy intake compared with low energy intake. However, there was uncertainty around the effect: MD −0.20 (95% CI −0.62 to 0.22).

Head circumference gain (cm/week)

Very low quality evidence from 1 observational study (n=15) showed a clinically important difference in head circumference gain between babies who received high energy intake compared with low energy intake, with greater head circumference gain in the group of babies receiving high energy intake. However, there was uncertainty around the effect: MD 0.40mm/week (95% CI 0.02 to 0.78).

Weight gain

Weight (g) at 7, 14, 21 and 28 days and 36 weeks’ corrected gestational age (CGA)

High quality evidence from 1 RCT (n=135) showed no clinically important difference in weight at 7 days in babies who received high energy intake compared with low energy intake: MD 31.00g (95% CI −8.22 to 70.22).
Moderate quality evidence from 1 RCT (n=135) showed no clinically important difference in weight at 14 days (MD 55.00g [95% CI 9.24 to 100.76]), 21 days (MD 75.00g [95% CI 20.78 to 129.22]) and at 28 days (MD 57.00g [95% CI −8.70 to 122.70]) in babies who received high energy intake compared with low energy intake. However, there was uncertainty around the effects. Moderate quality evidence from 2 RCTs (n=238) showed no clinically important difference in weight at 36 weeks’ CGA in babies who received high energy intake compared with low energy intake: MD 77.31g (95% CI 8.89 to 145.74).

Weight gain (g/day)

Very low quality evidence from 1 RCT (n=24) showed no clinically important difference in weight gain in babies who received high energy intake compared with low energy intake. However, there was high uncertainty around the effect: MD 10.00g/day (95% CI −21.7 to 41.7).

Weight gain (g/kg/day)

Very low quality evidence from 2 observational studies (n=46) showed a clinically important difference in weight gain between babies who received high energy intake compared with low energy intake, with greater weight gain in the group of babies receiving high energy intake. However, there was uncertainty around the effect: MD 7.12g/kg/day (95% CI −0.75 to 14.99).

Weight z-score at 36 weeks’ CGA

Low quality evidence from 1 RCT (n=114) showed no clinically important difference in weight z-score at 36 weeks’ CGA in babies who received high energy intake compared with low energy intake. However, there was uncertainty around the effect: MD 0.10 (95% CI −0.21 to 0.41).

Mid-arm circumference (cm) at 36 weeks’ CGA

Moderate quality evidence from 1 RCT (n=114) showed no clinically important difference in mid-arm circumference at 36 weeks’ CGA in babies who received high energy intake compared with low energy intake: MD 0.10cm (95% CI −0.19 to 0.39).

Height gain

Length (cm) at 36 weeks’ CGA

Low quality evidence from 1 RCT (n=114) showed no clinically important difference in length at 36 weeks’ CGA in babies who received high energy intake compared with low energy intake. However, there was uncertainty around the effect: MD 0.50cm (95% CI −0.31 to 1.31).

Length gain (cm/week)

Very low quality evidence from 2 observational studies (n=41) showed a clinically important difference in length gain between babies who received high energy intake compared with low energy intake, with greater length gain in the group of babies receiving high energy intake However, there was uncertainty around the effect: MD 0.29cm/week (95% CI 0.12 to 0.46)

Length z-score at 36 weeks’ CGA

Low quality evidence from 1 RCT (n=114) showed no clinically important difference in length z-score at 36 weeks’ CGA in babies who received high energy intake compared with low energy intake. However, there was uncertainty around the effect: MD 0.30 (95% CI −0.16 to 0.76).

Lower leg length (cm) at 36 weeks’ CGA

Moderate quality evidence from 1 RCT (n=114) showed no clinically important difference in lower leg length at 36 weeks’ CGA in babies who received high energy intake compared with low energy intake: MD 0.00cm (95% CI −0.26 to 0.26).

Mortality

Low quality evidence from 1 RCT showed no clinically important difference in rate of mortality at 28 days (Relative risk (RR) 1.17 [95% CI 0.45 to 3.07; n=150]) and at 36 weeks’ CGA (RR 0.93 [95% CI 0.44 to 1.95; n=127]) in babies who received high energy intake compared with low energy intake. However, there was high uncertainty around the effects.

Conjugated hyperbilirubinaemia (conjugated bilirubin > 50 mmol/L)

Low quality evidence from 1 RCT (n=135) showed a clinically important difference in rate of conjugated hyperbilirubinaemia at 28 days between babies who received high energy intake compared with low energy intake, with conjugated hyperbilirubinaemia associated with receiving high energy intake. However, there was high uncertainty around the effect: RR 0.78 (95% CI 0.29 to 2.14).
Very low quality evidence from 1 RCT (n=127) showed no clinically important difference in rate of conjugated hyperbilirubinaemia at 36 weeks’ CGA in babies who received high energy intake compared with low energy intake. However, there was high uncertainty around the effect: RR 1.10 [95% CI 0.54 to 2.22).

Energy intake

Energy intake (kcal/kg/d) in the first 48 hours of life and at week 1, 2, 3 and 4

Low quality evidence from 1 RCT (N=20) showed a clinically important difference in energy intake in the first 48 hours of life between babies who received high energy intake compared with low energy intake, with greater energy intake in the group of babies receiving high energy intake. However, there was uncertainty around the effect: MD 15.30kcal/kg/day (95% CI 4.07to 26.53).
High quality evidence from 1 RCT (n=135) showed a clinically important difference in energy intake at week 1 (MD 7.00kcal/kg/day [95% CI 4.61 to 9.39]) and week 2 (MD 17kcal/kg/day [95% CI 9.87 to 24.13]), with greater energy intake in the group of babies receiving high energy intake.
Moderate quality evidence from 1 RCT (n=135) showed no clinically important difference in energy intake at week 3 (MD 9.00kcal/kg/day [95% CI −2.35 to 20.35]) and week 4 (MD 5.00kcal/kg/day (95% CI −5.24 to 15.24]). However, there was uncertainty around the effects.

Cumulative energy intake (kcal/kg) in the first 28 days of life

Low quality evidence from 2 RCTs (n=249) showed no clinically important difference in cumulative energy intake in the first 28 days of life in babies who received high energy intake compared with low energy intake. However, there was uncertainty around the effect: MD 165.26 (95% CI 93.78 to 236.73).

Energy intake (kcal/kg/day) – timeframe unclear

Moderate quality evidence from 1 RCT (n=24) showed a clinically important difference in energy intake between babies receiving high energy intake compared with low energy intake, with greater energy intake in the group of babies receiving high energy intake: MD 25.00kcal/kg/day (95% CI 18.58 to 31.42).
Very low quality evidence from 1 observational study (n=16) showed a clinically important difference in energy intake between babies receiving high energy intake compared with low energy intake, with greater energy intake in the group of babies receiving high energy intake: MD 18.20kcal/kg/day (95% CI 15.65 to 20.75).

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

The committee agreed that body composition, nitrogen accretion and anthropometric measures should be included as critical outcomes as these are most directly influenced by overall energy intake. Mortality rates, PN associated liver disease, hyperglycaemia, hypophosphataemia, and hypercalcaemia were considered important outcomes, as these will be influenced by energy intake and other factors. The actual energy intake received by the baby was also selected as an important outcome because the actual intake could differ from the provided energy.

The quality of the evidence

The quality of the evidence for this review was assessed using GRADE methodology. The observational evidence was very low quality due to risk of bias in the included studies and uncertainty around the effects. The RCT evidence ranged from very low to high quality and was mainly downgraded due to uncertainty around the effects. There was also some heterogeneity across studies, selection bias, attrition bias and selective reporting bias. Blinding of pharmacists and personnel involved in administering PN was not possible in the RCTs due to safety reasons, however it was reported that this is unlikely to have affected clinical care so evidence was not downgraded for this reason. One of the included studies had a cross over design that only covered the first 48 hours after birth (Forsyth 1995), two studies included enteral feeding as well as parenteral feeding (Morgan 2014; Tan 2008), and one study assigned babies with hyperbilirubinaemia to the low energy arm (Zlotkin 1981).

The committee noted that the included studies differed according to the amount of macronutrients and energy intake, thus were not entirely comparable, and that the protocols in older studies did not reflect current practice.

Benefits and harms

There was evidence from RCT and observational studies that nitrogen retention and balance were higher in babies who received high energy intake compared with low energy intake; however, there was uncertainty around the effects.

The RCT evidence showed no clinically important differences in head circumference measured during the first 4 weeks of life and at 36 weeks’ controlled for gestational age. However, there was uncertainty around these effects and there was some observational evidence of greater gains in head circumference with high energy intake compared with low energy intake.

RCT evidence showed no clinically important differences between groups for any weight or height outcomes; however, there was uncertainty around the effects. There was greater weight and height gain shown in two observational studies but evidence was very low quality and one study, which showed the greatest difference between groups, assigned babies with hyperbilirubinaemia to low energy intake; therefore, it is unclear whether differences in growth outcomes are due to energy intake or hyperbilirubinaemia.

There were no clinically important differences in mortality based on energy intake, although there was high uncertainty around the effects. There was some evidence of reduced hyperbilirubinaemia at 28 days in babies who received high energy intake compared with low energy intake; however, there was uncertainty around the effect and this difference was not observed at 36 weeks’ CGA.

There was inconsistent evidence regarding whether babies who were prescribed high energy intake actually received higher energy intake than those prescribed low energy intake. Clinically important differences were observed in the first two weeks of life, but these differences were not observed in the third and fourth week of life, or for cumulative energy intake over the first 4 weeks of life. However, PN was decreased during the transition to enteral feeding, and was discontinued when 50 to 75% of nutrition was received from enteral feeds; therefore, differences may have been harder to detect during periods with lower PN. Further evidence from 1 RCT and 1 observational study where the timeframe for nutritional intake was unclear also showed higher energy intake in babies who were prescribed high energy. Therefore, the committee agreed that the evidence showed it was feasible to provide higher energy intakes.

The committee decided that they could not make recommendations on a specific ideal energy intake for all babies based on the limited evidence available. The committee also noted that the composition of macronutrient intake differed between trial groups, which makes it difficult to conclude if differences are based on energy intake or intake of other macronutrients such as protein. The recommendations were therefore based on informal consensus of the committee. They used their experience and expertise to conduct a theoretical exercise, taking into account knowledge regarding physiological and metabolic requirements of babies. In this exercise the committee worked backwards from the individual nutrients (for which there was evidence for the ranges advised and in which they had greater confidence – see section 1.5 of the guideline) and converted their respective dosages into calories.

The committee discussed the number of days over which energy intake should increase to reach the intended maintenance level, and agreed to align this with the recommendations on lipid, carbohydrates and amino acid increases (see section 1.5 of the guideline). The committee agreed that babies who start PN in the first 4 days after birth should have a starting range and increase up to a maintenance range over approximately 4 days. This timeframe was primarily selected because neonatal metabolic adaptation occurs in the early days of life, enabling the baby to metabolise the nutrients delivered. In addition, fluid volume allowances are commonly increased over the first few days of life and this means that increasing amounts of nutrition can be given parenterally. For babies starting PN after the first 4 days of life early metabolic adaptation is likely to have taken place and their fluid volume allowances would have already increased so this allows parenteral nutrition to be started using maintenance ranges.

Based on committee knowledge that PN-related complications would be higher in term babies that are critically ill or have just had surgery, they decided that giving energy intake in the lower range would be more appropriate for these groups because term babies’ energy stores tend to be more replete. However, they only made this recommendation for term babies who are critically because in critically ill preterm babies, who have limited nutritional stores, prioritising nutritional intake may be more important.

Cost effectiveness and resource use

No economic studies were identified which were applicable to this review question.

The committee explained that recommendations pertaining to an optimal nutritional intake in preterm and term babies who are receiving PN would not incur extra resource implications to the health care system.

The committee noted that getting the right nutritional intake may result in avoiding additional costs associated with nutritional deficit or providing energy in excess. For example, nutritional deficits which may occur during PN are known to be negatively associated with mortality, respiratory, growth and neurodevelopmental outcomes and may require expensive NHS care. Similarly, providing energy in excess of needs is associated with impaired liver function, and increased adiposity which also require expensive care.

The committee explained that recommendations in this area reflect practice across many units and as such cost savings to the NHS, if any, are likely to be negligible.

References

Duffy 1981
Duffy, B., Gunn, T., Collinge, J., Pencharz, P., The effect of varying protein quality and energy intake on the nitrogen metabolism of parenterally fed very low birthweight (<1600 g) infants, Pediatric Research, 15, 1040–1044, 1981 [PubMed: 6789293]
Forsyth 1995
Forsyth, J. S., Murdock, N., Crighton, A., Low birthweight infants and total parenteral nutrition immediately after birth. III. Randomised study of energy substrate utilisation, nitrogen balance, and carbon dioxide production, Archives of Disease in Childhood, Fetal and neonatal edition. 73, F13–6, 1995 [PMC free article: PMC2528376] [PubMed: 7552589]
Koletzko 2005
Koletzko,, B., Goulet, O., Hunt, J., Krohn, K., Shamir, R., G Guidelines on paediatric parenteral nutrition of the European Society of Paediatric Gastroenterology, Hepatology and Nutrition (ESPGHAN) and the European Society for Clinical Nutrition and Metabolism (ESPEN), supported by the European Society of Paediatric Research (ESPR), Journal of Pediatric Gastroenterology and Nutrition, 41, S1–S4, 2005 [PubMed: 16254497]
Morgan 2014
Morgan, C., McGowan, P., Herwitker, S., Hart, A. E., Turner, M. A., Postnatal head growth in preterm infants: a randomized controlled parenteral nutrition study, Pediatrics, 133, e120–8, 2014 [PubMed: 24379229]
Pineault 1988
Pineault, M., Chessex, P., Bisaillon, S., Brisson, G., Total parenteral nutrition in the newborn: impact of the quality of infused energy on nitrogen metabolism, American Journal of Clinical Nutrition, 47, 298–304, 1988 [PubMed: 3124593]
Tan 2008
Tan, M. J., Cooke, R. W., Improving head growth in very preterm infants - A randomised controlled trial I: Neonatal outcomes, Archives of Disease in Childhood: Fetal and Neonatal Edition, 93, f337–f341, 2008 [PubMed: 18252814]
Zlotkin 1981
Zlotkin, S. H., Bryan, M. H., Anderson, G. H., Intravenous nitrogen and energy intakes required to duplicate in utero nitrogen accretion in prematurely born human infants, The Journal of pediatrics, 99, 115–20, 1981 [PubMed: 7252648]

Appendices

Appendix A. Review protocols

Review protocol for review question: How many kcal/kg/day should be given to preterm and term babies receiving parenteral nutrition?

Table

Babies born preterm, up to 28 days after their due birth date (preterm babies) Babies born at term, up to 28 days after their birth (term babies)

Appendix B. Literature search strategies

Literature search strategies for review question: How many kcal/kg/day should be given to preterm and term babies receiving parenteral nutrition?

Databases: Medline; Medline EPub Ahead of Print; and Medline In-Process & Other Non-Indexed Citations

Databases: Embase; and Embase Classic

Databases: Cochrane Central Register of Controlled Trials; Cochrane Database of Systematic Reviews; Database of Abstracts of Reviews of Effects; and Health Technology Assessment

Appendix C. Clinical evidence study selection

Clinical study selection for review question: How many kcal/kg/day should be given to preterm and term babies receiving parenteral nutrition?

Figure 1. PRISMA Flow chart of clinical article selection for review question on energy needs of preterm and term babies

Appendix D. Clinical evidence tables

Clinical evidence tables for review question: How many kcal/kg/day should be given to preterm and term babies receiving parenteral nutrition?

Table 3. Clinical evidence table for included studies (PDF, 383K)

Appendix E. Forest plots

Forest plots for review question: How many kcal/kg/day should be given to preterm and term babies receiving parenteral nutrition?

Figure 2. Forest plot for comparison high energy intake versus low energy intake: Nitrogen retention (%)

Figure 3. Forest plot for comparison high energy intake versus low energy intake: Nitrogen balance

Figure 4. Forest plot for comparison high energy intake versus low energy intake: Weight (g)

Figure 5. Forest plot for comparison high energy intake versus low energy intake: Weight gain

Figure 6. Forest plot for comparison high energy intake versus low energy intake: Length gain (cm/week)

Figure 7. Forest plot for comparison high energy intake versus low energy intake: Energy intake

Appendix F. GRADE tables

GRADE tables for review question: How many kcal/kg/day should be given to preterm and term babies receiving parenteral nutrition?

Table 4. Clinical evidence profile for high energy intake versus low energy intake

Appendix G. Economic evidence study selection

Economic evidence study selection for review question: How many kcal/kg/day should be given to preterm and term babies receiving parenteral nutrition?

One global search was conducted for all review questions. See supplementary material D for further information.

Appendix H. Economic evidence tables

Economic evidence tables for review question: How many kcal/kg/day should be given to preterm and term babies receiving parenteral nutrition?

No evidence was identified which was applicable to this review question.

Appendix I. Health economic evidence profiles

Economic evidence profiles for review question: How many kcal/kg/day should be given to preterm and term babies receiving parenteral nutrition?

No evidence was identified which was applicable to this review question.

Appendix J. Health economic analysis

Economic evidence analysis for review question: How many kcal/kg/day should be given to preterm and term babies receiving parenteral nutrition?

No economic analysis was conducted for this review question.

Appendix K. Excluded studies

Excluded studies for review question: How many kcal/kg/day should be given to preterm and term babies receiving parenteral nutrition?

Clinical studies

Table 5. Excluded studies and reasons for their exclusion

Economic studies

No economic evidence was identified for this review. See supplementary material D for further information.

Appendix L. Research recommendations

Research recommendations for review question: How many kcal/kg/day should be given to preterm and term babies receiving parenteral nutrition?

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.

Bookshelf ID: NBK555670PMID: 32282171

Table 1Summary of the protocol (PICO table)

Population	Babies born preterm, up to 28 days after their due birth date (preterm babies) Babies born at term, up to 28 days after their birth (term babies)
Intervention	Different kcal/kg/day
Comparison	Each other
Outcomes	Critical Body composition (e.g., measured as lean mass, fat-free mass, fat mass, adipose tissue) Nitrogen accretion Growth/anthropometric measures Head circumference Weight gain Height gain Important Mortality Adverse effects of PN: PN related liver disease (abnormal liver function, cholestasis, conjugated hyperbilirubinaemia, intrahepatocellular lipid) Hyperglycaemia Hypophosphataemia/hypercalcaemia Energy intake (as the actual amount given)

: PN: Parenteral nutrition

Table 2Summary of included studies

Study

Population

Intervention

Comparison

Outcomes

Comments

Duffy 1981

RCT

Canada

N= 24

Preterm babies with BW <1600g

Mean GA

29.6 weeks (SD 1.8)

Mean BW

1261g (SD 198)

High energy (n=12)

Target total calorie intake of 93 kcal/kg/day

Amigen (casein amino acid) or Vamin (crystalline amino acid mixture patterned on egg albumin)

Low energy (n=12)

Target total calorie intake of 68 kcal/kg/day

Amigen (casein amino acid) or Vamin (crystalline amino acid mixture patterned on egg albumin)

Nitrogen balance
Nitrogen retention
Weight gain
Energy intake

Vamin has a higher nitrogen content than Amigen, which affected nitrogen intake.

The Vamin and Amigen groups were combined for the purpose of analysis in order to compare high energy and low energy groups.

Forsyth 1995

Cross-over RCT

N = 20

Inclusion criteria not reported

Mean GA

30.9 weeks (SD 1.8)

Mean BW

1314g (SD 291)

High glucose regimen (n=20)

12 g/kg/day (8.3 mg/kg/minute) of glucose

Low glucose regimen (n=20)

8 g/kg/day (5.5 mg/kg/minute) of glucose

Energy intake

After 24 hours, infants were changed to the alternative regimen which was continued again for 24 hours.

Morgan 2014

RCT

N = 135

Babies <29 weeks, weighing <1200g; admitted within 48 hours of birth

Mean GA

26.7 weeks (SD 1.4)

Mean BW

892g (SD 171)

SCAMP (n=66)

Target total calorie intake of 108 kcal/kg/day

Control (n=69)

Target total calorie intake of 85 kcal/kg/day

Head circumference
Weight gain
Mortality
Hyperbilirubinae mia
Energy intake

Study was not powered to assess differences in major complications.

Pineault 1988

Observation al study

Canada

N = 16

Appropriate-forgestational-age babies with unchanging clinical conditions

Mean GA

35 weeks (SD 2.8)

Mean BW

2150g (SD 447)

High energy (n=8)

Target total calorie intake of 80 kcal/kg⁻¹/d⁻¹

Low energy (n=8)

Target total calorie intake of 60 kcal/kg⁻¹/d⁻¹

Nitrogen balance
Nitrogen retention
Head circumference
Weight gain
Length gain
Energy intake

All babies completed both a low fat (1g/kg⁻¹/d⁻¹ lipids) and high fat (3g/kg⁻¹/d⁻¹ lipids) nutrition phase.

The high fat and low fat groups were combined (where analyses were not reported separately) for the purpose of analysis in order to compare high energy and low energy groups.

Tan 2008

RCT

N = 114

Babies <29 weeks; admitted within 7 days of birth

Mean GA

26.1 weeks (SD 1.5)

Mean BW

913g (SD 221)

Hyperalimentation (n=55)

Target total calorie intake of 117 kcal/kg/day

Control (n=59)

Target total calorie intake of 93 kcal/kg/day

Head circumference (as measured by occipitofrontal circumference)
Weight gain
Length gain
Lower leg length
Mid-arm circumference
Energy intake

Study was not powered to detect a difference in head circumference

Zlotkin 1981

Observational study

Canada

N = 22

Premature babies that were appropriate size for gestational age

Mean GA

29.2 weeks (Range 25–33)

Mean BW

Not reported

High energy (n=18)

Target non-protein calorie intake 80 kcal/kg/day

Nitrogen intake of 320, 480 or 640mg/kg/day

Low energy (n=12)

Target non-protein calorie intake 50 kcal/kg/day

Nitrogen intake of 480 or 640 mg/kg/day

Nitrogen retention
Weight gain
Length gain
Energy intake

Babies with hyperbilirubinaemia were assigned to the low energy group and babies without hyperbilirubinaemia were assigned to the high energy group; 8 babies were included in more than one group.

A low energy, low nitrogen group was not included due to risk of very poor nitrogen retention and growth.

The low, medium and high nitrogen groups were combined for the purpose of analysis in order to compare high energy and low energy groups.

: BW: birthweight; GA: gestational age; RCT: randomised controlled trial; SCAMP: standardised, concentrated with added macronutrients parenteral; SD: standard deviation.

Field (based on PRISMA-P)	Content
Review question	How many kcal/kg/day should be given to preterm and term babies receiving parenteral nutrition?
Type of review question	Intervention
Objective of the review	What are the energy needs of preterm and term babies receiving parenteral nutrition?
Eligibility criteria – population/disease/condition/issue/domain	Babies born preterm, up to 28 days after their due birth date (preterm babies) Babies born at term, up to 28 days after their birth (term babies)
Eligibility criteria – intervention(s)/exposure(s)/prognostic factor(s)	Different kcal/kg/day
Eligibility criteria – comparator(s)/control or reference (gold) standard	Each other
Outcomes and prioritisation	Critical outcomes: Body composition (measured as lean mass, fat-free mass, fat mass, adipose tissue) Nitrogen accretion Growth/anthropometric measures Head circumference Weight gain Height gain Important Outcomes: Mortality Adverse effects of PN: PN related liver disease (abnormal liver function, cholestasis, conjugated hyperbilirubinaemia, intrahepatocellular lipid) Hyperglycaemia Hypophosphataemia/hypercalcaemia Energy intake (as the actual amount given)
Eligibility criteria – study design	Systematic reviews of RCTs RCTs Comparative cohort studies (only if RCTs unavailable or limited data to inform decision making) Conference abstracts of RCTs will only be considered if no evidence is available from full published RCTs (if no evidence from RCTs or comparative cohort studies available and are recent i.e., in the last 2 years-authors will be contacted for further information).
Other inclusion exclusion criteria	No sample size restriction No date restriction Clinical settings that provide neonatal care or specialist paediatric care. UK and non-UK studies (non-UK studies from middle and high income countries according to WHO/World Bank criteria).
Proposed sensitivity/sub-group analysis, or meta-regression	Stratified analysis: Babies born preterm, up to 28 days after their due birth date (preterm babies) Babies born at term, up to 28 days after their birth (term babies) Subgroup analysis: The following groups will be considered for subgroup analysis: Age of baby (first 2 weeks versus later) Preterm (extremely preterm <28 weeks GA; very preterm: 28–31 weeks GA; moderately preterm: 32–36 weeks GA) Birthweight: low birthweight (<2500g); very low birthweight (<1500g) and extremely low birthweight (<1000g) Critically ill babies IUGR Specialist versus standard neonatal care Important confounders (when comparative observational studies are included for interventional reviews) Age of baby (first 2 weeks versus later) Birthweight: low birthweight (<2500g); very low birthweight (<1500g) and extremely low birthweight (<1000g) Actual dose received Other underlying conditions (e.g., chronic lung disease) Sex of baby Gestation (preterm vs. term)
Selection process – duplicate screening/selection/analysis	Sifting, data extraction, appraisal of methodological quality and GRADE assessment will be performed by the systematic reviewer. Quality control will be performed by the senior systematic reviewer. A random sample of the references identified in the search will be sifted by a second reviewer. This sample size will be 10% of the total, or 100 studies if the search identifies fewer than 1000 studies. All disagreements in study inclusion will be discussed and resolved between the two reviewers. The senior systematic reviewer or guideline lead will be involved if discrepancies cannot be resolved between the two reviewers.
Data management (software)	Data Analysis Where data is available, pair-wise meta-analysis using a fixed effects model, will be used to combine results from similar studies, this will be performed using Cochrane Review Manager (RevMan5). Heterogeneity will be considered, and if a random-effects model is considered more appropriate, it will be conducted. Quality Assessment Appraisal of methodological quality will be conducted using the appropriate tool: ROBIS (systematic reviews and meta-analyses), Cochrane risk of bias tool for RCT (RCT or comparative cohort studies). Cochrane risk of bias tool, ROBINS-I (Non-randomised studies) The quality of evidence for each outcome will be assessed using GRADEpro: Outcomes will be downgraded if the randomisation and/or concealment methods are unclear or inadequate. Outcomes will also be downgraded if there is considerable missing data (if there is a dropout of more than 20%, or if there is a difference of >20% between groups. Heterogeneity will be assessed using the I2, outcomes will be downgraded once if I2 >50%, twice if I2 >80%. Imprecision: Outcomes will be downgraded if the 95% CI is imprecise (i.e. crosses 0.8 or 1.25, (dichotomous) or −0.5 or 0.5 (continuous)). Outcomes will be downgraded two levels depending on how many lines of imprecision are crossed. If the clinical decision threshold is NOT crossed, we will consider whether the criterion for Optimal Information Size is met, if not we will downgrade one level for dichotomous outcomes with less than 300 events, and downgrade one level for continuous outcomes when less than 400 participants are included. Clinical effectiveness For dichotomous outcomes, minimal important differences will be considered using thresholds of RR >0.80 and <1.25. For continuous outcomes, minimal important differences will be considered 0.5 times the SD of the control group
Information sources – databases and dates	Sources to be searched: Medline, Medline In-Process, CCTR, CDSR, DARE, HTA, Embase. Limits (e.g. date, study design): All study designs. Apply standard animal/non-English language filters. No date limit. Supplementary search techniques: No supplementary search techniques were used. See appendix B for full strategies.
Identify if an update	This is not an update.
Author contacts	Developer: The National Guideline Alliance https://www.nice.org.uk/guidance/indevelopment/gid-ng10037
Highlight if amendment to previous protocol	For details please see section 4.5 of Developing NICE guidelines: the manual 2014.
Search strategy – for one database	For details please see appendix B.
Data collection process – forms/duplicate	A standardised evidence table format will be used, and published as appendix D (clinical evidence tables) or H (economic evidence tables).
Data items – define all variables to be collected	For details please see appendix B.
Methods for assessing bias at outcome/study level	Standard study checklists were used to critically appraise individual studies. For details please see section 6.2 of Developing NICE guidelines: the manual 2014. The risk of bias across all available evidence was evaluated for each outcome using an adaptation of the ‘Grading of Recommendations Assessment, Development and Evaluation (GRADE) toolbox’ developed by the international GRADE working group http://www.gradeworkinggroup.org/
Criteria for quantitative synthesis (where suitable)	For details please see section 6.4 of Developing NICE guidelines: the manual 2014.
Methods for analysis – combining studies and exploring (in)consistency	For details of the methods please see supplementary material C.
Meta-bias assessment – publication bias, selective reporting bias	For details please see section 6.2 of Developing NICE guidelines: the manual 2014. If sufficient relevant RCT evidence is available, publication bias will be explored using RevMan software to examine funnel plots. Trial registries will be examined to identify missing evidence: Clinical trials.gov, NIHR Clinical Trials Gateway.
Assessment of confidence in cumulative evidence	For details please see sections 6.4 and 9.1 of Developing NICE guidelines: the manual 2014.
Rationale/context – Current management	For details please see the introduction to the evidence review.
Describe contributions of authors and guarantor	A multidisciplinary committee developed the guideline. The committee was convened by the National Guideline Alliance and chaired by Joe Fawke (Consultant Neonatologist and Honorary Senior Lecturer, University Hospitals Leicester NHS Trust) in line with section 3 of Developing NICE guidelines: the manual 2014. Staff from the National Guideline Alliance undertook systematic literature searches, appraised the evidence, conducted meta-analysis and cost-effectiveness analysis where appropriate, and drafted the guideline in collaboration with the committee. For details of the methods please see supplementary material C.
Sources of funding/support	The National Guideline Alliance is funded by NICE and hosted by the Royal College of Obstetricians and Gynaecologists.
Name of sponsor	The National Guideline Alliance is funded by NICE and hosted by the Royal College of Obstetricians and Gynaecologists.
Roles of sponsor	NICE funds the National Guideline Alliance to develop guidelines for those working in the NHS, public health, and social care in England.
PROSPERO registration number	Not registered with PROSPERO.

: CDSR: Cochrane Database of Systematic Reviews; DARE: Database of Abstracts of Reviews of Effects; GA: gestational age; GRADE: Grading of Recommendations Assessment, Development and Evaluation; HTA: Health Technology Assessment; IUGR: intrauterine growth restriction; NGA: National Guideline Alliance; NHS: National health service; NICE: National Institute for Health and Care Excellence; PN: parenteral nutrition; RCT: randomised controlled trial; RoB: risk of bias; ROBINS-I: risk of bias in non-randomised studies of interventions; ROBIS; risk of bias in systematic reviews; SD: standard deviation; UK: United Kingdom; WHO: World Health Organisation.

Databases: Medline; Medline EPub Ahead of Print; and Medline In-Process & Other Non-Indexed Citations

#	Searches
1	INFANT, NEWBORN/
2	(neonat$ or newborn$ or new-born$ or baby or babies).ti,ab.
3	PREMATURE BIRTH/
4	((preterm$ or pre-term$ or prematur$ or pre-matur$) adj5 (birth? or born)).ab,ti.
5	exp INFANT, PREMATURE/
6	((preterm$ or pre-term$ or prematur$ or pre-matur$) adj5 infan$).ti,ab.
7	(pre#mie? or premie or premies).ti,ab.
8	exp INFANT, LOW BIRTH WEIGHT/
9	(low adj3 birth adj3 weigh$ adj5 infan$).ti,ab.
10	((LBW or VLBW) adj5 infan$).ti,ab.
11	INTENSIVE CARE, NEONATAL/
12	INTENSIVE CARE UNITS, NEONATAL/
13	NICU?.ti,ab.
14	or/1–13
15	PARENTERAL NUTRITION/
16	PARENTERAL NUTRITION, TOTAL/
17	PARENTERAL NUTRITION SOLUTIONS/
18	ADMINISTRATION, INTRAVENOUS/
19	INFUSIONS, INTRAVENOUS/
20	CATHETERIZATION, CENTRAL VENOUS/
21	exp CATHETERIZATION, PERIPHERAL/
22	(parenteral$ or intravenous$ or intra-venous$ or IV or venous$ or infusion?).ti,ab.
23	((peripheral$ or central$) adj3 (line? or catheter$)).ti,ab.
24	drip?.ti,ab.
25	or/15–24
26	ENERGY INTAKE/
27	(energy adj5 (need$ or requir$ or receiv$ or intake? or amount? or optimal$ or optimis$ or target? or goal? or suffic$)).ti,ab.
28	((kcal? or kilocalorie? or calori$) adj5 (need$ or requir$ or receiv$ or intake? or amount? or optimal$ or optimis$ or target? or goal? or suffic$)).ti,ab.
29	((kcal? or kilocalorie?) adj3 (kg? or kilogram?) adj3 (d or day)).ti,ab.
30	or/26–29
31	ENERGY METABOLISM/
32	(energy adj3 (metabolism or expend$)).ti,ab.
33	or/31–32
34	14 and 25 and 30
35	14 and 25 and 33
36	or/34–35
37	limit 36 to english language
38	LETTER/
39	EDITORIAL/
40	NEWS/
41	exp HISTORICAL ARTICLE/
42	ANECDOTES AS TOPIC/
43	COMMENT/
44	CASE REPORT/
45	(letter or comment*).ti.
46	or/38–45
47	RANDOMIZED CONTROLLED TRIAL/ or random*.ti,ab.
48	46 not 47
49	ANIMALS/ not HUMANS/
50	exp ANIMALS, LABORATORY/
51	exp ANIMAL EXPERIMENTATION/
52	exp MODELS, ANIMAL/
53	exp RODENTIA/
54	(rat or rats or mouse or mice).ti.
55	or/48–54
56	37 not 55

Databases: Embase; and Embase Classic

#	Searches
1	NEWBORN/
2	(neonat$ or newborn$ or new-born$ or baby or babies).ti,ab.
3	PREMATURITY/
4	((preterm$ or pre-term$ or prematur$ or pre-matur$) adj5 (birth? or born)).ab,ti.
5	((preterm$ or pre-term$ or prematur$ or pre-matur$) adj5 infan$).ti,ab.
6	(pre#mie? or premie or premies).ti,ab.
7	exp LOW BIRTH WEIGHT/
8	(low adj3 birth adj3 weigh$ adj5 infan$).ti,ab.
9	((LBW or VLBW) adj5 infan$).ti,ab.
10	NEWBORN INTENSIVE CARE/
11	NEONATAL INTENSIVE CARE UNIT/
12	NICU?.ti,ab.
13	or/1–12
14	PARENTERAL NUTRITION/
15	TOTAL PARENTERAL NUTRITION/
16	PERIPHERAL PARENTERAL NUTRITION/
17	PARENTERAL SOLUTIONS/
18	INTRAVENOUS FEEDING/
19	INTRAVENOUS DRUG ADMINISTRATION/
20	exp INTRAVENOUS CATHETER/
21	(parenteral$ or intravenous$ or intra-venous$ or IV or venous$ or infusion?).ti,ab.
22	((peripheral$ or central$) adj3 (line? or catheter$)).ti,ab.
23	drip?.ti,ab.
24	or/14–23
25	CALORIC INTAKE/
26	(energy adj5 (need$ or requir$ or receiv$ or intake? or amount? or optimal$ or optimis$ or target? or goal? or suffic$)).ti,ab.
27	((kcal? or kilocalorie? or calori$) adj5 (need$ or requir$ or receiv$ or intake? or amount? or optimal$ or optimis$ or target? or goal? or suffic$)).ti,ab.
28	((kcal? or kilocalorie?) adj3 (kg? or kilogram?) adj3 (d or day)).ti,ab.
29	or/25–28
30	ENERGY METABOLISM/
31	(energy adj3 (metabolism or expend$)).ti,ab.
32	or/30–31
33	13 and 24 and 29
34	13 and 24 and 32
35	or/33–34
36	limit 35 to english language
37	letter.pt. or LETTER/
38	note.pt.
39	editorial.pt.
40	CASE REPORT/ or CASE STUDY/
41	(letter or comment*).ti.
42	or/37–41
43	RANDOMIZED CONTROLLED TRIAL/ or random*.ti,ab.
44	42 not 43
45	ANIMAL/ not HUMAN/
46	NONHUMAN/
47	exp ANIMAL EXPERIMENT/
48	exp EXPERIMENTAL ANIMAL/
49	ANIMAL MODEL/
50	exp RODENT/
51	(rat or rats or mouse or mice).ti.
52	or/44–51
53	36 not 52

Databases: Cochrane Central Register of Controlled Trials; Cochrane Database of Systematic Reviews; Database of Abstracts of Reviews of Effects; and Health Technology Assessment

#	Searches
1	MeSH descriptor: [INFANT, NEWBORN] this term only
2	(neonat* or newborn* or new-born* or baby or babies):ti,ab
3	MeSH descriptor: [PREMATURE BIRTH] this term only
4	((preterm* or pre-term* or prematur* or pre-matur*) near/5 (birth? or born)).ab,ti.
5	MeSH descriptor: [INFANT, PREMATURE] explode all trees
6	((preterm* or pre-term* or prematur* or pre-matur) near/5 infan):ti,ab
7	(pre#mie? or premie or premies):ti,ab
8	MeSH descriptor: [INFANT, LOW BIRTH WEIGHT] explode all trees
9	(low near/3 birth near/3 weigh* near/5 infan*):ti,ab
10	((LBW or VLBW) near/5 infan*):ti,ab
11	MeSH descriptor: [INTENSIVE CARE, NEONATAL] this term only
12	MeSH descriptor: [INTENSIVE CARE UNITS, NEONATAL] this term only
13	NICU?:ti,ab
14	#1 or #2 or #3 or #4 or #5 or #6 or #7 or #8 or #9 or #10 or #11 or #12 or #13
15	MeSH descriptor: [PARENTERAL NUTRITION] this term only
16	MeSH descriptor: [PARENTERAL NUTRITION, TOTAL] this term only
17	MeSH descriptor: [PARENTERAL NUTRITION SOLUTIONS] this term only
18	MeSH descriptor: [ADMINISTRATION, INTRAVENOUS] this term only
19	MeSH descriptor: [INFUSIONS, INTRAVENOUS] this term only
20	MeSH descriptor: [CATHETERIZATION, CENTRAL VENOUS] this term only
21	MeSH descriptor: [CATHETERIZATION, PERIPHERAL] explode all trees
22	(parenteral* or intravenous* or intra-venous* or IV or venous* or infusion?):ti,ab
23	((peripheral* or central) near/3 (line? or catheter)):ti,ab
24	drip?:ti,ab
25	#15 or #16 or #17 or #18 or #19 or #20 or #21 or #22 or #23 or #24
26	MeSH descriptor: [ENERGY INTAKE] this term only
27	(energy near/5 (need* or requir* or receiv* or intake? or amount? or optimal* or optimis* or target? or goal? or suffic*)):ti,ab
28	((kcal? or kilocalorie? or calori) near/5 (need or requir* or receiv* or intake? or amount? or optimal* or optimis* or target? or goal? or suffic*)):ti,ab
29	((kcal? or kilocalorie?) and (kg? or kilogram?) and (d or day)):ti,ab
30	#26 or #27 or 28 or #29
31	MeSH descriptor: [ENERGY METABOLISM] this term only
32	(energy near/3 (metabolism or expend*)):ti,ab
33	#31 or #32
34	#14 and #25 and #30
35	#14 and #25 and #33
36	#34 or #35

Figure 1PRISMA Flow chart of clinical article selection for review question on energy needs of preterm and term babies

Figure 2Forest plot for comparison high energy intake versus low energy intake: Nitrogen retention (%)

Figure 3Forest plot for comparison high energy intake versus low energy intake: Nitrogen balance

Figure 4Forest plot for comparison high energy intake versus low energy intake: Weight (g)

Figure 5Forest plot for comparison high energy intake versus low energy intake: Weight gain

Figure 6Forest plot for comparison high energy intake versus low energy intake: Length gain (cm/week)

Figure 7Forest plot for comparison high energy intake versus low energy intake: Energy intake

Table 4Clinical evidence profile for high energy intake versus low energy intake

Quality assessment							No of patients		Effect		Quality	Importance
No of studies	Design	Risk of bias	Inconsistency	Indirectness	Imprecision	Other considerations	High energy intake	Low energy intake	Relative (95% CI)	Absolute	Quality	Importance
Nitrogen retention (%) (Better indicated by higher values)
1	randomised trials	serious¹	no serious inconsistency	no serious indirectness	serious²	none	12	12	-	14 higher (4.52 to 23.48 higher)	⨁⨁◯◯ LOW	CRITICAL
Nitrogen retention (%) (Better indicated by higher values)
2	observational studies	very serious³	very serious⁴	no serious indirectness	serious⁵	none	34^*	32^*	-	12.16 higher (1.73 to 22.58 higher)	⨁◯◯◯ VERY LOW	CRITICAL
Nitrogen balance - Nitrogen balance (mg/kg/day) (Better indicated by higher values)
1	randomised trials	serious¹	no serious inconsistency	no serious indirectness	serious⁶	none	12	12	-	MD 66 higher (14.98 to 117.02 higher)	⨁⨁◯◯ LOW	CRITICAL
Nitrogen balance - Nitrogen balance (mg/kg/day) (Better indicated by higher values)
2	observational studies	very serious³	no serious inconsistency	no serious indirectness	serious⁷	none	34^*	28^*	-	MD 33.59 higher (5.65 to 61.52 higher)	⨁◯◯◯ VERY LOW	CRITICAL
Head circumference (mm) - Day 7 (Better indicated by higher values)
1	randomised trials	no serious risk of bias	no serious inconsistency	no serious indirectness	no serious imprecision	none	66	69	-	MD 1 higher (3.39 lower to 5.39 higher)	⨁⨁⨁⨁ HIGH	CRITICAL
Head circumference (mm) - Day 14 (Better indicated by higher values)
1	randomised trials	no serious risk of bias	no serious inconsistency	no serious indirectness	no serious imprecision	none	66	69	-	MD 2 higher (2.39 lower to 6.39 higher)	⨁⨁⨁⨁ HIGH	CRITICAL
Head circumference (mm) - Day 21 (Better indicated by higher values)
1	randomised trials	no serious risk of bias	no serious inconsistency	no serious indirectness	serious⁸	none	66	69	-	MD 4 higher (1.07 lower to 9.07 higher)	⨁⨁⨁◯ MODERATE	CRITICAL
Head circumference (mm) - Day 28 (Better indicated by higher values)
1	randomised trials	no serious risk of bias	no serious inconsistency	no serious indirectness	serious⁹	none	66	69	-	MD 6 higher (0.43 to 11.57 higher)	⨁⨁⨁◯ MODERATE	CRITICAL
Head circumference (mm) - At 36 weeks’ CGA (Better indicated by higher values)
2	randomised trials	serious¹⁰	serious¹¹	no serious indirectness	serious¹²	none	118	122	-	MD 1.04 higher (6.8 lower to 8.88 higher)	⨁◯◯◯ VERY LOW	CRITICAL
Head circumference z-score at 36 weeks’ CGA (Better indicated by higher values)
1	randomised trials	serious¹⁰	no serious inconsistency	no serious indirectness	serious¹³	none	55	59	-	MD 0.2 lower (0.62 lower to 0.22 higher)	⨁⨁◯◯ LOW	CRITICAL
Head circumference gain (cm/week) (Better indicated by higher values)
1	observational studies	serious¹⁴	no serious inconsistency	no serious indirectness	serious¹⁵	none	7	8	-	MD 0.40 higher (0.02 to 0.78 higher)	⨁◯◯◯ VERY LOW	CRITICAL
Weight (g) - Day 7 (Better indicated by higher values)
1	randomised trials	no serious risk of bias	no serious inconsistency	no serious indirectness	no serious imprecision	none	66	69	-	31 higher (8.22 lower to 70.22 higher)	⨁⨁⨁⨁ HIGH	CRITICAL
Weight (g) - Day 14 (Better indicated by higher values)
1	randomised trials	no serious risk of bias	no serious inconsistency	no serious indirectness	serious¹⁶	none	66	69	-	55 higher (9.24 to 100.76 higher)	⨁⨁⨁◯ MODERATE	CRITICAL
Weight (g) - Day 21 (Better indicated by higher values)
1	randomised trials	no serious risk of bias	no serious inconsistency	no serious indirectness	serious¹⁷	none	66	69	-	75 higher (20.78 to 129.22 higher)	⨁⨁⨁◯ MODERATE	CRITICAL
Weight (g) - Day 28 (Better indicated by higher values)
1	randomised trials	no serious risk of bias	no serious inconsistency	no serious indirectness	serious¹⁸	none	66	69	-	57 higher (8.7 lower to 122.7 higher)	⨁⨁⨁◯ MODERATE	CRITICAL
Weight (g) - At 36 weeks’ CGA (Better indicated by higher values)
2	randomised trials	serious¹⁰	no serious inconsistency	no serious indirectness	no serious imprecision	none	117	121	-	77.31 higher (8.89 to 145.74 higher)	⨁⨁⨁◯ MODERATE	CRITICAL
Weight gain - g/day (Better indicated by higher values)
1	randomised trials	serious¹	no serious inconsistency	no serious indirectness	very serious¹⁹	none	12	12	-	MD 10 higher (21.7 lower to 41.7 higher)	⨁◯◯◯ VERY LOW	CRITICAL
Weight gain - g/kg/day (Better indicated by higher values)
2	observational studies	very serious³	serious¹¹	no serious indirectness	serious²⁰	none	26	20	-	MD 7.12 higher (0.75 lower to 14.99 higher)	⨁◯◯◯ VERY LOW	CRITICAL
Weight z-score at 36 weeks’ CGA (Better indicated by higher values)
1	randomised trials	serious¹⁰	no serious inconsistency	no serious indirectness	serious²¹	none	55	59	-	MD 0.1 higher (0.21 lower to 0.41 higher)	⨁⨁◯◯ LOW	CRITICAL
Mid-arm circumference (cm) at 36 weeks’ CGA (Better indicated by higher values)
1	randomised trials	serious¹⁰	no serious inconsistency	no serious indirectness	no serious imprecision	none	55	59	-	mean 0.10 higher (0.19 lower to 0.39 higher)	⨁⨁⨁◯ MODERATE	CRITICAL
Length (cm) at 36 weeks’ CGA (Better indicated by higher values)
1	randomised trials	serious¹⁰	no serious inconsistency	no serious indirectness	serious²²	none	55	59	-	MD 0.5 higher (0.31 lower to 1.31 higher)	⨁⨁◯◯ LOW	CRITICAL
Length gain (cm/week) (Better indicated by higher values)
2	observational studies	very serious³	no serious inconsistency	no serious indirectness	serious²³	none	21	20	-	MD 0.29 higher (0.12 to 0.46 higher)	⨁◯◯◯ VERY LOW	CRITICAL
Length z-score at 36 weeks’ CGA (Better indicated by higher values)
1	randomised trials	serious¹⁰	no serious inconsistency	no serious indirectness	serious²⁴	none	55	59	-	MD 0.3 higher (0.16 lower to 0.76 higher)	⨁⨁◯◯ LOW	CRITICAL
Lower leg length (cm) at 36 weeks’ CGA (Better indicated by higher values)
1	randomised trials	serious¹⁰	no serious inconsistency	no serious indirectness	no serious imprecision	none	55	59	-	MD 0 higher (0.26 lower to 0.26 higher)	⨁⨁⨁◯ MODERATE	CRITICAL
Mortality - Day 28
1	randomised trials	no serious risk of bias	no serious inconsistency	no serious indirectness	very serious²⁵	none	8/74 (10.8%)	7/76 (9.2%)	RR 1.17 (0.45 to 3.07)	16 more per 1000 (from 51 fewer to 191 more)	⨁⨁◯◯ LOW	IMPORTANT
Mortality - At 36 weeks’ CGA
1	randomised trials	no serious risk of bias	no serious inconsistency	no serious indirectness	very serious²⁵	none	11/63 (17.5%)	12/64 (18.8%)	RR 0.93 (0.44 to 1.95)	13 fewer per 1000 (from 105 fewer to 178 more)	⨁⨁◯◯ LOW	IMPORTANT
Conjugated hyperbilirubinaemia (conjugated bilirubin > 50 mmol/L) - Day 28
1	randomised trials	no serious risk of bias	no serious inconsistency	no serious indirectness	very serious²⁵	none	6/66 (9.1%)	8/69 (11.6%)	RR 0.78 (0.29 to 2.14)	26 fewer per 1000 (from 82 fewer to 132 more)	⨁⨁◯◯ LOW	IMPORTANT
Conjugated hyperbilirubinaemia (conjugated bilirubin > 50 mmol/L) - At 36 weeks’ CGA
1	randomised trials	no serious risk of bias	no serious inconsistency	no serious indirectness	very serious²⁵	none	13/63 (20.6%)	12/64 (18.8%)	RR 1.1 (0.54 to 2.22)	19 more per 1000 (from 86 fewer to 229 more)	⨁⨁◯◯ LOW	IMPORTANT
Energy intake - kcal/kg/d in the first 48 hours of life (Better indicated by higher values)
1	randomised trials	serious²⁶	no serious inconsistency	no serious indirectness	serious²⁷	none	20^ᵼ	20^ᵼ	-	MD 15.3 higher (4.07 to 26.53 higher)	⨁⨁◯◯ LOW	IMPORTANT
Energy intake - kcal/kg/d at week 1 (Better indicated by higher values)
1	randomised trials	no serious risk of bias	no serious inconsistency	no serious indirectness	no serious imprecision	none	66	69	-	MD 7 higher (4.61 to 9.39 higher)	⨁⨁⨁⨁ HIGH	IMPORTANT
Energy intake - kcal/kg/d at week 2 (Better indicated by higher values)
1	randomised trials	no serious risk of bias	no serious inconsistency	no serious indirectness	no serious imprecision	none	66	69	-	MD 17 higher (9.87 to 24.13 higher)	⨁⨁⨁⨁ HIGH	IMPORTANT
Energy intake - kcal/kg/d at week 3 (Better indicated by higher values)
1	randomised trials	no serious risk of bias	no serious inconsistency	no serious indirectness	serious²⁸	none	66	69	-	MD 9 higher (2.35 lower to 20.35 higher)	⨁⨁⨁◯ MODERATE	IMPORTANT
Energy intake - kcal/kg/d at week 4 (Better indicated by higher values)
1	randomised trials	no serious risk of bias	no serious inconsistency	no serious indirectness	serious²⁹	none	66	69	-	MD 5 higher (5.24 lower to 15.24 higher)	⨁⨁⨁◯ MODERATE	IMPORTANT
Energy intake - Cumulative kcal/kg in the first 28 days of life (Better indicated by higher values)
2	randomised trials	serious¹⁰	no serious inconsistency	no serious indirectness	serious³⁰	none	121	128	-	MD 165.26 higher (93.78 to 236.73 higher)	⨁⨁◯◯ LOW	IMPORTANT
Energy intake (kcal/kg/day) - timeframe unclear (Better indicated by higher values)
1	randomised trials	serious¹	no serious inconsistency	no serious indirectness	no serious imprecision	none	12	12	-	MD 25 higher (18.58 to 31.42 higher)	⨁⨁⨁◯ MODERATE	IMPORTANT
Energy intake (kcal/kg/day) - timeframe unclear (Better indicated by higher values)
1	observational studies	serious¹⁴	no serious inconsistency	no serious indirectness	no serious imprecision	none	8	8	-	MD 18.2 higher (15.65 to 20.75 higher)	⨁◯◯◯ VERY LOW	IMPORTANT

: CI: confidence interval; MD: mean difference; RR: risk ratio.

1: Evidence was downgraded by 1 due to unclear risk of selection bias

2: Evidence downgraded by 1 due to serious imprecision; 95% confidence intervals cross 1 default MID for continuous variables, calculated as 0.5 of SD of low energy group at baseline (8.28)

3: Evidence was downgraded by 2 due to high risk of selection bias in one study and moderate risk of selective reporting bias

4: Evidence was downgraded by 2 due to high heterogeneity

5: Evidence downgraded by 1 due to serious imprecision; 95% confidence intervals cross 1 default MID for continuous variables, calculated as 0.5 of SD of low energy group at baseline (5.62)

6: Evidence downgraded by 1 due to serious imprecision; 95% confidence intervals cross 1 default MID for continuous variables, calculated as 0.5 of SD of low energy group at baseline (32.95)

7: Evidence downgraded by 1 due to serious imprecision; 95% confidence intervals cross 1 default MID for continuous variables, calculated as 0.5 of SD of low energy group at baseline (26.35)

8: Evidence downgraded by 1 due to serious imprecision; 95% confidence intervals cross 1 default MID for continuous variables, calculated as 0.5 of SD of low energy group at baseline (8.00)

9: Evidence downgraded by 1 due to serious imprecision; 95% confidence intervals cross 1 default MID for continuous variables, calculated as 0.5 of SD of low energy group at baseline (8.50)

10: Evidence was downgraded by 1 due to high risk of attrition bias in one of the studies

11: Evidence was downgraded by 1 due to moderate heterogeneity

12: Evidence downgraded by 1 due to serious imprecision; 95% confidence intervals cross 1 default MID for continuous variables, calculated as 0.5 of SD of low energy group at baseline (7.02)

13: Evidence downgraded by 1 due to serious imprecision; 95% confidence intervals cross 1 default MID for continuous variables, calculated as 0.5 of SD of low energy group at baseline (−0.55)

14: Evidence was downgraded by 1 due to moderate risk of selective reporting bias

15: Evidence downgraded by 1 due to serious imprecision; 95% confidence intervals cross 1 default MID for continuous variables, calculated as 0.5 of SD of low energy group at baseline (0.17)

16: Evidence downgraded by 1 due to serious imprecision; 95% confidence intervals cross 1 default MID for continuous variables, calculated as 0.5 of SD of low energy group at baseline (85.5)

17: Evidence downgraded by 1 due to serious imprecision; 95% confidence intervals cross 1 default MID for continuous variables, calculated as 0.5 of SD of low energy group at baseline (104.50)

18: Evidence downgraded by 1 due to serious imprecision; 95% confidence intervals cross 1 default MID for continuous variables, calculated as 0.5 of SD of low energy group at baseline (121.00)

19: Evidence downgraded by 2 due to very serious imprecision; 95% confidence intervals cross 2 default MIDs for continuous variables, calculated as 0.5 of SD of low energy group at baseline (−15.05, 15.05)

20: Evidence downgraded by 1 due to serious imprecision; 95% confidence intervals cross 1 default MID for continuous variables, calculated as 0.5 of SD of low energy group at baseline (3.85)

21: Evidence downgraded by 1 due to serious imprecision; 95% confidence intervals cross 1 default MID for continuous variables, calculated as 0.5 of SD of low energy group at baseline (0.40)

22: Evidence downgraded by 1 due to serious imprecision; 95% confidence intervals cross 1 default MID for continuous variables, calculated as 0.5 of SD of low energy group at baseline (1.05)

23: Evidence downgraded by 1 due to serious imprecision; 95% confidence intervals cross 1 default MID for continuous variables, calculated as 0.5 of SD of low energy group at baseline (0.16)

24: Evidence downgraded by 1 due to serious imprecision; 95% confidence intervals cross 1 default MID for continuous variables, calculated as 0.5 of SD of low energy group at baseline (0.60)

25: Evidence downgraded by 2 due to very serious imprecision; 95% confidence intervals cross 2 default MIDs for dichotomous outcomes (0.80, 1.25)

26: Evidence was downgraded by 1 due to unclear risk of selection bias and high risk of other bias

27: Evidence downgraded by 1 due to serious imprecision; 95% confidence intervals cross 1 default MID for continuous variables, calculated as 0.5 of SD of low energy group at baseline (8.95)

28: Evidence downgraded by 1 due to serious imprecision; 95% confidence intervals cross 1 default MID for continuous variables, calculated as 0.5 of SD of low energy group at baseline (15.5)

29: Evidence downgraded by 1 due to serious imprecision; 95% confidence intervals cross 1 default MID for continuous variables, calculated as 0.5 of SD of low energy group at baseline (13.00)

30: Evidence downgraded by 1 due to serious imprecision; 95% confidence intervals cross 1 default MID for continuous variables, calculated as 0.5 of SD of low energy group at baseline (168.36)

*: 8 babies were included in each arm in Pineault 1988, but two nutrition phases were completed resulting in n=16 in each arm

ᵼ: cross over study – 20 babies, acting as their own control

Table 5Excluded studies and reasons for their exclusion

Study	Reason for Exclusion
Bajaj, N., Preterm nutrition and neurodevelopment: An overview, Perinatology, 17, 153–162, 2017	Narrative review.
Balasubramanian, H., Nanavati, R. N., Kabra, N. S., Effect of two different doses of parenteral amino acid supplementation on postnatal growth of very low birth weight neonates - A randomized controlled trial, Indian Pediatrics, 50, 1131–6, 2013 [PubMed: 23999674]	Study intervention does not meet protocol eligibility criteria - study compares amino acid intakes.
Bell, E. F., Filer, L. J., Jr., Wong, A. P., Stegink, L. D., Effects of a parenteral nutrition regimen containing dicarboxylic amino acids on plasma, erythrocyte, and urinary amino acid concentrations of young infants, The American journal of clinical nutrition, 37, 99–107, 1983 [PubMed: 6129797]	Study intervention does not meet protocol eligibility criteria - both interventions receive the same calorie intake.
Ben, X. M., Nutritional management of newborn infants: Practical guidelines, World Journal of Gastroenterology, 14, 6133–6139, 2008 [PMC free article: PMC2761573] [PubMed: 18985802]	Study design does not meet protocol eligibility criteria - Guideline publication - references checked for relevant papers.
Blau, Jonathan, Sridhar, Shanthy, Mathieson, Susan, Chawla, Anupama, Effects of protein/nonprotein caloric intake on parenteral nutrition associated cholestasis in premature infants weighing 600–1000 grams, JPEN. Journal of parenteral and enteral nutrition, 31, 487–90, 2007 [PubMed: 17947604]	Study intervention does not meet protocol eligibility criteria - different kcal/kg/day not stated for each regimen, only actual intakes reported for cholestasis vs non cholestasis infants.
Bockenkamp, B., Jouvet, P., Arsenault, V., Beausejour, M., Pelletier, V. A., Assessment of calories prescribed and delivered to critically ill children, e-SPEN, 4, e172–e175, 2009	Study intervention does not meet protocol eligibility criteria - Infants receive both parenteral and enteral nutrition.
Bolisetty, S., Pharande, P., Nirthanakumaran, L., Quy-Phong Do, T., Osborn, D., Smyth, J., Sinn, J., Lui, K., Improved nutrient intake following implementation of the consensus standardised parenteral nutrition formulations in preterm neonates a before-after intervention study, BMC Pediatrics, 14, 309, 2014 [PMC free article: PMC4275977] [PubMed: 25514973]	Study does not meet protocol eligibility criteria - a retrospective before and after cohort study. The intervention does not meet inclusion criteria - the study compares the effect of introducing a new management protocol and does not stated administered calorie levels.
Bonsante,F., Iacobelli,S., Chantegret,C., Martin,D., Gouyon,J.B., The effect of parenteral nitrogen and energy intake on electrolyte balance in the preterm infant, European Journal of Clinical Nutrition, 65, 1088–1093, 2011 [PubMed: 21587281]	Study design does not meet protocol eligibility criteria - non-comparative cohort study.
Brans, Y. W., Andrew, D. S., Carrillo, D. W., Dutton, E. P., Menchaca, E. M., Puleo-Scheppke, B. A., Tolerance of fat emulsions in very-low-birth-weight neonates, American journal of diseases of children (1960), 142, 145–52, 1988 [PubMed: 3124602]	Study intervention does not meet eligibility criteria - amount of administered kcal/kg/day not stated.
Brener Dik, P. H., Galletti, M. F., Bacigalupo, L. T., Jonusas, S. F., Mariani, G. L., Hypercalcemia and hypophosphatemia among preterm infants receiving aggressive parenteral nutrition, Archivos Argentinos de Pediatria, 116, e371–e377, 2018 [PubMed: 29756708]	Intervention does not meet inclusion criteria - the study compares the effect of introducing a new nutrition protocol and does not state prescribed calorie levels.
Burattini, I., Bellagamba, M. P., Spagnoli, C., D’Ascenzo, R., Mazzoni, N., Peretti, A., Cogo, P. E., Carnielli, V. P., Targeting 2.5 versus 4 g/kg/day of amino acids for extremely low birth weight infants: A randomized clinical trial, Journal of Pediatrics, 163, 1278, 2013 [PubMed: 23941670]	Study intervention does not meet protocol eligibility criteria - energy provided was the same across intervention arms.
Burgess, L., Flanagan, B., Turner, M., Morgan, C., Elevated essential amino acid levels in very preterm infants receiving total parenteral nutrition, Journal of Pediatric Gastroenterology and Nutrition, 64, 797, 2017	Study intervention does not meet protocol eligibility criteria - amounts of energy administered not stated.
Burgess, Laura, Morgan, Colin, Mayes, Kelly, Tan, Maw, Plasma arginine levels and blood glucose control in very preterm infants receiving 2 different parenteral nutrition regimens, JPEN. Journal of parenteral and enteral nutrition, 38, 243–53, 2014 [PubMed: 23474648]	Study intervention does not meet protocol eligibility criteria - combination of PN and EN.
Butler, T. J., Szekely, L. J., Grow, J. L., A standardized nutrition approach for very low birth weight neonates improves outcomes, reduces cost and is not associated with increased rates of necrotizing enterocolitis, sepsis or mortality, Journal of Perinatology, 33, 851–7, 2013 [PubMed: 23765172]	Study intervention does not meet protocol eligibility criteria - the study is a before and after comparison of a standardised nutrition guidelines within a centre (which includes enteral feeding).
Calkins, K. L., Havranek, T., Kelley-Quon, L., Gibson, L., Venick, R., Shew, S., Low dose soybean oil for the prevention of parenteral nutrition associated cholestasis in neonates with congenital gastrointestinal disorders, Journal of Investigative Medicine, 61, 157–158, 2013	Study intervention does not meet protocol eligibility criteria-energy administered not stated and infants also received EN.
Can, E., Bulbul, A., Uslu, S., Comert, S., Bolat, F., Nuhoglu, A., Evaluation of two different types of parenteral nutrition on early growth of preterm infants, Early Human Development, 86, S85, 2010	Conference abstract.
Chessex, P., Gagne, G., Pineault, M., Vaucher, J., Bisaillon, S., Brisson, G., Metabolic and clinical consequences of changing from high-glucose to high-fat regimens in parenterally fed newborn infants, Journal of Pediatrics, 115, 992–997, 1989 [PubMed: 2511292]	Study intervention does not meet protocol eligibility criteria - calorie intake equal across interventions.
Choi, A. Y., Lee, Y. W., Chang, M. Y., Modification of nutrition strategy for improvement of postnatal growth in very low birth weight infants, Korean Journal of Pediatrics, 59, 165–173, 2016 [PMC free article: PMC4865639] [PubMed: 27186226]	Study intervention does not meet protocol eligibility criteria - change of protocol for parenteral and enteral feeding.
Collins, Carmel T., Chua, Mei Chien, Rajadurai, Victor S., McPhee, Andrew J., Miller, Lisa N., Gibson, Robert A., Makrides, Maria, Higher protein and energy intake is associated with increased weight gain in pre-term infants, Journal of Paediatrics and Child Health, 46, 96–102, 2010 [PubMed: 20105257]	Study intervention does not meet protocol eligibility criteria - EN.
Cooke, R. J., Zee, P., Yeh, Y. Y., Safflower oil emulsion administration during parenteral nutrition in the preterm infant. 1. Effect on essential fatty acid status, Journal of pediatric gastroenterology and nutrition, 4, 799–803, 1985 [PubMed: 3930688]	Study intervention does not meet protocol eligibility criteria - energy administered not stated.
De Lima, A. M., Goulart, A. L., Bortoluzzo, A. B., Kopelman, B. I., Nutritional practices and postnatal growth restriction in preterm newborns, Revista da Associacao Medica Brasileira, 61, 500–506, 2015 [PubMed: 26841159]	Study design and intervention do not meet protocol eligibility criteria - retrospective cohort; infants received both PN and EN.
Deprettere, A. J., Van Acker, K. J., Van Reempts, P. J., De Leeuw, I., Inadequate intravenous feeding in sick neonates: a retrospective study, Clinical nutrition (Edinburgh, Scotland), 13, 161–5, 1994 [PubMed: 16843376]	Study design and intervention do not meet inclusion criteria - retrospective study; infants received PN and EN.
Dinerstein, A., Nieto, R. M., Solana, C. L., Perez, G. P., Otheguy, L. E., Larguia, A. M., Early and aggressive nutritional strategy (parenteral and enteral) decreases postnatal growth failure in very low birth weight infants, Journal of Perinatology, 26, 436–42, 2006 [PubMed: 16801958]	Study intervention does not meet protocol eligibility criteria - EN and PN.
Feng, Y., Hong, L., Pan, L., Li, J., Chang, P., Cumulative energy intakes in the first two weeks of life are associated with hospital outcomes in birth weight less than 1500 g infants, Journal of Pediatric Gastroenterology and Nutrition, 66 (Supplement 2), 1068, 2018	Abstract only
Fenton, T. R., McMillan, D. D., Sauve, R. S., Nutrition and growth analysis of very low birth weight infants, Pediatrics, 86, 378–83, 1990 [PubMed: 2117742]	Study design does not meet protocol eligibility criteria - prospective cohort; energy administered not stated.
Fischer, Celine Julie, Maucort-Boulch, Delphine, Essomo Megnier-Mbo, Christine Murielle, Remontet, Laurent, Claris, Olivier, Early parenteral lipids and growth velocity in extremely-low-birth-weight infants, Clinical nutrition (Edinburgh, Scotland), 33, 502–8, 2014 [PubMed: 23958274]	Study intervention does not meet protocol eligibility criteria - amounts of energy administered not stated. Infants receive human milk.
Georgieff, M. K., Hoffman, J. S., Pereira, G. R., Bernbaum, J., Hoffman-Williamson, M., Effect of neonatal caloric deprivation on head growth and 1-year developmental status in preterm infants, The Journal of pediatrics, 107, 581–7, 1985 [PubMed: 3930680]	Study intervention does not meet protocol eligibility criteria - parenteral and enteral feeding.
Georgieva, R. W., Van De Lagemaat, M., Lafeber, H. N., Schaafsma, A., Are current ESPGHAN recommendations for enteral nutrient supply for preterm infants also applicable for late preterm infants?, Journal of Pediatric Gastroenterology and Nutrition, 62, 837–838, 2016	Study intervention does not meet protocol eligibility criteria - energy intake is equal across interventions.
Guellec, Isabelle, Gascoin, Geraldine, Beuchee, Alain, Boubred, Farid, Tourneux, Pierre, Ramful, Duksha, Zana-Taieb, Elodie, Baud, Olivier, Biological Impact of Recent Guidelines on Parenteral Nutrition in Preterm Infants, Journal of pediatric gastroenterology and nutrition, 61, 605–9, 2015 [PubMed: 26147627]	Narrative review.
Guzman,J.M., Jaraba,M.P., De La Torre,M.J., Ruiz-Gonzalez,M.D., Huertas,M.D., Alvarez,R., Zapatero,M., Parenteral nutrition and immature neonates. Comparative study of neonates weighing under 1000 and 1000–1250 g at birth, Early Human Development, 65 Suppl, S133–S144, 2001 [PubMed: 11755044]	Study intervention does not meet protocol eligibility criteria - similar energy administered for all infants.
Hay, W. W., Fetal nutrition-what can we learn to better nourish the preterm infant?, Archives of Disease in Childhood, 97, A28, 2012	Conference abstract.
Heird, W. C., Hay, W., Helms, R. A., Storm, M. C., Kashyap, S., Dell, R. B., Pediatric parenteral amino acid mixture in low birth weight infants, Pediatrics, 81, 41–50, 1988 [PubMed: 3122162]	Study intervention does not meet protocol eligibility criteria - babies receive both PN and EN.
Hentschel, R., Homburg, A., Franck, P., Kunze, M., Impact of early aggressive nutrition on very low birth weight infants on weight, length and head circumference. A retrospective study, Journal of Neonatal-Perinatal Medicine, 10, 221, 2017	Abstract only.
Herrmann, K. R., Early parenteral nutrition and successful postnatal growth of premature infants, Nutrition in Clinical Practice, 25, 69–75, 2010 [PubMed: 20130159]	Study intervention does not meet protocol eligibility criteria - includes EN; PN energy administered not stated.
Janeiro, P., Cunha, M., Marques, A., Moura, M., Barroso, R., Carreiro, H., Caloric intake and weight gain in a neonatal intensive care unit, European Journal of Pediatrics, 169, 99–105, 2010 [PubMed: 19437038]	Study intervention does not meet protocol eligibility criteria - unclear if babies in different time periods received different energy intakes; and infants received EN.
Jones, M. O., Pierro, A., Garlick, P. J., McNurlan, M. A., Donnell, S. C., Lloyd, D. A., Protein metabolism kinetics in neonates: effect of intravenous carbohydrate and fat, Journal of pediatric surgery, 30, 458–62, 1995 [PubMed: 7760242]	Study intervention does not meet protocol eligibility criteria - both groups received equal calorie intake.
Jones, M. O., Pierro, A., Hammond, P., Nunn, A., Lloyd, D. A., Glucose utilization in the surgical newborn infant receiving total parenteral nutrition, Journal of pediatric surgery, 28, 1121–5, 1993 [PubMed: 8308674]	Study intervention does not meet protocol eligibility criteria - unclear if energy administered differed across groups as this information was not stated.
Kamarudin, Nor Aini, Manan, Mohamed Mansor, Zulkifly, Hanis Hanum, Neoh, Chin Fen, Ali, Salmiah Mohd, Ming, Long Chiau, Amino acid dosing in parenteral nutrition for very low birth weight preterm neonates: an outcome assessment, Asia Pacific Journal of Clinical Nutrition, 25, 53–61, 2016 [PubMed: 26965762]	Study design does not meet protocol eligibility criteria - retrospective chart review; energy administered not stated.
Kofler, M., Beer, R., Marinoni, S., Schiefecker, A. J., Sohm, F., Pfausler, B., Thome, C., Schmutzhard, E., Helbok, R., Nutrition in aneurysmal subarachnoid hemorrhage patients, Neurocritical Care, 23, S216, 2015	Conference abstract.
Lai, N. M., Rajadurai, S. V., Tan, K. H., Increased energy intake for preterm infants with (or developing) bronchopulmonary dysplasia/chronic lung disease, Cochrane database of systematic reviews (Online), 3, CD005093, 2006 [PubMed: 16856077]	Cochrane systematic review - references checked for inclusion (EN only).
Leow, L. Y. C., Oh, C. C., Neo, S. L., Chua, M. C., Role of standardized parenteral nutrition bags for neonates, Journal of Perinatal Medicine, 41, 2013	Conference abstract.
Levit, O. L., Calkins, K. L., Gibson, L. C., Kelley-Quon, L., Robinson, D. T., Elashoff, D. A., Grogan, T. R., Li, N., Bizzarro, M. J., Ehrenkranz, R. A., Low-dose intravenous soybean oil emulsion for prevention of cholestasis in preterm neonates, Journal of Parenteral and Enteral Nutrition, 40, 374–382, 2016 [PMC free article: PMC4537394] [PubMed: 24963025]	Study intervention does not meet protocol eligibility criteria-study compares different does of fat emulsions. Study does not state energy administered per group.
Loys, C. M., Maucort-Boulch, D., Guy, B., Putet, G., Picaud, J. C., Hays, S., Extremely low birthweight infants: how neonatal intensive care unit teams can reduce postnatal malnutrition and prevent growth retardation, Acta Paediatrica, 102, 242–8, 2013 [PubMed: 23167480]	Study intervention does not meet protocol eligibility criteria - parenteral and enteral feeding.
Marchildon, M. B., Parenteral 20% safflower oil emulsion safety and effectiveness as a caloric source in newborn infants, JPEN. Journal of parenteral and enteral nutrition, 6, 25–9, 1982 [PubMed: 6804651]	Study design does not meet protocol eligibility criteria-case series.
Meurling, S., Grotte, G., Complete parenteral nutrition in the surgery of the newborn infant, Acta chirurgica Scandinavica, 147, 465–73, 1981 [PubMed: 6798802]	Study design does not meet protocol eligibility criteria - case series.
Moltu, S. J., Blakstad, E. W., Strommen, K., Almaas, A. N., Nakstad, B., Ronnestad, A., Braekke, K., Veierod, M. B., Drevon, C. A., Iversen, P. O., Westerberg, A. C., Enhanced feeding and diminished postnatal growth failure in very-low-birth-weight infants, Journal of Pediatric Gastroenterology & Nutrition, 58, 344–51, 2014 [PMC free article: PMC3940525] [PubMed: 24556755]	Study intervention does not meet protocol eligibility criteria - EN and PN.
Morgan, C., Parry, S., Tan, M., Neurodevelopmental outcome at 2.5 years in very preterm infants randomised to receive two different parenteral nutrition regimens at birth: The SCAMP nutrition study, Journal of Pediatric Gastroenterology and Nutrition, 64, 764, 2017	Conference abstract.
Morgan, C., Parry, S., Tan, M., Neurodevelopmental outcome in very preterm infants randomized to receive two different parenteral nutrition regimens: The scamp nutrition study, Journal of Neonatal-Perinatal Medicine, 10, 220–221, 2017	Abstract only.
Morgan, J. B., Nutrition of the very low birthweight infant, Care of the Critically Ill, 8, 122–124, 1992	Narrative review.
Pharande, P., Nirthanakumaran, L., Do, T., Smyth, J., Lui, K., Sinn, J., Bolisetty, S., Implementation of consensus neonatal parenteral nutrition formulations and improved nutrient intakes in preterm neonates, Journal of Paediatrics and Child Health, 50, 56, 2014	Conference abstract.
Pineault, M., Chessex, P., Bisaillon, S., Lepage, D., Dallaire, L., Total parenteral nutrition in the newborn: amino acids-energy interrelationships, American Journal of Clinical Nutrition, 48, 1065–9, 1988 [PubMed: 3138906]	Study outcomes do not meet protocol eligibility criteria - no relevant outcomes reported.
Pineault, M., Chessex, P., Piedboeuf, B., Bisaillon, S., Beneficial effect of coinfusing a lipid emulsion on venous patency, Journal of Parenteral and Enteral Nutrition, 13, 637–640, 1989 [PubMed: 2614865]	Study outcomes do not meet protocol eligibility criteria - No relevant outcomes reported.
Pineault, M., Lepage, G., Bisaillon, S., Roy, C. C., Chessex, P., Total parenteral nutrition in the newborn: Energy substrates and plasma total fatty acids, Pediatric Research, 26, 290–293, 1989 [PubMed: 2508050]	Study outcomes do not meet protocol eligibility criteria - No relevant outcomes reported.
Ribed Sanchez, A., Romero Jimenez, R. M., Sanchez De Orgaz, M. C., De Juan, A., Tovar Pozo, M., Diaz Garzon, J., Sanjurjo Saez, M., Early aggressive parenteral nutrition in preterm infants, International Journal of Clinical Pharmacy, 35, 983, 2013	Conference abstract.
Rizzi, G., Gaio, P., Meneghelli, M., Tessari, A., Pasinato, A., Fantinato, M., Valerio, E., Verlato, G., Parenteral nutrition in preterm infants of birth weight <1250 G: Possible influences on growth and bone status, Journal of Maternal-Fetal and Neonatal Medicine, 27, 333–334, 2014	Conference abstract - not an RCT.
Rochow,N., Fusch,G., Muhlinghaus,A., Niesytto,C., Straube,S., Utzig,N., Fusch,C., A nutritional program to improve outcome of very low birth weight infants, Clinical Nutrition, 31, 124–131, 2012 [PubMed: 21890250]	Study intervention does not meet protocol eligibility criteria - EN and PN.
Roggero, Paola, Gianni, Maria L., Orsi, Anna, Amato, Orsola, Piemontese, Pasqua, Liotto, Nadia, Morlacchi, Laura, Taroni, Francesca, Garavaglia, Elisa, Bracco, Beatrice, Agosti, Massimo, Mosca, Fabio, Implementation of nutritional strategies decreases postnatal growth restriction in preterm infants, PloS one, 7, e51166, 2012 [PMC free article: PMC3515560] [PubMed: 23227249]	Study intervention does not meet protocol eligibility criteria - EN and PN.
Romero, R., Kleinman, R. E., Feeding the very low-birth-weight infant, Pediatrics in review, 14, 123–32, 1993 [PubMed: 8516236]	Narrative review.
Rook, D., Schierbeek, H., Vlaardingerbroek, H., Dorst, K., Vermeulen, M. J., Van Goudoever, J. B., Increased energy intake directly following birth does not increase gsh synthesis rates in preterm infants, Journal of Pediatric Gastroenterology and Nutrition, 52, E78–E79, 2011	Conference abstract; outcomes do not meet protocol eligibility criteria.
Rubecz, I., Energy metabolism, substrate utilization, metabolite and hormone levels in infants fed various parenteral solutions, Acta paediatrica Academiae Scientiarum Hungaricae, 23, 59–68, 1982 [PubMed: 6807051]	Study design does not meet protocol eligibility criteria - case series.
Rubecz, I., Mestyan, J., Varga, P., Klujber, L., Energy metabolism, substrate utilization, and nitrogen balance in parenterally fed postoperative neonates and infants. The effect of glucose, glucose + amino acids, lipid + amino acids infused in isocaloric amounts, Journal of Pediatrics, 98, 42–46, 1981 [PubMed: 6778983]	Study intervention does not meet protocol eligibility criteria - energy administered similar across groups.
Rubecz, I., Mestyan, J., Varga, P., Soltesz, G., Metabolic and hormonal responses of low birthweight infants to intravenously infused calories not exceeding the maintenance energy expenditure, Archives of disease in childhood, 54, 499–505, 1979 [PMC free article: PMC1545482] [PubMed: 114120]	Study design does not meet protocol eligibility criteria - case series.
Salas-Salvado, J., Molina, J., Figueras, J., Masso, J., Marti-Henneberg, C., Jimenez, R., Effect of the quality of infused energy on substrate utilization in the newborn receiving total parenteral nutrition, Pediatric research, 33, 112–7, 1993 [PubMed: 8433885]	Study intervention does not meet protocol eligibility criteria - energy administered not stated.
Schwalbe-Terilli, Courtney R., Hartman, Diane H., Nagle, Monica L., Gallagher, Paul R., Ittenbach, Richard F., Burnham, Nancy B., Gaynor, J. William, Ravishankar, Chitra, Enteral feeding and caloric intake in neonates after cardiac surgery, American journal of critical care : an official publication, American Association of Critical-Care Nurses, 18, 52–7, 2009 [PubMed: 19116405]	Study intervention does not meet protocol eligibility criteria - EN.
Senterre, T., Habibi,, Rigo, F. J., Postnatal growth restriction may be limited in very-low-birthweight infants, Journal of Maternal-Fetal and Neonatal Medicine, 23, 325–326, 2010	Conference abstract - not an RCT.
Sjostrom, E. S., Lundgren, P., Ohlund, I., Holmstrom, G., Hellstrom, A., Domellof, M., Low energy intake during the first 4 weeks of life increases the risk for severe retinopathy of prematurity in extremely preterm infants, Archives of Disease in Childhood: Fetal and Neonatal Edition, 101, F108–F113, 2016 [PMC free article: PMC4789715] [PubMed: 25678632]	Study intervention does not meet protocol eligibility criteria - EN and PN.
Spath, Cornelia, Zamir, Itay, Sjostrom, Elisabeth Stoltz, Domellof, Magnus, Use of Concentrated Parenteral Nutrition Solutions Is Associated With Improved Nutrient Intakes and Postnatal Growth in Very Low-Birth-Weight Infants, JPEN. Journal of parenteral and enteral nutrition, 2019 [PMC free article: PMC7064909] [PubMed: 30747444]	Intervention does not meet inclusion criteria - the study compares the effect of introducing a new PN regimen and does not state prescribed calorie levels.
Stephens, Bonnie E., Walden, Rachel V., Gargus, Regina A., Tucker, Richard, McKinley, Leslie, Mance, Martha, Nye, Julie, Vohr, Betty R., First-week protein and energy intakes are associated with 18-month developmental outcomes in extremely low birth weight infants, Pediatrics, 123, 1337–43, 2009 [PubMed: 19403500]	Study intervention does not meet protocol eligibility criteria - EN and PN.
Stoltz Sjostrom, E., Zamir, I., Spath, C., Domellof, M., A more concentrated parenteral nutrition solution improves nutrient intakes and postnatal weight gain in very low birth weight infants, European Journal of Pediatrics, 175, 1732, 2016	Conference abstract - not an RCT.
Sun, J., Liu, D., Bei, F., Aggressive parenteral nutrition support in premature low birth weight infants, Pediatric Critical Care Medicine, 12, A148, 2011	Conference abstract - not an RCT.
Tagare, A., Walawalkar, M., Vaidya, U., Aggressive parenteral nutrition in sick very low birth weight babies: A randomized controlled trial, Indian Pediatrics, 50, 954–956, 2013 [PubMed: 23798635]	Study intervention does not meet protocol eligibility criteria - energy administered not stated.
Tan, M., Parry, S., Morgan, C., Neurodevelopmental outcome in very preterm infants randomised to receive two different parenteral nutrition regimens: The SCAMP nutrition study, Archives of Disease in Childhood, 101, A5, 2016	Conference abstract - energy administered not stated.
Terui, Keita, Usui, Noriaki, Tazuke, Yuko, Nagata, Kouji, Ito, Miharu, Okuyama, Hiroomi, Hayakawa, Masahiro, Taguchi, Tomoaki, Sato, Yasunori, Yoshida, Hideo, The Impact of Nutrition in the Congenital Diaphragmatic Hernia Treatment, Pediatrics international : official journal of the Japan Pediatric Society, 2019 [PubMed: 30888699]	Study intervention does not meet protocol eligibility criteria - grouped based on energy received, not prescribed regimens.
Tian, Tina, Coons, Joshua, Chang, Hong, Chwals, Walter J., Overfeeding-associated hyperglycemia and injury-response homeostasis in critically ill neonates, Journal of pediatric surgery, 53, 1688–1691, 2018 [PubMed: 29550034]	No relevant outcomes.
Tottman, A. C., Alsweiler, J. M., Bloomfield, F. H., Gamble, G. D., Jiang, Y., Leung, M., Poppe, T., Thompson, B., Wouldes, T. A., Harding, J. E., Neonatal nutritional intakes and neurodevelopment at school age in infants born preterm, Journal of Paediatrics and Child Health, 54, 50, 2018	Abstract only.
Tottman, A. C., Bloomfield, F. H., Cormack, B. E., Harding, J. E., Mohd Slim, M. A., Weston, A. F., Alsweiler, J. M., Relationships between Early Nutrition and Blood Glucose Concentrations in Very Preterm Infants, Journal of Pediatric Gastroenterology and Nutrition, 66, 960–966, 2018 [PubMed: 29481441]	Intervention does not meet inclusion criteria - the study compares the effect of introducing a new nutrition protocol and does not state prescribed calorie levels.
Urs, A. N., Somisetty, S. K., Hawkes, L., Paterson, M., Thethy, R. S., Evaluation of aggressive nutritional intervention in very low birth weight infants (VLBW) during the first 28 days of life, Paediatrics and Child Health, 20, 250, 2010	Conference abstract - energy administered not stated.
Vakrilova, L., Slancheva, B., Emilova, Z., Radulova, P., Hitrova, S., Petrova, G., Early parenteral nutrition of very low birth weight infants: Practical application, Intensive Care Medicine, 37, S398, 2011	Conference abstract - energy administered not stated; infants received EN.
Vakrilova, L., Slancheva, B., Emilova, Z., Yarakova, N., Early parenteral nutrition with very low and extremely low birth weight infants - Practical approach, Early Human Development, 86, S86–S87, 2010 [PubMed: 20734671]	Conference abstract - energy administered not stated.
Van Aerde, J. E., Sauer, P. J., Pencharz, P. B., Smith, J. M., Heim, T., Swyer, P. R., Metabolic consequences of increasing energy intake by adding lipid to parenteral nutrition in full-term infants, The American journal of clinical nutrition, 59, 659–62, 1994 [PubMed: 8116545]	Study intervention does not meet protocol eligibility criteria.
Van Aerde, J. E., Sauer, P. J., Pencharz, P. B., Smith, J. M., Swyer, P. R., Effect of replacing glucose with lipid on the energy metabolism of newborn infants, Clinical science (London, England : 1979), 76, 581–8, 1989 [PubMed: 2736877]	Study intervention does not meet protocol eligibility criteria.
Weinstein, M. R., Haugen, K., Bauer, J. H., Hewitt, J., Finan, D., Intravenous energy and amino acids in the preterm newborn infant: effects on metabolic rate and potential mechanisms of action, The Journal of pediatrics, 111, 119–23, 1987 [PubMed: 3598772]	Study outcomes do not meet protocol eligibility criteria - outcomes of interest not measured.
Westin, Vera, Klevebro, Susanna, Domellof, Magnus, Vanpee, Mireille, Hallberg, Boubou, Stoltz Sjostrom, Elisabeth, Improved nutrition for extremely preterm infants - A population based observational study, Clinical nutrition ESPEN, 23, 245–251, 2018 [PubMed: 29460807]	Intervention does not meet inclusion criteria - prescribed calorie intake did not differ before and after implementation of nutrition interventions.