Higher versus lower amino acid intake in parenteral nutrition for newborn infants

Abstract

Background

Sick newborn and preterm infants frequently are not able to be fed enterally, necessitating parenteral fluid and nutrition. Potential benefits of higher parenteral amino acid (AA) intake for improved nitrogen balance, growth, and infant health may be outweighed by the infant's ability to utilise high intake of parenteral AA, especially in the days after birth.

Objectives

The primary objective is to determine whether higher versus lower intake of parenteral AA is associated with improved growth and disability‐free survival in newborn infants receiving parenteral nutrition.

Secondary objectives include determining whether:

• higher versus lower starting or initial intake of amino acids is associated with improved growth and disability‐free survival without side effects;
 • higher versus lower intake of amino acids at maximal intake is associated with improved growth and disability‐free survival without side effects; and
 • increased amino acid intake should replace non‐protein energy intake (glucose and lipid), should be added to non‐protein energy intake, or should be provided simultaneously with non‐protein energy intake.

We conducted subgroup analyses to look for any differences in the effects of higher versus lower intake of amino acids according to gestational age, birth weight, age at commencement, and condition of the infant, or concomitant increases in fluid intake.

Search methods

We used the standard search strategy of the Cochrane Neonatal Review Group to search the Cochrane Central Register of Controlled Trials (2 June 2017), MEDLINE (1966 to 2 June 2017), Embase (1980 to 2 June 2017), and the Cumulative Index to Nursing and Allied Health Literature (CINAHL) (1982 to 2 June 2017). We also searched clinical trials databases, conference proceedings, and citations of articles.

Selection criteria

Randomised controlled trials of higher versus lower intake of AAs as parenteral nutrition in newborn infants. Comparisons of higher intake at commencement, at maximal intake, and at both commencement and maximal intake were performed.

Data collection and analysis

Two review authors independently selected trials, assessed trial quality, and extracted data from included studies. We performed fixed‐effect analyses and expressed treatment effects as mean difference (MD), risk ratio (RR), and risk difference (RD) with 95% confidence intervals (CIs) and assessed the quality of evidence using the GRADE approach.

Main results

Thirty‐two studies were eligible for inclusion. Six were short‐term biochemical tolerance studies, one was in infants at > 35 weeks' gestation, one in term surgical newborns, and three yielding no usable data. The 21 remaining studies reported clinical outcomes in very preterm or low birth weight infants for inclusion in meta‐analysis for this review.

Higher AA intake had no effect on mortality before hospital discharge (typical RR 0.90, 95% CI 0.69 to 1.17; participants = 1407; studies = 14; I² = 0%; quality of evidence: low). Evidence was insufficient to show an effect on neurodevelopment and suggest no reported benefit (quality of evidence: very low). Higher AA intake was associated with a reduction in postnatal growth failure (< 10th centile) at discharge (typical RR 0.74, 95% CI 0.56 to 0.97; participants = 203; studies = 3; I² = 22%; typical RD ‐0.15, 95% CI ‐0.27 to ‐0.02; number needed to treat for an additional beneficial outcome (NNTB) 7, 95% CI 4 to 50; quality of evidence: very low). Subgroup analyses found reduced postnatal growth failure in infants that commenced on high amino acid intake (> 2 to ≤ 3 g/kg/day); that occurred with increased amino acid and non‐protein caloric intake; that commenced on intake at < 24 hours' age; and that occurred with early lipid infusion.

Higher AA intake was associated with a reduction in days needed to regain birth weight (MD ‐1.14, 95% CI ‐1.73 to ‐0.56; participants = 950; studies = 13; I² = 77%). Data show varying effects on growth parameters and no consistent effects on anthropometric z‐scores at any time point, as well as increased growth in head circumference at discharge (MD 0.09 cm/week, 95% CI 0.06 to 0.13; participants = 315; studies = 4; I² = 90%; quality of evidence: very low).

Higher AA intake was not associated with effects on days to full enteral feeds, late‐onset sepsis, necrotising enterocolitis, chronic lung disease, any or severe intraventricular haemorrhage, or periventricular leukomalacia. Data show a reduction in retinopathy of prematurity (typical RR 0.44, 95% CI 0.21 to 0.93; participants = 269; studies = 4; I² = 31%; quality of evidence: very low) but no difference in severe retinopathy of prematurity.

Higher AA intake was associated with an increase in positive protein balance and nitrogen balance. Potential biochemical intolerances were reported, including risk of abnormal blood urea nitrogen (typical RR 2.77, 95% CI 2.13 to 3.61; participants = 688; studies = 7; I² = 6%; typical RD 0.26, 95% CI 0.20 to 0.32; number needed to treat for an additional harmful outcome (NNTH) 4; 95% CI 3 to 5; quality of evidence: high). Higher amino acid intake in parenteral nutrition was associated with a reduction in hyperglycaemia (> 8.3 mmol/L) (typical RR 0.69, 95% CI 0.49 to 0.96; participants = 505; studies = 5; I² = 68%), although the incidence of hyperglycaemia treated with insulin was not different.

Authors' conclusions

Low‐quality evidence suggests that higher AA intake in parenteral nutrition does not affect mortality. Very low‐quality evidence suggests that higher AA intake reduces the incidence of postnatal growth failure. Evidence was insufficient to show an effect on neurodevelopment. Very low‐quality evidence suggests that higher AA intake reduces retinopathy of prematurity but not severe retinopathy of prematurity. Higher AA intake was associated with potentially adverse biochemical effects resulting from excess amino acid load, including azotaemia. Adequately powered trials in very preterm infants are required to determine the optimal intake of AA and effects of caloric balance in parenteral nutrition on the brain and on neurodevelopment.

Plain language summary

Higher versus lower amino acid intake in parenteral nutrition for newborn infants

Review question

In newborn infants, does administration of intravenous nutrition with higher amino acid (protein) content during the first few days after birth result in improved growth and disability‐free survival in newborn infants?

Background

Sick and preterm newborns are at risk of malnutrition and growth failure from an inability to receive protein at a dose equivalent to that received when they were in the womb. Although administering a higher dose of amino acids in parenteral nutrition via a vein provides potential benefits, possible side effects from excess protein due to immaturity of the infant's liver and kidneys, which are responsible for utilising protein and removing protein waste from the body, remain a matter of concern.

Study characteristics

The review included 21 studies that reported clinical outcomes in very preterm or low birth weight infants. Reporting was incomplete for all outcomes. Searches for studies were conducted in June 2017.

Key results

Higher amino acid intake did not affect survival in preterm or low birth weight infants. Not enough information is available to determine whether this had an effect on neurodevelopment. Higher amino acid intake was associated with lower rates of growth failure, increased head growth, and fewer premature eye problems (eye problems were not severe). Higher amino acid intake was also associated with increased levels of protein breakdown products (urea) and a lower incidence of high blood glucose levels.

Conclusions

Higher amino acid intake did not affect survival but reduced the incidence of growth failure up to the time of hospital discharge. Higher amino acid intake may produce other effects, including an increase in head growth and a reduction in eye problems (retinopathy of prematurity), although these effects are uncertain. Evidence suggests that high amino acid intake may not be tolerated by all infants. Further research is needed to determine the optimal amino acid intake for parenteral nutrition and nutritional balance in preterm infants.

Quality of evidence

Low‐quality evidence suggests that higher AA intake in parenteral nutrition does not affect mortality. Very low‐quality evidence suggests that higher AA intake reduces the incidence of postnatal growth failure, and that higher AA intake reduces retinopathy of prematurity, but not severe retinopathy. Evidence was insufficient to show whether higher AA intake had an effect on neurodevelopment.

Summary of findings

Summary of findings for the main comparison. Higher versus lower amino acid intake in parenteral nutrition for newborn infants.

Higher versus lower amino acid intake in parenteral nutrition for newborn infants
Patient or population: preterm infants Settings: neonatal intensive care Intervention: higher versus lower amino acid intake in parenteral nutrition
Outcomes	Illustrative comparative risks* (95% CI)		Relative effect (95% CI)	No. of participants (studies)	Quality of the evidence (GRADE)	Comments
	Assumed risk	Corresponding risk
	Control	Higher vs lower amino acid intake in parenteral nutrition
Mortality to hospital discharge Follow‐up: to discharge	Study population		RR 0.9 (0.69 to 1.17)	1407 (14 studies)	⊕⊕⊝⊝ lowa,b	No significant differences found in subgroup analyses according to amino acid intake at commencement, at maximal intake, or at commencement and maximal intake; according to management of caloric balance (non‐protein caloric intake); in very preterm or very low birth weight infants; according to age of commencement; or according to timing of lipid intake Quality of evidence downgraded owing to imprecision and potential for publication or reporting bias
	131 per 1000	118 per 1000 (90 to 153)
	Moderate
	127 per 1000	114 per 1000 (88 to 149)
Neurodevelopmental disability Follow‐up: to discharge	Study population		RR 1.04 (0.48 to 2.23)	201 (2 studies)	⊕⊝⊝⊝ very lowa,b,c,d	Limited neurodevelopmental data. No significant differences found for any secondary outcome including cerebral palsy, developmental delay, blindness, deafness, Bayley Scales of Infant Development scores, or autism Quality of evidence downgraded owing to risk of bias, inconsistency, imprecision, and potential for publication or reporting bias
	118 per 1000	122 per 1000 (56 to 262)
	Moderate
	108 per 1000	112 per 1000 (52 to 241)
Postnatal growth failure at discharge (weight < 10th centile) Follow‐up: to discharge	Study population		RR 0.74 (0.56 to 0.97)	203 (3 studies)	⊕⊝⊝⊝ very lowb,e,f	Subgroup analyses found significant reduction in postnatal growth failure at discharge for infants commenced on high amino acid intake (> 2 to ≤ 3 g/kg/d) that increased amino acid and non‐protein caloric intake; commenced intake at < 24 hours' age; and provided early lipid infusion. Quality of evidence downgraded owing to risk of bias, imprecision, and potential for publication or reporting bias
	554 per 1000	410 per 1000 (310 to 538)
	Moderate
	684 per 1000	506 per 1000 (383 to 663)
Weight gain to discharge (g/kg/d)		Mean weight gain to discharge (g/kg/d) in intervention groups was 0.76 higher (0.02 lower to 1.54 higher).		291 (4 studies)	⊕⊝⊝⊝ very lowa,b,c	No significant subgroup effects found according to intake; timing of commencement; management of caloric balance; or timing of lipid intake Reduction in weight gain to 1 month age attributable to the effect of a single study (Balasubramanian 2013) that did not provide a lipid infusion Quality of evidence downgraded owing to risk of bias, imprecision, and potential for publication or reporting bias
Head circumference growth to discharge (cm/week) Follow‐up: to discharge		Mean head circumference growth to discharge (cm/week) in intervention groups was 0.09 higher (0.06 to 0.13 higher).		315 (4 studies)	⊕⊝⊝⊝ very lowb,c,d,f	Subgroup analyses found a significant increase in head circumference growth to discharge for infants on high amino acid intake (> 2 to ≤ 3 g/kg/d) at commencement; and for infants on high (> 3 to ≤ 4 g/kg/d) amino acid intake at maximal intake. All studies provided isocaloric non‐protein energy intake and early lipid infusion in both groups. Quality of evidence downgraded owing to risk of bias, inconsistency, imprecision, and potential for publication or reporting bias
Retinopathy of prematurity Follow‐up: to discharge	Study population		RR 0.44 (0.21 to 0.93)	269 (4 studies)	⊕⊝⊝⊝ very lowb,e,f	Subgroup analyses found reduction in retinopathy of prematurity in studies that commenced high (> 2 to ≤ 3 g/kg/d) amino acid intake; that increased amino acid and non‐protein caloric intake; in very preterm or very low birth weight infants; that commenced intake at < 24 hours' age; and provided early lipid infusion. Quality of evidence downgraded owing to risk of bias, imprecision, and potential for publication or reporting bias
	144 per 1000	63 per 1000 (30 to 134)
	Moderate
	179 per 1000	79 per 1000 (38 to 166)
Abnormal blood urea nitrogen (various criteria) Follow‐up: to discharge	Study population		RR 2.77 (2.13 to 3.61)	688 (7 studies)	⊕⊕⊕⊕ high	Various criteria for abnormal blood urea nitrogen reported ranging from 10.0 mmol/L up to 21.4 mmol/L Significant subgroup effect with increasing level of amino acid intake
	147 per 1000	406 per 1000 (312 to 529)
	Moderate
	53 per 1000	147 per 1000 (113 to 191)
*The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). CI: confidence interval; RR: risk ratio.
GRADE Working Group grades of evidence. High quality: Further research is very unlikely to change our confidence in the estimate of effect. Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate. Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate. Very low quality: We are very uncertain about the estimate.

^aWide confidence intervals do not preclude a significant effect.
 ^bNot reported by a substantial number of studies.
 ^cStudies had methodological concerns.
 ^dSignificant and high level of heterogeneity.
 ^eSingle study at low risk of bias reported a significant effect.
 ^fWide confidence intervals close to no effect level.

Background

Description of the condition

Nutrition is important for survival, growth, and development. Sick newborn and preterm infants frequently are not able to be fed enterally, necessitating parenteral fluid and nutrition. Despite advances in neonatal care, postnatal growth failure continues to be a ubiquitous problem among preterm neonates. In a 1995 to 1996 cohort of very low birth weight (VLBW) infants in the National Institute of Health and Child Development Research Network, 22% of the cohort was small for gestational age (SGA) at birth; however by 36 weeks' postmenstrual age (PMA), 97% of the cohort was below the 10th percentile in weight (Lemons 2001). Although inadequate nutritional support increases risks of postnatal growth failure and neurodevelopmental impairment among preterm infants (Lucas 1998), aggressive nutritional support might place them at higher risk of protein intolerance, development of metabolic syndrome with insulin resistance, and cardiovascular disease in later childhood and adulthood (Ehrenkranz 2006; Embleton 2001; Ong 2007).

Description of the intervention

Parenteral nutrition is widely used to prevent growth failure and malnutrition when nutritional support is provided to sick neonates who are unable to tolerate enteral intake owing to prematurity or the nature of their illness (AAP 2009; EPSGHAN 2005; Fusch 2009). An idealised optimal nutritional goal for neonates is one that duplicates normal in utero foetal growth rates (AAP 1998). Maximal weight‐specific protein gain occurs before 32 weeks' gestation (Micheli 1993), and the foetus uses amino acids as a major energy source (Gresham 1971; Lemons 1976). Postnatally, nutrition is generally introduced gradually over the first week of life because of concerns about nutrient intolerance by extreme preterm infants or very ill neonates. Lipids and glucose are frequently used at rates that exceed in utero delivery rates, but amounts of amino acid are lower than those provided at in utero delivery rates. Increasing amino acid intake during parenteral nutrition provided shortly after birth has the potential to increase protein accretion rates and growth in newborn infants. Amino acid intake may be increased during parenteral nutrition by providing increased start or initial intake of amino acids, increased rate of grading of amino acids, increased final intake of amino acids, or a combination of these strategies. Amino acid intake, particularly in the early transitional phase of a preterm infant's life, is limited by the range of fluid load and protein intake that an adapting or sick infant can deal with, as well as by the stability of the parenteral nutrition formulation (EPSGHAN 2005).

How the intervention might work

A concern associated with high amino acid intake in parenteral nutrition involves protein intolerance as reflected by higher ammonia and blood urea levels. These higher levels may reflect effective use of amino acids rather than protein intolerance (Thureen 1999). In contrast, low initial amino acids have been associated with postnatal malnutrition and have produced measurable growth failure at hospital discharge (Ehrenkranz 1999; Lucas 1994; Ziegler 1991). Low early protein intake is also associated with poor long‐term developmental outcomes (Lucas 1998).

Prevention of a negative nitrogen balance is achieved in preterm infants by providing amino acids at a rate of 1 to 1.5 g/kg/d (Kashyap 1994a; Rivera 1993; Thureen 2003; van Lingen 1992). Achieving a body composition that more closely resembles foetal body composition may require a higher amino acid intake. In the extremely low birth weight infant, achieving intrauterine protein accretion rates may require up to 3.85 g/kg/d of protein (Ziegler 1994). Evidence suggests that preterm infants may have a higher protein turnover rate relative to term infants (Hay 1996). Animal studies such as Lemons 1976 and human studies such as Gresham 1971 have shown that amino acids are a significant source of energy during intrauterine life. In addition to protein intake, energy is required for protein anabolism (Kashyap 1994). Intake of 25 to 40 kcal of non‐protein energy per gram of protein allows optimal protein accretion (Cauderay 1988). When energy availability from a non‐protein nitrogen source is limited, protein anabolism is decreased and protein is used for energy. When energy is limited and protein is used as an energy source, optimal protein synthesis cannot occur (Kashyap 1994). On the other hand, increasing non‐protein nitrogen calories without increasing protein intake is also not helpful. Preterm and term infants showed an increase in protein synthesis of a similar magnitude with parenteral nutrition, whereas increasing intravenous glucose administration did not decrease proteolysis despite a threefold increase in insulin concentration (Denne 1996).

Potential benefits of higher protein intake also include greater growth of lean tissue and bone mass, thereby preventing postnatal growth failure and leading to improved glucose tolerance, synthesis of hormones and enzymes, and maintenance of oncotic pressure (Fomon 1993). In an animal study, higher protein intake was shown to accelerate maturation of the renal tubules (Jakobsson 1990; Thureen 2003). Deficiency of protein in infants leads to growth failure causing oedema and decreased resistance to infection (Nayak 1989).

Risks of higher protein intake include increased concentrations of amino acids (especially tyrosine and phenylalanine), metabolic acidosis, hyperammonaemia, and elevated blood urea nitrogen (Micheli 1993; Senterre 1983). This risk is more pronounced with increasing prematurity. High protein intake could lead to cholestasis, and the phosphate content of amino acid solutions may increase the neonate's tendency toward hypocalcaemia (Andronikou 1983). Renal hypertrophy and increased circulating insulin‐like growth factor‐1 have been reported secondary to high protein intake (Murray 1993). High protein intake in early life may increase risks of long‐term obesity and development of diabetes (Raiha 2001; Rolland 1995; Scaglioni 2000). Therefore, it is important for researchers and care providers to consider the consequences of early nutrition.

Why it is important to do this review

Despite significant advances in neonatal care, postnatal growth failure is an event of major concern. Potential benefits of higher amino acid intake during parenteral nutrition of improved nitrogen balance, growth, and infant health may be outweighed by the infant's ability to utilise high intakes of parenteral amino acid, especially in the days after birth, resulting in high concentrations of amino acids, ammonia, and urea, and an exacerbation of metabolic acidosis. It is important to determine the optimal amount of amino acid intake via parenteral nutrition for the growth and health of newborn infants.

Objectives

The primary objective is to determine whether higher versus lower intake of amino acid is associated with improved growth and disability‐free survival in newborn infants receiving parenteral nutrition.

Secondary objectives include determining whether:

• higher versus lower starting or initial intake of amino acids is associated with improved growth and disability‐free survival without side effects;

• higher versus lower intake of amino acids at maximal intake is associated with improved growth and disability‐free survival without side effects; and

• increased amino acid intake should replace non‐protein energy intake (glucose and lipid), should be added to non‐protein energy intake, or should be provided simultaneously with non‐protein energy intake.

We conducted subgroup analyses to look for differences in the effects of higher versus lower intake of amino acids according to gestational age, birth weight, age at commencement, and condition of the infant, or concomitant increases in fluid intake.

Methods

Criteria for considering studies for this review

Types of studies

Randomised, quasi‐randomised, and cluster‐randomised trials were eligible.

Types of participants

We included trials enrolling neonates (postnatal age ≤ 28 days) admitted to the intensive care unit while receiving parenteral nutrition (PN). We excluded trials enrolling neonates with genetic or metabolic disease affecting protein metabolism.

Types of interventions

We performed separate primary comparisons of studies according to the method of increase in intake of amino acid.

• Higher versus lower amino acid intake at commencement of parenteral nutrition.

• Higher versus lower amino acid intake at maximal intake of parenteral nutrition.

• Higher versus lower amino acid intake at commencement and maximal intake of parenteral nutrition.

Amino acid intake at commencement and maximal intake refer to the dose of parenteral amino acid at these points.

Definitions of amino acid intake at commencement of parenteral nutrition include the following.

• Very low amino acid intake (≤ 1 g/kg/d).

• Low amino acid intake (> 1 to ≤ 2 g/kg/d).

• High amino acid intake (> 2 to ≤ 3 g/kg/d).

• Very high amino acid intake (> 3 g/kg/d).

Definitions of amino acid intake at maximal infusion of parenteral nutrition include the following.

• Very low amino acid intake (≤ 2 g/kg/d).

• Low amino acid intake (> 2 to ≤ 3 g/kg/d).

• High amino acid intake (> 3 to ≤ 4 g/kg/d).

• Very high amino acid intake (> 4 g/kg/d).

Amino acid intake refers only to parenteral intake.

Types of outcome measures

Primary outcomes

• Mortality before hospital discharge

• Neurodevelopmental disability at ≥ 18 months' postnatal age (defined as neurological abnormality including cerebral palsy on clinical examination, developmental delay more than two standard deviations below the population mean on a standardised test of development, blindness (visual acuity < 6/60), or deafness (any hearing impairment requiring amplification) at any time after term corrected)

• Postnatal growth failure (weight < 10th percentile near term corrected age or at discharge)

Secondary outcomes

Growth of infant

• Days to regain birth weight

• Maximal weight loss

  • Gram

  • Per cent

• Weight gain

  • Up to age 1 month (g/kg/d)

  • At latest time measured (g/kg/d) (definition = from 1 month to time of discharge)

  • To follow‐up beyond 12 months (kg/y)

• Linear growth

  • Up to age 1 month (cm/week)

  • At latest time measured (cm/week)

  • To follow‐up beyond 12 months (cm/y)

• Head circumference

  • Up to age 1 month (cm/week)

  • At latest time measured (cm/week)

  • To follow‐up beyond 12 months (cm/y)

Change in standardised growth

• Change in weight z‐score

  • Up to age 1 month

  • At latest time measured

  • To follow‐up beyond 12 months

• Change in length z‐score

  • Up to age 1 month

  • At latest time measured

  • To follow‐up beyond 12 months

• Change in head circumference z‐score

  • Up to age 1 month

  • At latest time measured

  • To follow‐up beyond 12 months

Other secondary outcomes

• Days to full enteral feeds

• Late‐onset sepsis (positive bacterial culture in cerebrospinal fluid (CSF), sterile urine, or blood at > 48 hours)

• Necrotising enterocolitis (Bell's stage > 1)

• Chronic lung disease (respiratory support or oxygen requirement at or beyond 36 weeks' postmenstrual age)

• Intraventricular haemorrhage (any or severe ‐ grade III or IV) (Papile 1978)

• Periventricular leukomalacia (cystic)

• Term magnetic resonance imaging (MRI) brain abnormalities graded as normal, mild, moderate, or severe (e.g. Inder 2003)

• Retinopathy of prematurity (any or severe ‐ grade 3 or 4) (International Committee 2005)

• Individual components of neurodevelopment at least 18 months' postnatal age

  • Cerebral palsy on clinical examination

  • Developmental delay more than two standard deviations below population mean on a standardised test of development

  • Blindness (visual acuity < 6/60)

  • Deafness (any hearing impairment requiring amplification) at any time after term corrected

Biochemical abnormalities occurring during the first week of life

• Negative nitrogen balance

• Incidence of abnormal serum ammonia > 122 μmol/L, as reported by Usmani 1993, and blood urea nitrogen (BUN) levels > 14.3 mmol/L [mg/dL × 0.357], as reported by Ridout 2005 [Conversion BUN = blood urea divided by 2.14] [post hoc analysis: upper 95% confidence interval (CI) for plasma ammonia in healthy term infants at birth: 63 μmol/L, and for preterm infants at 7 days: 69 μmol/L]

• Incidence of hyperglycaemia, plasma glucose > 8.3 mmol/L [mg/dL × 0.0555], as reported by Hays 2006, or any hyperglycaemia treated with insulin therapy

• Incidence of hypoglycaemia < 2.6 mmol/L (Duvanel 1999; Lucas 1988)

• Incidence of low serum albumin, preterm < 18 g/L [g/dL × 10], as reported by Reading 1990 and Zlotkin 1987), and > 37 weeks < 25 g/L, as reported by Zlotkin 1987

• Incidence of metabolic acidosis where pH < 7.25, as reported by Koch 1968, or base excess (BE) > ‐5, or both

• Incidence of cholestasis, serum level of direct bilirubin > 20% of total serum bilirubin, or serum level of direct bilirubin > 34 mmol/L [mg/dL × 17.10], as reported by AAP 2004

Search methods for identification of studies

Electronic searches

We used the criteria and standard methods of Cochrane and the Cochrane Neonatal Review Group (see the Cochrane Neonatal Group search strategy for specialized register).
 
 We conducted a comprehensive search including the Cochrane Central Register of Controlled Trials (CENTRAL; 2016, Issue 9) in the Cochrane Library; MEDLINE via PubMed (1966 to September 2016); Embase (1980 to September 2016); and the Cumulative Index to Nursing and Allied Health Literature (CINAHL) (1982 to September 2016). We documented search strategies in Appendix 1 and Appendix 2 and did not apply language restrictions. We documented in Appendix 3 the search as updated on 2 June 2017.

Searching other resources

We identified abstracts and conference and symposia proceedings from the Society of Pediatric Research and the American Academy of Pediatrics; the Perinatal Society of Australia and New Zealand (PSANZ); the European Society for Paediatric Gastroenterology, Hepatology and Nutrition; and the North American Society for Pediatric Gastroenterology, Hepatology and Nutrition. We (DO and SB) independently reviewed cross‐references for additional relevant titles and abstracts of articles up to 50 years old. We contacted experts to ask about other studies relevant to the topic.

We identified completed and ongoing trials in trial registries at the following websites: www.clinicaltrials.gov; www.controlled‐trials.com; anzctr.org.au; and who.int/ictrp.

Data collection and analysis

We used the standardised review method of the Cochrane Neonatal Review Group (CNRG) in conducting this systematic review (http://neonatal.cochrane.org/en/index.html). We entered and cross‐checked data using RevMan 5 software (RevMan 2014).

Selection of studies

Two review authors (DO and SB) independently assessed eligibility for inclusion in this review. When we were uncertain about inclusion of the study, we retrieved the full text. We resolved differences by consensus.

Data extraction and management

We extracted data independently (DO, LJ, and TS) using RevMan 5 software (RevMan 2014). We resolved differences by consensus. We sought data from one unpublished trial by trying to contact the trial author but without success (Kashyap 2007).

Assessment of risk of bias in included studies

We assessed risk of bias (DO and SB) for each study using the criteria outlined in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011).

• Random sequence generation: selection bias (biased allocation to interventions) due to inadequate generation of a randomised sequence.

• Allocation concealment: selection bias (biased allocation to interventions) due to inadequate concealment of allocations before assignment.

• Blinding of participants and personnel: performance bias due to knowledge of allocated interventions by participants and personnel during the study.

• Blinding of outcome assessment: detection bias due to knowledge of allocated interventions by outcome assessors.

• Incomplete outcome data: attrition bias due to quantity, nature, or handling of incomplete outcome data.

• Selective reporting:reporting bias due to selective outcome reporting.

• Other bias: bias due to problems not covered elsewhere in the table.

See Appendix 4 for a detailed description of risk of bias for each domain.

Quality of evidence

We assessed the quality of evidence for the main comparison at the outcome level using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach (Guyatt 2011a). This methodological approach considers evidence from randomised controlled trials as high quality that may be downgraded based on consideration of any of five areas: design (risk of bias), consistency across studies, directness of evidence, precision of estimates, and presence of publication bias (Guyatt 2011a).

The GRADE approach yields an assessment of the quality of a body of evidence according to one of four grades (Schünemann 2013).

• High: We are very confident that the true effect lies close to that of the estimate of the effect.

• Moderate: We are moderately confident in the effect estimate: The true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different.

• Low: Our confidence in the effect estimate is limited: The true effect may be substantially different from the estimate of the effect.

• Very low: We have very little confidence in the effect estimate: The true effect is likely to be substantially different from the estimate of effect.

Review authors (DO and LJ) independently assessed the quality of evidence obtained for outcomes identified as critical or important for clinical decision‐making. These outcomes included mortality to hospital discharge, neurodevelopmental disability, postnatal growth failure at discharge, weight gain (g/kg/d) to discharge, head circumference growth (cm/week) to discharge, and retinopathy of prematurity. Biochemical effects including abnormal blood urea nitrogen and hyperglycaemia were considered retrospectively.

In cases for which we considered risk of bias as arising from inadequate concealment of allocation, randomised assignment, complete follow‐up, or blinded outcome assessment, to reduce our confidence in effect estimates, we downgraded the quality of evidence accordingly (Guyatt 2011b). We evaluated consistency by determining similarity of point estimates, extent of overlap of confidence intervals, and statistical criteria including measurement of heterogeneity (I²). We downgraded the quality of evidence when we noted large and unexplained inconsistency across study results (i.e. when some studies suggest important benefit and others report no effect or harm without a clinical explanation) (Guyatt 2011d). We assessed precision from the width of the 95% confidence interval (CI) and by calculating the optimal information size (OIS). If the total number of participants included in the pooled effect estimate was less than the number of participants generated by a conventional sample size calculation for a single adequately powered trial, we considered rating down for imprecision (Guyatt 2011c). When trials were conducted in populations other than the target population, we downgraded the quality of evidence because of indirectness (Guyatt 2011e).
 
 We entered data (i.e. pooled estimates of effects and corresponding 95% CIs) and explicit judgements for each of the assessed aspects into the Guideline Development Tool, the software used to create ‘Summary of findings’ tables (GRADEpro 2008). We explained all judgements involving assessment of study characteristics described above in footnotes or comments within the Table 1.

Measures of treatment effect

We carried out statistical analysis using standard methods of the Cochrane Neonatal Review Group.

Dichotomous data

We reported dichotomous data using risk ratio (RR) and risk difference (RD), each with the 95% confidence interval (CI). If we noted a statistically significant reduction in RD, we calculated the number needed to treat for an additional beneficial outcome (NNTB) or the number needed to treat for an additional harmful outcome (NNTH) and associated 95% CIs.

Continuous data

We reported continuous data by using mean difference (MD) with 95% CI.

Conversion of non‐parametric data

For studies that reported non‐parametric data, we calculated means and standard deviations using medians and interquartile ranges. When sample sizes are large and the distribution of the outcome is similar to the normal distribution, the width of the interquartile range will be approximately 1.35 standard deviations (Hozo 2005).

Unit of analysis issues

The unit of randomisation was the intended unit of analysis, and we expected this to be individual infants. Cluster‐randomised controlled trials were eligible for inclusion.

Cluster‐randomised trials

We planned to include cluster‐randomised trials in the analyses along with individually randomised trials. We intended to analyse them in keeping with methods described in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011), using an estimate of the intracluster correlation coefficient (ICC) derived from the trial (if possible) or from another source. If ICCs from other sources were used, we intended to report this and conduct sensitivity analyses to investigate effects of variations in the ICC. If we identified both cluster‐randomised trials and individually randomised trials, we planned to synthesise the relevant information. We considered it reasonable to combine results from both if we noted little heterogeneity between study designs, and if we considered interaction between effect of the intervention and choice of the randomisation unit to be unlikely.

Dealing with missing data

We obtained missing data from trial authors when possible. When missing data were not obtained, we examined the effect of excluding trials with substantial (e.g. > 10% losses) missing data by performing a sensitivity analysis.

Assessment of heterogeneity

We used RevMan 5 software (RevMan 2014) to assess the heterogeneity of treatment effects between trials. We used the following.

• Chi² test, to assess whether observed variability in effect sizes between studies is greater than would be expected by chance. As this test has low power when the number of studies included in the meta‐analysis is small, we set the probability at the 10% level of significance.

• I² statistic, to ensure that pooling of data was valid. We graded the degree of heterogeneity as follows: < 25% none, 25% to 49% low, 50% to 74% moderate, and 75%+ high.

We assessed the source of heterogeneity by performing sensitivity and subgroup analyses to look for evidence of bias or methodological differences between trials when evidence suggested apparent or statistical heterogeneity.

Assessment of reporting biases

We assessed reporting bias by comparing stated primary and secondary outcomes and reported outcomes. When study protocols were available, we compared these against study publications to determine the likelihood of reporting bias. We investigated reporting biases (such as publication bias) by using funnel plots. We assessed funnel plot asymmetry visually. We did not use formal tests to assess funnel plot asymmetry. We planned to perform exploratory analyses to investigate when asymmetry was detected by visual assessment.

Data synthesis

We performed statistical analyses according to recommendations of the CNRG (http://neonatal.cochrane.org/en/index.html). We analysed all randomised infants on an intention‐to‐treat (ITT) basis. We analysed treatment effects in individual trials. We used a fixed‐effect model in the first instance to combine data. For any meta‐analyses for categorical outcomes, we calculated typical estimates of RR and RD, each with the 95% CI; for continuous outcomes, we calculated the mean difference (MD) if outcomes were measured in the same way between trials, and standardised mean difference (SMD) to combine trials that measured the same outcome while using different scales. We planned to analyse and interpret individual trials separately when we judged meta‐analysis to be inappropriate.

Subgroup analysis and investigation of heterogeneity

We performed subgroup analyses of trial results (restricted to primary comparisons) according to the following.

• Management of caloric balance (protein, carbohydrate, and lipid) within trials.

• • Increase in amino acids to provide isocaloric nutrition compared with lower amino acid intake.

  • Increase in amino acids and provision of isocaloric non‐protein nutrition compared with lower amino acid intake.

  • Increase in amino acids and non‐protein caloric intake together compared with lower amino acid intake.

• Type of infant at commencement.

• • Studies enrolling relatively healthy infants or infants not selected on the basis of 'health status'.

  • Studies enrolling 'sick' infants (e.g. infants with moderate‐severe respiratory distress, receiving cardiovascular support, possible sepsis, acidosis).

  • Studies enrolling 'surgical' or postoperative infants or infants post cardiopulmonary bypass.

• Gestational age.

• • Studies enrolling term infants (≥ 37 weeks).

  • Studies enrolling preterm infants (< 37 weeks' gestational age).

  • Studies enrolling extremely preterm infants (< 28 weeks' gestation).

• Birth weight.

• • Studies enrolling low birth weight infants (< 2500 grams).

  • Studies enrolling very low birth weight infants (< 1500 grams).

  • Studies enrolling extremely low birth weight infants (< 1000 grams).

• Age at commencement.

• • Total parenteral nutrition (TPN) at < 24 hours' age.

  • TPN at ≥ 24 to < 48 hours' age.

  • TPN at ≥ 48 to < 72 hours' age.

  • TPN at ≥ 72 hours' age.

• According to lipid intake (not prespecified).

• • Early lipid infusion.

  • Delayed lipid infusion ≥ 5 days.

  • No lipid infusion.

• Concomitant increases in fluid intake.

• • Trials increasing amino acid intake with constant fluid intake in both groups.

  • Trials increasing amino acid intake by increasing fluid intake in the higher amino acid group.

Sensitivity analysis

We explored methodological heterogeneity by performing sensitivity analyses when sufficient data were available. We performed sensitivity analyses by excluding trials of lower quality based on lack of any of the following: allocation concealment, adequate randomisation, blinding of treatment, less than 10% loss to follow‐up.

Results

Description of studies

Results of the search

The CENTRAL search strategy yielded 140 records, and the MEDLINE and Embase search strategy 221 records. An updated search conducted in June 2017 identified an additional included study (Uthaya 2016), additional publications of included studies (Morgan 2014; Vlaardingerbroek 2013), and an additional excluded study (Bellagamba 2016). In total, we assessed 56 full reports for eligibility, resulting in 32 included studies, 23 excluded studies, and one ongoing study (Bloomfield 2015) (see PRISMA diagram in Figure 1).

1.

Study flow diagram.

Included studies

We assessed 32 studies that compared higher versus lower amino acid intake in parenteral nutrition (PN) as eligible for inclusion. We have reported the specifics of inclusion and exclusion criteria under Characteristics of included studies and in Table 2.

1. Summary of included studies.

Trial	Infants	Higher AA group	Lower AA group	Lipid	Enteral feed
Anderson 1979	Infants at < 37 weeks, AGA	2.5 g/kg/d day 1 to 5	0 g/kg/d day 1 to 5	No lipid. Isocaloric	No enteral feeds
Balasubramanian 2013	Birth weight 900 to 1250 grams	3 g/kg day 1 graded to 4 g/kg day 2	1 g/kg day 1 graded to 4 g/kg day 4	No lipid	Similar early enteral feeds
Black 1981	Infants with respiratory distress	Graded up to 2.8 g/kg/d from day 3 to 4	0 g/kg/d from day 3 to 4	Lipid in amino acid group	Similar delayed enteral feeds
Blanco 2008	Birth weight < 1000 grams	2.0 g/kg day 1 graded to 4.0 g/kg day 3	0.5 g/kg day 2 graded to 3.0 g/kg day 7	Similar lipid from day 1	Enteral feeds unclear
Bulbul 2012	Infants at < 32 weeks' gestation	3 g/kg from day 1	1 g/kg day 1 graded to 3 g/kg day 3	Lipid 3 g/kg day 1 vs 1 g/kg day 1 increasing to 3 g/kg day 3	Similar early enteral feeds
Burattini 2013	Birth weight 500 to 1249 grams	2.5 g/kg day 1 graded to 4.0 g/kg day 4	1.5 g/kg day 1 graded to 2.5 g/kg day 3	Similar lipid from day 5	Similar early enteral feeds
Can 2012	Infants at 27 to 33 weeks' gestation	3.0 g/kg day 1 graded to 4.0 g/kg day 2	1.5 g/kg day 1 graded to 4.0 g/kg day 3	Higher early lipid from day 1 (2 g/kg day 1 and 3 g/kg day 2 vs 1 g/kg day 1 graded to 3 g/kg day 3)	Similar early enteral feeds
Can 2013	Infants at < 32 weeks' gestation	3.0 g/kg day 1 graded to 4.0 g/kg day 2	1.5 g/kg day 1 graded to 4.0 g/kg day 3	Higher early lipid from day 1 (2 g/kg day 1 and 3 g/kg day 2 vs 1 g/kg day 1 graded to 3 g/kg day 3)	Similar early enteral feeds
Clark 2007	Infants at 23 to < 30 weeks' gestation	1.5 g/kg day 2 graded to 3.5 g/kg day 3	1.0 g/kg day 2 graded to 2.5 g/kg day 4	Similar early lipid from day 1	Similar early enteral feeds
Hata 2002	Surgical term infants	3.45 g/kg/d	2.59 g/kg/d vs 1.72 g/kg/d	No lipid	No enteral feeds
Heimler 2010	Infants at < 34 weeks' gestation	1.5 g/kg day 1 graded to 2.5 g/kg day 3	0 g/kg day 1 to 3 graded to 2.5 g/kg day 7	Similar lipid from day 4	No enteral feeds to day 4
Ibrahim 2004	Birth weight 501 to 1250 grams and at 24 to 32 weeks' gestation	3.5 g/kg day 1 to 7	0 g/kg day 1 to 2, 2.0 g/kg day 3 graded to 3.5 g/kg day 7	Higher early lipid from day 1	No enteral feeds to day 7
Kashyap 2007	Birth weight < 1250 grams	18% protein:NPE day 1 graded to 4.0 g/kg/d	12.5% protein:NPE graded to 3.0 g/kg/d	Early lipid from day 1	Similar early enteral feeds
Liu 2014	Birth weight 1000 to 2000 grams	3.0 g/kg day 1 graded to 4.0 g/kg/d	2.0 g/kg day 1 graded to 3.7 g/kg/d 1.0 g/kg day 1 graded to 3.5 g/kg/d	Similar early lipid from day 2	Similar early enteral feeds from day 3
Makay 2007	Infants at ≥ 35 weeks' gestation	1.0 g/kg day 1 graded to 3.0 g/kg day 5	0 g/kg day 1 graded to 3.0 g/kg day 7	Higher lipid from day 2	No enteral feeds
Morgan 2014	Infants at < 29 weeks’ gestation and birth weight < 1200 grams	1.8 g/kg day 1 to 2; 2.9 g/kg day 3 to 4 increased to 3.9 g/kg day 5	1.8 g/kg day 1 to 2; AA 2.4 g/kg day 3 to 4 increased to 2.8 g/kg day 5	Similar early lipid from day 1; higher lipid from day 5 Similar glucose day 1 to 2; higher glucose from day 3	Similar early enteral feeds
Murdoch 1995	Birth weight < 2000 grams	1.0 g/kg day 1 and 1.4 g/kg day 2	0 g/kg day 1 to 2	Higher lipid (no lipid control group)	No enteral feeds
Pappoe 2009	Birth weight 600 to 1200 grams	2.0 g/kg day 1 graded to 3.5 g/kg day 3	1.0 g/kg day 1 graded to 3.5 g/kg day 6	Higher lipid from day 1	Similar early enteral feeds
Pildes 1973	Infants < 1500 grams at 24 to 48 hours' age	Unclear intake (solution 3.4 g/100 mL)	0 g/kg/d	No lipid	Similar enteral feeds
Rivera 1993	Preterm infants with respiratory distress < 24 hours old on mechanical ventilation	1.5 g/kg day 1 to 3	0 g/kg/d	No lipid	No enteral feeds
Scattolin 2013	Birth weight < 1250 grams	2.0 g/kg day 1 graded to 4.0 g/kg day 4	1.5 g/kg day 1 graded to 3.0 g/kg day 4	Lipid intake not reported	Similar early enteral feeds
Tan 2008	Infants at < 33 weeks' gestation	1.0 g/kg day 1 graded to 4.0 g/kg day 7	1.0 g/kg day 1 graded to 3.0 g/kg day 7	Higher lipid from day 1	Similar early enteral feeds
Tang 2009	Birth weight 1000 to 2000 grams	2.4 g/kg day 1 graded to 3.6 g/kg day 2	1.0 g/kg day 1 graded to 3.0 g/kg day 6 vs 0 g/kg day 1 graded to 3.0 g/kg day 9	Similar lipid from day 3	Enteral feeds unclear
te Braake 2005	Birth weight ≤ 1500 grams	2.4 g/kg day 1 to 4	0 g/kg day 1 to 2 graded to 2.4 g/kg day 3 to 4	Similar early lipid from day 2	Similar early enteral feeds
Thureen 2003	Birth weight ≤ 1300 grams	2.56 g/kg day 1 to 2	0.85 g/kg day 1 to 2	Similar early lipid from day 1	No early enteral feeds
Uthaya 2016	Infants at < 31 weeks' gestation	3.6 g/kg/d from day 1	1.7 g/kg/d day 1, 2.1 g/kg/d day 2, maximum 2.7 g/kg/d day 3	Similar early lipid from day 1	Similar early enteral feeds
Vaidya 1995	Birth weight < 1250 grams	0.5 g/kg day 3 graded to 3.0 g/kg day 7	0 g/kg/d	Higher lipid from day 5 (control no lipid)	Early enteral feed
van Goudoever 1995	Birth weight < 2000 grams	1.15 g/kg day 1	0 g/kg/d	No lipid	No enteral feeds
van Lingen 1992	Preterm infants	Average 1.9 g/kg/d	0 g/kg/d	Similar early lipid from day 2	No enteral feeds
Vlaardingerbroek 2013	Birth weight < 1500 grams	3.6 g/kg day 2 to 6	2.4 g/kg day 2 to 6	Similar early lipid from day 1	No enteral feeds
Weiler 2006	Infants at 24 to 32 weeks' gestation	1.0 g/kg day 1 graded to 3.0 g/kg/d	0 g/kg day 1, 1.0 g/kg day 2 graded to 3.0 g/kg/d	Similar lipid from day 3	Factorial trial minimal enteral feeds from 3 days
Wilson 1997	Birth weight < 1200 grams or 1200 to 1499 grams on mechanical ventilation	0.5 g/kg day 1 graded to 3.5 g/kg day 7	0 g/kg day 1 to 2 graded to 2.5 g/kg day 7	Higher early lipid intake from day 1	Higher early enteral intake
Xie 2014	Infants at < 34 weeks' gestation	1.5 g/kg day 1 graded to 3.5 g/kg/d: graded by 1.0 g/kg/d	1.5 g/kg day 1 graded to 3.5 g/kg/d: graded by 0.5 g/kg/d	Similar lipid from day 1	Enteral feeds unclear

Participants

Three studies enrolled preterm or low birth weight infants: Anderson 1979 enrolled preterm infants not expected to receive enteral feeds for five days; van Goudoever 1995 infants at birth weight < 2000 grams; and Xie 2014 infants at < 34 weeks' gestation with birth weight 1000 to 1800 grams.

Most of the remaining trials enrolled very low birth weight or very preterm infants (n = 26): Balasubramanian 2013 enrolled infants with birth weight 900 to 1250 grams; Blanco 2008 birth weight < 1000 grams; Bulbul 2012 at < 32 weeks' gestation; Burattini 2013 birth weight 500 to 1249 grams; Can 2012 at 27 to 33 weeks' gestation; Can 2013 at < 32 weeks' gestation; Clark 2007 at 23 to < 30 weeks' gestation; Heimler 2010 at < 34 weeks' gestation; Ibrahim 2004 birth weight 501 to 1250 grams and at 24 to 32 weeks' gestation; Kashyap 2007 birth weight < 1250 grams; Liu 2015 birth weight 1000 to 2000 grams; Morgan 2014 at < 29 weeks’ gestation and birth weight < 1200 grams; Murdock 1995 birth weight < 2000 grams; Pappoe 2009 birth weight 600 to 1200 grams; Pildes 1973 birth weight < 1500 grams; Rivera 1993 preterm infants with respiratory distress at mean gestation 28.5 weeks; Scattolin 2013 birth weight < 1250 grams; Tan 2008 at < 33 weeks' gestation; Tang 2009 birth weight 1000 to 2000 grams; te Braake 2005 birth weight ≤ 1500 grams; Thureen 2003 birth weight ≤ 1300 grams; Uthaya 2016 at < 31 weeks' gestation; Vaidya 1995 birth weight < 1250 grams; van Lingen 1992 at mean gestation higher group 30.7 weeks and lower group 31.0 weeks; Vlaardingerbroek 2013 birth weight < 1500 grams; and Weiler 2006 at 24 to 32 weeks' gestation.

Two studies enrolled term or near term infants: Makay 2007 enrolled infants at ≥ 35 weeks' gestation whose clinical condition precluded oral feeding for three days; and Hata 2002 enrolled surgical term infants receiving fat‐free parenteral nutrition for 10 days.

Black 1981 enrolled infants admitted for respiratory distress but did not report gestation or birth weight.

Interventions

Higher versus lower amino acid intake at commencement of PN

Anderson 1979 compared 2.5 g/kg day 1 to 5 versus 0 g/kg day 1 to 5. Investigators provided no lipid and no enteral feeds.

Balasubramanian 2013 compared 3 g/kg day 1 advanced to 4 g/kg day 2 versus 1 g/kg day 1 advanced to 4 g/kg day 4. Investigators provided no lipid and gave similar early enteral feeds to both groups.

Bulbul 2012 compared 3 g/kg day 1 versus 1 g/kg day 1 advanced to 3 g/kg day 3. Lipid intake was 3 g/kg day 1 versus 1 g/kg day 1 increased to 3 g/kg day 3. Investigators provided similar early enteral feeds to both groups.

Can 2012 compared 3.0 g/kg day 1 advanced to 4.0 g/kg day 2 versus 1.5 g/kg day 1 advanced to 4.0 g/kg day 3. Both groups had early lipid and the higher AA group also received higher early lipid from day 1. Investigators provided similar early enteral feeds to both groups.

Can 2013 compared 3.0 g/kg day 1 advanced to 4.0 g/kg day 2 versus 1.5 g/kg day 1 advanced to 4.0 g/kg day 3. Both groups had early lipid and the higher AA group also received higher early lipid from day 1. Investigators provided similar early enteral feeds to both groups.

Heimler 2010 compared 1.5 g/kg day 1 advanced to 2.5 g/kg day 3 versus 0 g/kg days 1 to 3 advanced to 2.5 g/kg day 7. Both groups had similar lipid from day 4 and received no enteral feeds to day 4.

Ibrahim 2004 compared 3.5 g/kg day 1 to 7 versus 0 g/kg day 1 to 2 and 2.0 g/kg day 3 advanced to 3.5 g/kg day 7. Infants in the higher AA group received higher early lipid from day 1 and received no enteral feeds to day 7.

Liu 2015 compared 3.0 g/kg day 1 advanced to 4.0 g/kg/d versus 2.0 g/kg day 1 advanced to 3.7 g/kg/d versus 1.0 g/kg day 1 advanced to 3.5 g/kg/d. Both groups received similar early lipid from day 2 and similar early enteral feeds from day 3.

Makay 2007 compared 1.0 g/kg day 1 advanced to 3.0 g/kg day 5 versus 0 g/kg day 1 advanced to 3.0 g/kg day 7. The higher AA group received higher lipid from day 2 and received no enteral feeds to day 7.

Murdock 1995 compared 1.0 g/kg day 1 and 1.4 g/kg day 2 versus 0 g/kg day 1 to 2. The higher AA group also received lipid, and the lower AA group received no lipid. Investigators provided no enteral feeds during the study period.

Pappoe 2009 compared 2.0 g/kg day 1 advanced to 3.5 g/kg day 3 versus 1.0 g/kg day 1 advanced to 3.5 g/kg day 6. The higher AA group received lipid from day 1. Both groups received similar early enteral feeds.

Rivera 1993 compared 1.5 g/kg day 1 to 3 versus 0 g/kg/d. Investigators provided no lipids and no enteral feeds to either group.

Thureen 2003 compared 2.56 g/kg day 1 to 2 versus 0.85 g/kg day 1 to 2. Both groups received similar early lipid from day 1 and received no early enteral feeds.

van Goudoever 1995 compared 1.15 g/kg from day 1 onwards versus no AA intake. Investigators provided no lipid and no enteral feeds.

van Lingen 1992 compared an average 1.9 g/kg/d versus no AA intake. Both groups received similar early lipid from day 2 and received no enteral feeds.

Vlaardingerbroek 2013 compared 3.6 g/kg day 2 to 6 versus 2.4 g/kg day 2 to 6. Both groups received similar early lipid from day 2 and received no enteral feeds.

Weiler 2006 compared 1.0 g/kg day 1 advanced to 3.0 g/kg/d versus 0 g/kg day 1, 1.0 g/kg day 2 advanced to 3.0 g/kg/d. Both groups received similar lipid from day 3 and in a factorial designed trial received minimal enteral feeds from 3 days.

Higher versus lower amino acid intake at maximal intake of PN

Morgan 2014 compared 1.8 g/kg day 1 to 2, then 2.9 g/kg day 3 to 4 increased to 3.9 g/kg day 5 versus 1.8 g/kg day 1 to 2, then 2.4 g/kg day 3 to 4 increased to 2.8 g/kg day 5. The higher amino acid group received similar early lipid from day 1 but higher lipid from day 5. The higher amino acid group received similar glucose days 1 to 2 but higher glucose from day 3. Both groups received similar early enteral feeds.

Tan 2008 compared 1.0 g/kg day 1 advanced to 4.0 g/kg day 7 versus 1.0 g/kg day 1 advanced to 3.0 g/kg day 7. The higher AA group received higher lipid from day 1. Both groups received similar early enteral feeds.

Higher versus lower amino acid intake at commencement and maximal intake of PN

Black 1981 compared grading up to 2.5 g/kg/d from day 3 to 4 versus 0 g/kg/d from day 3 to 4. Investigators provided higher lipid to the higher amino acid group and similar delayed enteral feeds to both groups.

Blanco 2008 compared 2.0 g/kg day 1 advanced to 4.0 g/kg day 3 versus 0.5 g/kg day 2 advanced to 3.0 g/kg day 7. Both groups received similar lipid intake from day 1. The enteral feed regimen was unclear.

Burattini 2013 compared 2.5 g/kg day 1 advanced to 4.0 g/kg day 4 versus 1.5 g/kg day 1 advanced to 2.5 g/kg day 3. Both groups received similar lipid from day 5 and similar early enteral feeds.

Clark 2007 compared 1.5 g/kg day 2 advanced to 3.5 g/kg day 3 versus 1.0 g/kg day 2 advanced to 2.5 g/kg day 4. Both groups received similar early lipid from day 1 and similar early enteral feeds.

Liu 2015 compared 3.0 g/kg day 1 advanced to 4.0 g/kg/d versus 2.0 g/kg day 1 advanced to 3.7 g/kg/d versus 1.0 g/kg day 1 advanced to 3.5 g/kg/d. Both groups received similar early lipid from day 2 and similar early enteral feeds from day 3.

Pildes 1973 compared use of an amino acid solution at 3.4 g/100 mL versus 0 g/kg/d. Investigators provided no lipid to either group and similar enteral feeds to both groups and did not report actual amino acid intakes.

Scattolin 2013 compared 2.0 g/kg day 1 advanced to 4.0 g/kg day 4 versus 1.5 g/kg day 1 advanced to 3.0 g/kg day 4. Investigators did not report lipid intake, so it is likely lipid was not given. Investigators provided similar early enteral feeds to both groups.

Tang 2009 compared three groups receiving 2.4 g/kg day 1 advanced to 3.6 g/kg day 2 versus 1.0 g/kg day 1 advanced to 3.0 g/kg day 6 versus 0 g/kg day 1 advanced to 3.0 g/kg day 9. All groups received similar early lipid from day 3. The enteral feed regimen is unclear.

te Braake 2005 compared 2.4 g/kg day 1 to 4 versus 0 g/kg day 1 to 2 advanced to 2.4 g/kg day 3 to 4. Both groups received similar early lipid from day 2 and similar early enteral feeds.

Uthaya 2016 compared 3.6 g/kg/d from day 1 versus 1.7 g/kg/d from day 1, 2.1 g/kg/d from day 2, and a maximum of 2.7 g/kg/d from day 3. Both groups received similar early lipid from day 1 and similar early enteral feeds.

Vaidya 1995 compared 0.5 g/kg day 3 advanced to 3.0 g/kg day 7 versus no AA intake. The higher AA group received lipid from day 5. Both groups received similar early enteral feeds.

Faster rate of grading of amino acid intake

Xie 2014 compared 1.5 g/kg day 1 graded by 1.0 g/kg/d to 3.5 g/kg/d versus 1.5 g/kg day 1 graded by 0.5 g/kg/d to 3.5 g/kg/d. Both groups received similar early lipid from day 1. The enteral feed regimen is unclear.

Term surgical infants

Hata 2002 compared three groups of surgical infants receiving 3.45 g/kg/d versus 2.59 g/kg/d versus 1.72 g/kg/d. Investigators provided no lipid and no enteral feeds.

Management of caloric balance

Trials that increased amino acids and provided isocaloric non‐protein caloric intake include the following: Anderson 1979; Balasubramanian 2013; Blanco 2008; Burattini 2013; Clark 2007; Hata 2002; Heimler 2010; Kashyap 2007; Liu 2015; Pildes 1973; Rivera 1993; Scattolin 2013; Tang 2009; te Braake 2005; Thureen 2003; Uthaya 2016; van Goudoever 1995; van Lingen 1992; Vlaardingerbroek 2013; Weiler 2006; Xie 2014.

Trials that increased amino acids and non‐protein caloric intake include the following: Black 1981; Bulbul 2012; Can 2012; Can 2013; Ibrahim 2004; Makay 2007; Morgan 2014; Murdock 1995; Pappoe 2009; Tan 2008; Vaidya 1995.

Management of lipid infusion

Trials that provided early lipid infusion include the following: Black 1981; Blanco 2008; Bulbul 2012; Can 2012; Can 2013; Clark 2007; Heimler 2010; Ibrahim 2004; Kashyap 2007; Liu 2015; Makay 2007; Morgan 2014; Murdock 1995; Pappoe 2009; Tan 2008; Tang 2009; te Braake 2005; Thureen 2003; Uthaya 2016; van Lingen 1992; Vlaardingerbroek 2013; Weiler 2006; Xie 2014.

Trials that provided delayed lipid infusion ≥ 5 days include the following: Burattini 2013; Vaidya 1995.

Trials that provided no lipid infusion include the following: Anderson 1979; Balasubramanian 2013; Hata 2002; Pildes 1973; Rivera 1993; Scattolin 2013; van Goudoever 1995.

Outcomes

See Characteristics of included studies for details of outcome reporting for each study. Of the 33 included studies, six were short‐term biochemical studies (Anderson 1979; Murdock 1995; Rivera 1993; Thureen 2003; van Goudoever 1995; van Lingen 1992), one was a trial that enrolled term surgical infants (Hata 2002), and another included infants at > 35 weeks (Makay 2007) ‐ all without substantial clinical reporting. Anderson 1979 reported mean weight loss, mean nitrogen balance, and mean BUN values, but we were not able to use the data in this review. Murdock 1995 reported biochemical tolerance during the first 48 hours, but we were not able to use the data in this review. Pildes 1973 reported mortality, biochemical data, days to regain birth weight, weight gain to 21 days, and time to reach discharge weight but did not report denominators, so we were unable to use the data in this review. Hata 2002 reported cholestasis but no other clinical outcomes. Kashyap 2007 has not yet published data. Of the 21 studies reporting clinical effects that could be included in this review, outcome reporting was variable across studies both for outcomes reported and for timing of reporting. Outcomes reported by more than 50% of studies (≥ 10 of 21) included mortality (14 studies), days to regain birth weight (12 studies), late‐onset sepsis (15 studies), necrotising enterocolitis (14 studies), chronic lung disease (10 studies), and severe intraventricular haemorrhage (11 studies).

We have reported several additional analyses in the primary comparison "Higher versus lower amino acid intake in parenteral nutrition" including weight, length, and head circumference; weight, length, and head circumference z‐scores; patent ductus arteriosus; development quotient scores; nitrogen and protein balance; maximal blood urea nitrogen; hyperkalaemia, and discontinued PN due to biochemical intolerance. As these outcomes were not prespecified, we did not include them in subsequent comparisons and in subgroup analyses.

Primary outcomes

Fifteen studies reported mortality. Balasubramanian 2013 reported losses due to death or discharge against advice together, so we could not use these data. Studies failing to report mortality included Anderson 1979,Black 1981,Bulbul 2012,Heimler 2010,Liu 2015,Makay 2007,Pildes 1973,Rivera 1993,Tang 2009,Weiler 2006, and Xie 2014. Only three studies reported developmental outcomes. Blanco 2008 evaluated infants at 0, 3, 6, 12, and 18 months' corrected gestational age and at 24 months' chronological age by examination and Bayley Scales of Infant Development (BSID II). te Braake 2005 assessed neurological status and Bayley SCID II at two years and reported postnatal growth failure at six weeks and two years of age (< 10th centile). Investigators reported the Bayley Mental Development Index (MDI) only for infants without disability. Vlaardingerbroek 2013 reported death or major disability at two years' corrected age using clinical examination and Bayley III (Bayley Scales of Infant and Toddler Development–Third Edition). Only three studies reported postnatal growth failure (Can 2012; Pappoe 2009; te Braake 2005).

Secondary outcomes

Only a minority of studies reported prespecified clinical outcomes. Investigators reported growth outcomes incompletely and variably and did not frequently report change in growth parameter or growth parameter z‐score. In addition, reporting of timing was variable.

Several studies assessed the safety and tolerance of parenteral nutrition provided for short periods. Anderson 1979 reported biochemical tolerance during the first five days, but we were not able to use the data in this review. Black 1981 reported effects up to day 7 on cholestasis parameters, although we did not report these data in this review as the reporting period is insufficient. Murdock 1995 reported biochemical tolerance during the first 48 hours, but were not able to use the data in this review. Pildes 1973 reported biochemical data but did not report denominators, so we were unable to use the data in this review. Rivera 1993 reported nitrogen and protein balances and provided no clinical data. Thureen 2003 reported short‐term protein balance and provided no clinical data. van Goudoever 1995 reported nitrogen balances and amino acid profiles but no clinical data. van Lingen 1992 reported nitrogen balances and provided no clinical data. Several other studies provided protein/nitrogen balances as well as other clinical outcomes (Heimler 2010; Ibrahim 2004; Xie 2014). No study reported negative nitrogen balance.

Excluded studies

We assessed 23 studies as studies to be excluded (see Characteristics of excluded studies for reasons for exclusion).

Risk of bias in included studies

We assessed only five studies as high quality with low risk of bias from allocation concealment, randomisation, blinding of treatment, and less than 10% loss to follow‐up for all reported outcomes (Bulbul 2012; Can 2012; Can 2013; Clark 2007; Morgan 2014). We assessed Blanco 2008 as having low risk of bias for mortality outcomes and biochemical outcomes, and Uthaya 2016 at low risk of bias for reporting mortality, sepsis, and necrotising enterocolitis; we determined that both were at high risk of attrition bias for other outcomes. We were not able to assess Kashyap 2007 for risk of bias. All other studies had methodological concerns as documented below. See risk of bias graph (Figure 2) and risk of bias summary (Figure 3).

2.

Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages across all included studies.

3.

Risk of bias summary: review authors' judgements about each risk of bias item for each included study.

Allocation

We assessed random sequence generation as low risk for 12 studies (Balasubramanian 2013; Black 1981; Bulbul 2012; Burattini 2013; Can 2012; Can 2013; Clark 2007; Morgan 2014; Tan 2008; Uthaya 2016; Vlaardingerbroek 2013; Xie 2014). We assessed allocation concealment as low risk for 14 studies (Balasubramanian 2013; Black 1981; Blanco 2008; Bulbul 2012; Burattini 2013; Can 2012; Can 2013; Clark 2007; Ibrahim 2004; Morgan 2014; Tan 2008; Uthaya 2016; Vlaardingerbroek 2013; Weiler 2006) and selection bias as unclear in 19 studies (Anderson 1979; Blanco 2008; Hata 2002; Heimler 2010; Ibrahim 2004; Liu 2015; Makay 2007; Murdock 1995; Pappoe 2009; Pildes 1973; Rivera 1993; Scattolin 2013; Tang 2009; te Braake 2005; Thureen 2003; Vaidya 1995; van Goudoever 1995; van Lingen 1992; Weiler 2006).

Blinding

We assessed nine studies as having low risk of performance and detection bias in terms of reporting of blinding of participants, personnel, and outcome assessment (Balasubramanian 2013; Blanco 2008; Bulbul 2012; Can 2012; Can 2013; Morgan 2014; Scattolin 2013; Uthaya 2016; Xie 2014). Twelve studies reported the method of blinding of outcome assessment (Balasubramanian 2013; Blanco 2008; Bulbul 2012; Burattini 2013; Can 2012; Can 2013; Morgan 2014; Scattolin 2013; te Braake 2005; Uthaya 2016; Vlaardingerbroek 2013; Xie 2014). We assessed 18 studies as high risk (Burattini 2013; Hata 2002; Heimler 2010; Ibrahim 2004; Liu 2015; Makay 2007; Murdock 1995; Pappoe 2009; Rivera 1993; Tan 2008; Tang 2009; te Braake 2005; Thureen 2003; Vaidya 1995; van Goudoever 1995; van Lingen 1992; Vlaardingerbroek 2013; Weiler 2006).

Incomplete outcome data

We assessed 15 studies as having low risk of attrition bias, reporting < 10% loss to follow‐up (Bulbul 2012; Can 2012; Can 2013; Clark 2007; Ibrahim 2004; Liu 2015; Morgan 2014; Pappoe 2009; Tang 2009; te Braake 2005; Uthaya 2016; Vaidya 1995; van Lingen 1992; Vlaardingerbroek 2013; Xie 2014). Studies reporting > 10% post‐randomisation losses include Anderson 1979 (35%); Balasubramanian 2013 (18%); Blanco 2008 (2% for mortality and biochemical outcomes; 47% for other clinical and long‐term outcomes); Burattini 2013 (13%); Heimler 2010 (15%); Makay 2007 (25%); Murdock 1995 (34%); Scattolin 2013 (15%); Thureen 2003 (21%); Uthaya 2016 (none for mortality, sepsis, and NEC, but 11% for other outcomes); van Goudoever 1995 (17%); and Weiler 2006 (21%). Reporting of losses was unclear for two studies (Hata 2002; Tan 2008). In addition, Black 1981 excluded 2 of 21 infants owing to other reasons for cholestasis ‐ the primary outcome of this study.

Selective reporting

Most studies documented primary outcomes and standard reporting definitions of clinical outcomes included in the review. However, few studies had available trial protocols or trial registrations, so we assessed most trials as having unclear risk of selective reporting bias. We assessed five studies as having low risk of selective reporting bias (Blanco 2008; Clark 2007; Morgan 2014; Uthaya 2016; Vlaardingerbroek 2013).

Other potential sources of bias

Eight studies showed imbalance between groups in baseline characteristics (Blanco 2008; Hata 2002; Liu 2015; Makay 2007; Murdock 1995; Rivera 1993; te Braake 2005; Xie 2014). Ibrahim 2004 had a reporting concern, in that denominators for each group appear to have been transposed in Table 3. Two studies reported insufficient baseline characteristics (Black 1981; Pildes 1973).

Effects of interventions

See: Table 1

Higher versus lower amino acid intake in parenteral nutrition

Primary outcomes

Mortality to discharge (Analysis 1.1; Figure 4): Data show no difference in mortality to discharge (typical RR 0.90, 95% CI 0.69 to 1.17; participants = 1407; studies = 14; I² = 0%; quality of evidence: low). We downgraded quality of evidence owing to imprecision and potential for publication or reporting bias.

1.1. Analysis.

Comparison 1 Higher versus lower amino acid intake in parenteral nutrition, Outcome 1 Mortality to hospital discharge.

4.

Funnel plot of comparison: 1 Higher versus lower amino acid intake in parenteral nutrition, outcome: 1.1 Mortality to hospital discharge.

Neurodevelopmental disability at 2 years age (Analysis 1.2): Data show no difference in neurodevelopmental disability (typical RR 1.04, 95% CI 0.48 to 2.23; participants = 201; studies = 2; I² = 82% [high]; quality of evidence: very low). Neither study reported a significant difference (te Braake 2005; Vlaardingerbroek 2013). We downgraded quality of evidence owing to risk of bias, inconsistency, imprecision, and potential for publication or reporting bias.

1.2. Analysis.

Comparison 1 Higher versus lower amino acid intake in parenteral nutrition, Outcome 2 Neurodevelopmental disability.

Postnatal growth failure at discharge (weight < 10th percentile) (Analysis 1.3): Data show a reduction in postnatal growth failure (weight < 10th percentile) at discharge (typical RR 0.74, 95% CI 0.56 to 0.97; participants = 203; studies = 3; I² = 22%; RD ‐0.15, 95% CI ‐0.27 to ‐0.02; NNTB 7, 95% CI 4 to 50; quality of evidence: very low). We downgraded quality of evidence owing to risk of bias, imprecision, and potential for publication or reporting bias.

1.3. Analysis.

Comparison 1 Higher versus lower amino acid intake in parenteral nutrition, Outcome 3 Postnatal growth failure at discharge (weight < 10th centile).

Postnatal growth failure at discharge (weight 2 SD below mean)(Analysis 1.4) (not a prespecified outcome): A single study reported no difference in growth failure (weight 2 standard deviations (SDs) below mean) up at discharge (RR 0.96, 95% CI 0.66 to 1.40; participants = 114) (Burattini 2013).

1.4. Analysis.

Comparison 1 Higher versus lower amino acid intake in parenteral nutrition, Outcome 4 Postnatal growth failure at discharge (weight 2 SD below mean).

Postnatal growth failure post discharge (Analysis 1.5) (not a prespecified outcome): A single study reported no difference in growth failure at two years (RR 0.66, 95% CI 0.33 to 1.32; participants = 111) (te Braake 2005).

1.5. Analysis.

Comparison 1 Higher versus lower amino acid intake in parenteral nutrition, Outcome 5 Postnatal growth failure post discharge.

Secondary outcomes

Days to regain birth weight (Analysis 1.6): Data show a significant reduction in days to regain birth weight (MD ‐1.14, 95% CI ‐1.73 to ‐0.56; participants = 950; studies = 13; I² = 77%; heterogeneity: high).

1.6. Analysis.

Comparison 1 Higher versus lower amino acid intake in parenteral nutrition, Outcome 6 Days to regain birth weight.

Maximal weight loss in grams (Analysis 1.7): Data show a reduction in maximal weight loss in grams (MD ‐22.71 g, 95% CI ‐33.68 to ‐11.74; participants = 235; studies = 3; I² = 81%; heterogeneity: high).

1.7. Analysis.

Comparison 1 Higher versus lower amino acid intake in parenteral nutrition, Outcome 7 Maximal weight loss (grams).

Weight loss per cent (Analysis 1.8): Data show no difference in weight loss per cent (MD ‐0.33%, 95% CI ‐1.61 to 0.96; participants = 288; studies = 4; I² = 38%; heterogeneity: low). The two meta‐analyses of weight loss outcomes comprise different studies.

1.8. Analysis.

Comparison 1 Higher versus lower amino acid intake in parenteral nutrition, Outcome 8 Maximal weight loss %.

Weight gain to 1 month age (Analysis 1.9): Data show a reduction in weight gain to one month of age (MD ‐1.50 g/kg/d, 95% CI ‐2.56 to ‐0.44; participants = 373; studies = 4; I² = 87%; heterogeneity: high).

1.9. Analysis.

Comparison 1 Higher versus lower amino acid intake in parenteral nutrition, Outcome 9 Weight gain g/kg/d.

Weight gain to discharge (Analysis 1.9): Data show no difference in weight gain up to discharge (MD 0.76 g/kg/d, 95% CI ‐0.02 to 1.54; participants = 291; studies = 4; I² = 0%; quality of evidence: very low). We downgraded quality of evidence owing to risk of bias, imprecision, and potential for publication or reporting bias.

Linear growth to 1 month (Analysis 1.10): Data show a reduction in linear growth to one month (MD ‐0.16 cm/week, 95% CI ‐0.26 to ‐0.06; participants = 245; studies = 2; I² = 86%; heterogeneity: high).

1.10. Analysis.

Comparison 1 Higher versus lower amino acid intake in parenteral nutrition, Outcome 10 Linear growth cm/week.

Head circumference growth to one month (Analysis 1.11): Data show no difference in head circumference growth to one month (MD 0.01 cm/week, 95% CI ‐0.04 to 0.06; participants = 476; studies = 4; I² = 92%; heterogeneity: high).

1.11. Analysis.

Comparison 1 Higher versus lower amino acid intake in parenteral nutrition, Outcome 11 Head circumference growth cm/week.

Head circumference growth to discharge (Analysis 1.11): Data show an increase in head circumference growth to discharge (MD 0.09 cm/week, 95% CI 0.06 to 0.13; participants = 315; studies = 4; I² = 90%; heterogeneity: high; quality of evidence: very low). We downgraded quality of evidence owing to risk of bias, inconsistency, imprecision, and potential for publication or reporting bias.

Weight change z‐score to 1 month (Analysis 1.12): A single study reported no difference in weight change z‐score to one month (MD ‐0.20, 95% CI ‐0.62 to 0.22; participants = 96) (Vlaardingerbroek 2013).

1.12. Analysis.

Comparison 1 Higher versus lower amino acid intake in parenteral nutrition, Outcome 12 Weight change z‐score.

Weight change z‐score to discharge (Analysis 1.12): Data show no difference in weight change in z‐score to discharge (MD 0.01, 95% CI ‐0.33 to 0.36; participants = 207; studies = 2; I² = 48%; heterogeneity: low).

Weight change z‐score post discharge (Analysis 1.12): Data show no difference in weight change in z‐score post discharge (MD 0.13, 95% CI ‐0.26 to 0.52; participants = 201; studies = 2; I² = 47%; heterogeneity: low).

Length change z‐score: This was not reported.

Head circumference change in z‐score to 1 month (Analysis 1.13): Data show an increase in head circumference change in z‐score to one month (MD 0.27, 95% CI 0.08 to 0.46; participants = 231; studies = 2; I² = 66%).

1.13. Analysis.

Comparison 1 Higher versus lower amino acid intake in parenteral nutrition, Outcome 13 Head circumference change z‐score.

Head circumference change in z‐score to discharge (Analysis 1.13): Data show no difference in head circumference change in z‐score to discharge (MD 0.18, 95% CI ‐0.15 to 0.50; participants = 207; studies = 2; I² = 63%; heterogeneity: moderate).

Head circumference change in z‐score post discharge (Analysis 1.13): Data show no difference in head circumference change in z‐score post discharge ((MD 0.25, 95% CI ‐0.14 to 0.64; participants = 201; studies = 2; I² = 50%).

Weight at one month (Analysis 1.14) (not a prespecified outcome): Data show no difference in weight at one month (MD ‐18.45 g/kg/d, 95% CI ‐68.42 to 31.52; participants = 430; studies = 4; I² = 78%; heterogeneity: high).

1.14. Analysis.

Comparison 1 Higher versus lower amino acid intake in parenteral nutrition, Outcome 14 Weight (grams).

Weight at discharge (Analysis 1.14) (not a prespecified outcome): Data show an increase in weight at discharge (MD 81.07 g/kg/d, 95% CI 36.59 to 125.56; participants = 874; studies = 10; I² = 0%).

Weight post discharge (Analysis 1.14) (not a prespecified outcome): Data show no difference in weight post discharge (MD ‐11.07 g, 95% CI ‐493.31 to 471.18; participants = 211; studies = 2; I² = 0%).

Length at one month (Analysis 1.15) (not a prespecified outcome): Data show no difference in length at one month (MD ‐0.41 cm, 95% CI ‐1.03 to 0.20; participants = 295; studies = 3; I² = 76%; heterogeneity: high).

1.15. Analysis.

Comparison 1 Higher versus lower amino acid intake in parenteral nutrition, Outcome 15 Length (cm).

Length at discharge (Analysis 1.15) (not a prespecified outcome): Data show an increase in length at discharge (MD 0.57 cm, 95% CI 0.17 to 0.98; participants = 553; studies = 6; I² = 47%; heterogeneity: low).

Length post discharge (Analysis 1.15) (not a prespecified outcome): A single study reported no difference in length post discharge (MD ‐0.10 cm, 95% CI ‐1.81 to 1.61; participants = 100) (Burattini 2013).

Head circumference at one month (Analysis 1.16) (not a prespecified outcome): Data show no difference in head circumference to one month (MD 0.19 cm, 95% CI ‐0.13 to 0.51; participants = 430; studies = 4; I² = 81%; heterogeneity: high).

1.16. Analysis.

Comparison 1 Higher versus lower amino acid intake in parenteral nutrition, Outcome 16 Head circumference (cm).

Head circumference at discharge (Analysis 1.16) (not a prespecified outcome): Data show no difference in head circumference at discharge (MD 0.08, 95% CI ‐0.14 to 0.29; participants = 834; studies = 9; I² = 59%; heterogeneity: moderate).

Head circumference post discharge (Analysis 1.16) (not a prespecified outcome): Data show no difference in head circumference post discharge (MD ‐0.04, 95% CI ‐0.52 to 0.44; participants = 211; studies = 2; I² = 3%).

Weight z‐score at one month (Analysis 1.17) (not a prespecified outcome): A single study reported no difference in weight z‐score at one month (MD 0.14, 95% CI ‐0.11 to 0.39; participants = 135) (Morgan 2014).

1.17. Analysis.

Comparison 1 Higher versus lower amino acid intake in parenteral nutrition, Outcome 17 Weight z‐score.

Weight z‐score at discharge (Analysis 1.17) (not a prespecified outcome): Data show no difference in weight z‐score at discharge (MD 0.16, 95% CI ‐0.02 to 0.33; participants = 352; studies = 3; I² = 0%).

Length z‐score at discharge (Analysis 1.18) (not a prespecified outcome): Data show no difference in length z‐score at discharge (MD 0.12, 95% CI ‐0.14 to 0.38; participants = 228; studies = 2; I² = 0%).

1.18. Analysis.

Comparison 1 Higher versus lower amino acid intake in parenteral nutrition, Outcome 18 Length z‐score.

Head circumference z‐score at one month (Analysis 1.19) (not a prespecified outcome): A single study reported an increase in head circumference z‐score to one month (MD 0.30, 95% CI 0.01 to 0.59; participants = 135) (Morgan 2014).

1.19. Analysis.

Comparison 1 Higher versus lower amino acid intake in parenteral nutrition, Outcome 19 Head circumference z‐score.

Head circumference z‐score at discharge (Analysis 1.19) (not a prespecified outcome): Data show no difference in head circumference z‐score at discharge (MD 0.04, 95% CI ‐0.18 to 0.26; participants = 354; studies = 3; I² = 57%; heterogeneity: moderate).

Head circumference z‐score at post discharge (Analysis 1.19) (not a prespecified outcome): A single study reported no difference in head circumference z‐score at post discharge (MD ‐0.01, 95% CI ‐0.50 to 0.48; participants = 100) (Burattini 2013).

Days to full enteral feeds (Analysis 1.20): Data show no difference in days to full enteral feeds (MD ‐0.19, 95% CI ‐1.07 to 0.70; participants = 778; studies = 11; I² = 46%; heterogeneity: low).

1.20. Analysis.

Comparison 1 Higher versus lower amino acid intake in parenteral nutrition, Outcome 20 Days to full enteral feeds.

Late‐onset sepsis (Analysis 1.21): Data show no difference in late‐onset sepsis (typical RR 0.96, 95% CI 0.79 to 1.18; participants = 1255; studies = 15; I² = 0%).

1.21. Analysis.

Comparison 1 Higher versus lower amino acid intake in parenteral nutrition, Outcome 21 Late‐onset sepsis.

Necrotising enterocolitis (Analysis 1.22): Data show no difference in necrotising enterocolitis (typical RR 1.00, 95% CI 0.68 to 1.47; participants = 1301; studies = 14; I² = 0%).

1.22. Analysis.

Comparison 1 Higher versus lower amino acid intake in parenteral nutrition, Outcome 22 Necrotising enterocolitis.

Chronic lung disease (Analysis 1.23): Data show no difference in chronic lung disease (typical RR 1.04, 95% CI 0.89 to 1.23; participants = 819; studies = 10; I² = 22%).

1.23. Analysis.

Comparison 1 Higher versus lower amino acid intake in parenteral nutrition, Outcome 23 Chronic lung disease at ≥ 36 weeks' PMA.

Patent ductus arteriosus (Analysis 1.24) (not a prespecified outcome): Data show no difference in patent ductus arteriosus (typical RR 0.83, 95% CI 0.67 to 1.02; participants = 607; studies = 7; I² = 13%).

1.24. Analysis.

Comparison 1 Higher versus lower amino acid intake in parenteral nutrition, Outcome 24 Patent ductus arteriosus.

Intraventricular haemorrhage (Analysis 1.25): Data show no difference in intraventricular haemorrhage (typical RR 1.12, 95% CI 0.74 to 1.69; participants = 341; studies = 3; I² = 0%).

1.25. Analysis.

Comparison 1 Higher versus lower amino acid intake in parenteral nutrition, Outcome 25 Intraventricular haemorrhage.

Severe intraventricular haemorrhage (Analysis 1.26): Data show no difference in severe intraventricular haemorrhage (typical RR 1.16, 95% CI 0.74 to 1.82; participants = 904; studies = 11; I² = 0%).

1.26. Analysis.

Comparison 1 Higher versus lower amino acid intake in parenteral nutrition, Outcome 26 Severe intraventricular haemorrhage.

Periventricular leukomalacia (Analysis 1.27): Data show no difference in periventricular leukomalacia (typical RR 0.55, 95% CI 0.24 to 1.25; participants = 720; studies = 7; I² = 13%).

1.27. Analysis.

Comparison 1 Higher versus lower amino acid intake in parenteral nutrition, Outcome 27 Periventricular leukomalacia.

MRI brain abnormality at term: No data were reported.

Retinopathy of prematurity (Analysis 1.28): Data show a reduction in retinopathy of prematurity (typical RR 0.44, 95% CI 0.21 to 0.93; participants = 269; studies = 4; I² = 31%; heterogeneity: low).

1.28. Analysis.

Comparison 1 Higher versus lower amino acid intake in parenteral nutrition, Outcome 28 Retinopathy of prematurity.

Severe retinopathy of prematurity (Analysis 1.29): Data show no difference in severe retinopathy of prematurity (typical RR 0.96, 95% CI 0.56 to 1.63; participants = 672; studies = 8; I² = 34%; heterogeneity: low; quality of evidence: very low). We downgraded quality of evidence owing to risk of bias, imprecision, and potential for publication or reporting bias.

1.29. Analysis.

Comparison 1 Higher versus lower amino acid intake in parenteral nutrition, Outcome 29 Severe retinopathy of prematurity (> stage 2 or treated).

Cerebral palsy (Analysis 1.30): Data show no difference in cerebral palsy (typical RR 4.00, 95% CI 0.89 to 17.97; participants = 122; studies = 2; I² = 0%).

1.30. Analysis.

Comparison 1 Higher versus lower amino acid intake in parenteral nutrition, Outcome 30 Cerebral palsy.

Developmental delay (Analysis 1.31): Data show no difference in developmental delay (typical RR 1.35, 95% CI 0.52 to 3.53; participants = 301; studies = 3; I² = 0%).

1.31. Analysis.

Comparison 1 Higher versus lower amino acid intake in parenteral nutrition, Outcome 31 Developmental delay at ≥ 18 months.

Blindness (Analysis 1.32): Data show no difference in blindness (typical RR 2.00, 95% CI 0.20 to 19.91; participants = 122; studies = 2; I² = 0%).

1.32. Analysis.

Comparison 1 Higher versus lower amino acid intake in parenteral nutrition, Outcome 32 Blindness.

Deafness (Analysis 1.33): A single study reported no severe hearing impairment at two years in either group (Vlaardingerbroek 2013).

1.33. Analysis.

Comparison 1 Higher versus lower amino acid intake in parenteral nutrition, Outcome 33 Deafness.

Bayley Mental Development Index (MDI) at ≥ 18 months (Analysis 1.34): Data show no difference in Bayley MDI at ≥ 18 months (MD ‐4.18, 95% CI ‐8.53 to 0.17; participants = 105; studies = 2; I² = 0%).

1.34. Analysis.

Comparison 1 Higher versus lower amino acid intake in parenteral nutrition, Outcome 34 Bayley MDI at ≥ 18 months.

Bayley Psychomotor Development Index (PDI) at ≥ 18 months (Analysis 1.36): A single study reported no difference in Bayley PDI ≥ 18 months (MD 3.00, 95% CI ‐6.41 to 12.41; participants = 32) (Blanco 2008).

1.36. Analysis.

Comparison 1 Higher versus lower amino acid intake in parenteral nutrition, Outcome 36 Bayley PDI at ≥ 18 months.

Bayley III score ≥ 18 months (Analysis 1.35): A single study reported no difference in Bayley III score ≥ 18 months (MD 3.00, 95% CI ‐2.52 to 8.52; participants = 100) (Burattini 2013).

1.35. Analysis.

Comparison 1 Higher versus lower amino acid intake in parenteral nutrition, Outcome 35 Bayley III score at ≥ 18 months.

Autism (Analysis 1.37) (not a prespecified outcome): A single study reported no difference in autism (RR 1.00, 95% CI 0.07 to 14.64; participants = 32) (Blanco 2008).

1.37. Analysis.

Comparison 1 Higher versus lower amino acid intake in parenteral nutrition, Outcome 37 Autism.

Nitrogen balance (Analysis 1.38): Data show an increase in nitrogen balance (MD 505.20 mg/kg/d, 95% CI 492.01 to 518.39; participants = 153; studies = 6; I² = 99%; heterogeneity: high). Studies are ordered by initial amino acid intake. We noted significant subgroup differences (P < 0.00001).

1.38. Analysis.

Comparison 1 Higher versus lower amino acid intake in parenteral nutrition, Outcome 38 Nitrogen balance.

Protein balance (Analysis 1.39) (not a prespecified outcome): Data show an increase in protein balance (MD 1.57 g/kg/d, 95% CI 1.47 to 1.66; participants = 52; studies = 3; I² = 93%; heterogeneity: high). Studies are ordered by initial amino acid intake. We noted significant subgroup differences (P < 0.00001).

1.39. Analysis.

Comparison 1 Higher versus lower amino acid intake in parenteral nutrition, Outcome 39 Protein balance.

Abnormal serum ammonia (Analysis 1.40): A single study reported no difference in ammonia > 69 μmol/L (RR 13.42, 95% CI 0.79 to 228.24; participants = 61) and ammonia > 122 μmol/L (RR 3.10, 95% CI 0.13 to 73.16; participants = 61) (Blanco 2008). Data show no difference in ammonia > 100 μmol/L (typical RR 9.29, 95% CI 0.52 to 165.45; participants = 105; studies = 2; I² = 0%). All infants with high ammonia were included in the higher amino acid group.

1.40. Analysis.

Comparison 1 Higher versus lower amino acid intake in parenteral nutrition, Outcome 40 Abnormal serum ammonia.

Abnormal blood urea nitrogen (Analysis 1.41): Criteria for abnormal blood urea nitrogen differed between studies. Data show a significant increase in abnormal blood urea nitrogen level (various criteria) (RD 0.26, 95% CI 0.20 to 0.32; participants = 688; studies = 7; I² = 90%; heterogeneity: high; RD 0.26, 95% CI 0.20 to 0.32; NNTH 4; 95% CI 3 to 5).

1.41. Analysis.

Comparison 1 Higher versus lower amino acid intake in parenteral nutrition, Outcome 41 Abnormal blood urea nitrogen (various criteria).

Maximal blood urea nitrogen (Analysis 1.42) (not a prespecified outcome): Data show an increase in maximal blood urea nitrogen (MD 4.48, 95% CI 3.43 to 5.53; participants = 159; studies = 2; I² = 96%; heterogeneity: high; quality of evidence: high).

1.42. Analysis.

Comparison 1 Higher versus lower amino acid intake in parenteral nutrition, Outcome 42 Maximum blood urea nitrogen mmol/L.

Hyperglycaemia (plasma glucose > 8.3 mmol/L) (Analysis 1.43): Data show a reduction in hyperglycaemia (typical RR 0.69, 95% CI 0.49 to 0.96; participants = 505; studies = 5; I² = 68%; heterogeneity: moderate).

1.43. Analysis.

Comparison 1 Higher versus lower amino acid intake in parenteral nutrition, Outcome 43 Hyperglycaemia, plasma glucose > 8.3 mmol/L.

Hyperglycaemia treated with insulin (Analysis 1.44): Data show no difference in hyperglycaemia treated with insulin (typical RR 1.24, 95% CI 0.93 to 1.66; participants = 534; studies = 5; I² = 67%; heterogeneity: moderate).

1.44. Analysis.

Comparison 1 Higher versus lower amino acid intake in parenteral nutrition, Outcome 44 Hyperglycaemia treated with insulin.

Hypoglycaemia (Analysis 1.45): Data show no difference in hypoglycaemia (typical RR 1.17, 95% CI 0.84 to 1.63; participants = 376; studies = 3; I² = 0%).

1.45. Analysis.

Comparison 1 Higher versus lower amino acid intake in parenteral nutrition, Outcome 45 Hypoglycaemia.

Hypoalbuminaemia: This was not reported.

Metabolic acidosis (Analysis 1.46): Data show no difference in metabolic acidosis (typical RR 2.05, 95% CI 0.94 to 4.47; participants = 305; studies = 4; I² = 22%).

1.46. Analysis.

Comparison 1 Higher versus lower amino acid intake in parenteral nutrition, Outcome 46 Metabolic acidosis.

Cholestasis (Analysis 1.47): Data show no difference in cholestasis (typical RR 1.26, 95% CI 0.86 to 1.84; participants = 616; studies = 5; I² = 8%).

1.47. Analysis.

Comparison 1 Higher versus lower amino acid intake in parenteral nutrition, Outcome 47 Cholestasis.

Hyperkalaemia (Analysis 1.48) (not a prespecified outcome): A single study reported no difference in hyperkalaemia (RR 0.62, 95% CI 0.16 to 2.37; participants = 61) (Blanco 2008).

1.48. Analysis.

Comparison 1 Higher versus lower amino acid intake in parenteral nutrition, Outcome 48 Hyperkalaemia.

Discontinued PN due to biochemical intolerance (Analysis 1.49) (not a prespecified outcome): A single study reported no difference in discontinued PN due to biochemical intolerance (RR 13.42, 95% CI 0.79 to 228.24; participants = 61) (Blanco 2008). All six infants who discontinued PN were in the higher amino acid group.

1.49. Analysis.

Comparison 1 Higher versus lower amino acid intake in parenteral nutrition, Outcome 49 Discontinued PN owing to biochemical intolerance.

Subgroup analyses

No data were available for review authors to determine the effect of higher versus lower amino acid intake in parenteral nutrition subgrouped by studies enrolling 'sick' infants (e.g. infants with moderate‐severe respiratory distress, receiving cardiovascular support, with possible sepsis, acidosis); and studies enrolling 'surgical' or postoperative infants or infants post cardiopulmonary bypass. The following analyses substantially relate to preterm and low birth weight infants.

Higher versus lower amino acid intake at commencement of parenteral nutrition, subgrouped by commencement intake

Fifteen studies compared higher versus lower amino acid intake at commencement of parenteral nutrition (Anderson 1979; Balasubramanian 2013; Bulbul 2012; Can 2012; Can 2013; Heimler 2010; Ibrahim 2004; Makay 2007; Murdock 1995; Pappoe 2009; Thureen 2003; van Goudoever 1995; van Lingen 1992; Vlaardingerbroek 2013; Weiler 2006).

Primary outcomes

Mortality to discharge (Analysis 2.1): Data show no difference in mortality (typical RR 0.78, 95% CI 0.45 to 1.36; participants = 433; studies = 6) and no subgroup differences by commencement intake; testing for subgroup differences: P = 0.79, I² = 0%.

2.1. Analysis.

Comparison 2 Higher versus lower amino acid intake at commencement of parenteral nutrition: subgrouped by commencement intake, Outcome 1 Mortality before hospital discharge.

Neurodevelopmental disability at 2 years (Analysis 2.2): Data show no difference in neurodevelopmental disability at two years (typical RR 1.04, 95% CI 0.48 to 2.23; participants = 201; studies = 2); testing for subgroup differences was significant: P = 0.02, I² = 81.2%. Neither study reported a significant difference (high AA intake > 2 to ≤ 3 g/kg/d ‐ te Braake 2005; very high AA intake > 3 g/kg/d ‐ Vlaardingerbroek 2013).

2.2. Analysis.

Comparison 2 Higher versus lower amino acid intake at commencement of parenteral nutrition: subgrouped by commencement intake, Outcome 2 Neurodevelopmental disability.

Postnatal growth failure at discharge (Analysis 2.3): Data show a reduction in postnatal growth failure at discharge (typical RR 0.74, 95% CI 0.56 to 0.97; participants = 203; studies = 3) and no subgroup differences by commencement intake; testing for subgroup differences: P = 0.21, I² = 37.6%. For subgroups, a single study commencing low amino acid intake (> 1 to ≤ 2 g/kg/d) among infants reported no difference in growth failure at discharge (RR 0.95, 95% CI 0.62 to 1.46; participants = 42) (Pappoe 2009). Infants commenced on high amino acid intake (2 to ≤ 3 g/kg/d) showed a reduction in postnatal growth failure at discharge (typical RR 0.67, 95% CI 0.48 to 0.94; participants = 161; studies = 2).

2.3. Analysis.

Comparison 2 Higher versus lower amino acid intake at commencement of parenteral nutrition: subgrouped by commencement intake, Outcome 3 Postnatal growth failure at discharge.

Postnatal growth failure post discharge (Analysis 2.4): A single study commencing high amino acid intake (> 2 to ≤ 3 g/kg/d) reported no difference in postnatal growth failure at two years (RR 0.66, 95% CI 0.33 to 1.32; participants = 111) (te Braake 2005).

2.4. Analysis.

Comparison 2 Higher versus lower amino acid intake at commencement of parenteral nutrition: subgrouped by commencement intake, Outcome 4 Postnatal growth failure post discharge.

Secondary outcomes

Days to regain birth weight (Analysis 2.5): Data show no difference in days to regain birth weight (MD 0.43, 95% CI ‐0.51 to 1.37; participants = 303; studies = 6) and no subgroup difference by commencement intake; testing for subgroup differences: P = 0.06, I² = 64.2%.

2.5. Analysis.

Comparison 2 Higher versus lower amino acid intake at commencement of parenteral nutrition: subgrouped by commencement intake, Outcome 5 Days to regain birth weight.

Maximal weight loss in grams (Analysis 2.6): A single study commencing with high amino acid intake (> 2 to ≤ 3 g/kg/d) reported no difference in maximal weight loss in grams (MD 22.60, 95% CI ‐7.25 to 52.45; participants = 50) (Can 2012).

2.6. Analysis.

Comparison 2 Higher versus lower amino acid intake at commencement of parenteral nutrition: subgrouped by commencement intake, Outcome 6 Maximal weight loss (grams).

Maximal weight loss per cent (Analysis 2.7): Data show no difference in maximal weight loss per cent (MD ‐2.73, 95% CI ‐5.71 to 0.25; participants = 59; studies = 2; I² = 40%). Both studies commenced with low amino acid intake (> 1 to ≤ 2 g/kg/d).

2.7. Analysis.

Comparison 2 Higher versus lower amino acid intake at commencement of parenteral nutrition: subgrouped by commencement intake, Outcome 7 Maximal weight loss %.

Weight gain to one month (Analysis 2.8): Data show reduced weight gain to one month (MD ‐3.17 g/kg/d, 95% CI ‐4.49 to ‐1.84; participants = 219; studies = 2) with significant subgroup differences; testing for subgroup differences: P = 0.01, I² = 83.3%. For subgroups, Balasubramanian 2013 commencing 3 g/kg/d versus 1 g/kg/d amino acid on day 1 reported reduced weight gain to one month of age (MD ‐4.48, 95% CI ‐6.17 to ‐2.79; participants = 123). Vlaardingerbroek 2013 commencing with 3.6 g/kg/d versus 2.4 g/kg/d at day 2 to 6 reported no difference in weight gain to one month (MD ‐1.10, 95% CI ‐3.22 to 1.02; participants = 96).

2.8. Analysis.

Comparison 2 Higher versus lower amino acid intake at commencement of parenteral nutrition: subgrouped by commencement intake, Outcome 8 Weight gain g/kg/day to 1 month age.

Weight gain to discharge (Analysis 2.9): Data show no difference in weight gain to discharge (MD 1.05, 95% CI ‐0.55 to 2.66; participants = 140; studies = 2) and no subgroup difference by commencement intake; testing for subgroup differences: P = 0.34; I² = 0%.

2.9. Analysis.

Comparison 2 Higher versus lower amino acid intake at commencement of parenteral nutrition: subgrouped by commencement intake, Outcome 9 Weight gain g/kg/day to discharge.

Linear growth to one month (Analysis 2.10): A single study commencing 3 g/kg/d versus 1 g/kg/d amino acid on day 1 reported a reduction in linear growth to one month (MD ‐0.27, 95% CI ‐0.40 to ‐0.14; participants = 123) (Balasubramanian 2013).

2.10. Analysis.

Comparison 2 Higher versus lower amino acid intake at commencement of parenteral nutrition: subgrouped by commencement intake, Outcome 10 Linear growth cm/week to 1 month age.

Head circumference growth to one month (Analysis 2.11): Data show reduced head circumference growth to one month (MD ‐0.12, 95% CI ‐0.21 to ‐0.04; participants = 219; studies = 2) with significant subgroup differences: P < 0.0001; I² = 94.9%. For subgroups, Balasubramanian 2013 commencing 3 g/kg/d versus 1 g/kg/d amino acid on day 1 reported reduced head circumference growth to one month of age (MD ‐0.38, 95% CI ‐0.51 to ‐0.24; participants = 123). Vlaardingerbroek 2013 commencing 3.6 g/kg/d versus 2.4 g/kg/d on day 2 to 6 reported no difference in head circumference growth to one month (MD 0.02, 95% CI ‐0.09 to 0.13; participants = 96).

2.11. Analysis.

Comparison 2 Higher versus lower amino acid intake at commencement of parenteral nutrition: subgrouped by commencement intake, Outcome 11 Head circumference growth cm/week to 1 month age.

Head circumference growth to discharge (Analysis 2.12): A single study commencing 3.6 g/kg/d versus 2.4 g/kg/d on day 2 to 6 reported no difference in head circumference growth to discharge (MD 0.03, 95% CI ‐0.03 to 0.09; participants = 96) (Vlaardingerbroek 2013).

2.12. Analysis.

Comparison 2 Higher versus lower amino acid intake at commencement of parenteral nutrition: subgrouped by commencement intake, Outcome 12 Head circumference growth cm/week to discharge.

Weight gain change z‐score up to one month (Analysis 2.13): A single study commencing 3.6 g/kg/d versus 2.4 g/kg/d on day 2 to 6 reported no difference in weight gain change z‐score up to one month (MD ‐0.20, 95% CI ‐0.62 to 0.22; participants = 96) (Vlaardingerbroek 2013).

2.13. Analysis.

Comparison 2 Higher versus lower amino acid intake at commencement of parenteral nutrition: subgrouped by commencement intake, Outcome 13 Weight change z‐score to 1 month age.

Weight gain change z‐score to discharge (Analysis 2.14): Data show no difference in weight gain change z‐score up to discharge (MD 0.01, 95% CI ‐0.33 to 0.36; participants = 207; studies = 2) and no subgroup difference by commencement intake; testing for subgroup differences: P = 0.17; I² = 48%.

2.14. Analysis.

Comparison 2 Higher versus lower amino acid intake at commencement of parenteral nutrition: subgrouped by commencement intake, Outcome 14 Weight change z‐score to discharge.

Weight gain change z‐score post discharge (Analysis 2.15): Data show no difference in weight gain change z‐score post discharge (MD 0.13, 95% CI ‐0.26 to 0.52; participants = 201; studies = 2) and no subgroup difference by commencement intake; testing for subgroup differences: P = 0.17, I² = 47.1%.

2.15. Analysis.

Comparison 2 Higher versus lower amino acid intake at commencement of parenteral nutrition: subgrouped by commencement intake, Outcome 15 Weight change z‐score post discharge.

Head circumference change z‐score up to one month (Analysis 2.16): A single study commencing 3.6 g/kg/d versus 2.4 g/kg/d on day 2 to 6 reported no difference in head circumference change z‐score up to one month (MD 0.00, 95% CI ‐0.36 to 0.36; participants = 96) (Vlaardingerbroek 2013).

2.16. Analysis.

Comparison 2 Higher versus lower amino acid intake at commencement of parenteral nutrition: subgrouped by commencement intake, Outcome 16 Head circumference change z‐score to 1 month age.

Head circumference change z‐score to discharge (Analysis 2.17): Data show no difference in head circumference change z‐score up to discharge (MD 0.18, 95% CI ‐0.15 to 0.50; participants = 207; studies = 2) and no subgroup difference by commencement intake; testing for subgroup differences: P = 0.10, I² = 62.7%. Neither study reported a significant effect on head circumference change z‐score to discharge.

2.17. Analysis.

Comparison 2 Higher versus lower amino acid intake at commencement of parenteral nutrition: subgrouped by commencement intake, Outcome 17 Head circumference change z‐score to discharge.

Head circumference change z‐score post discharge (Analysis 2.18): Data show no difference in head circumference change z‐score up to discharge (MD 0.25, 95% CI ‐0.14 to 0.64; participants = 201; studies = 2) and no subgroup difference by commencement intake; testing for subgroup differences: P = 0.16, I² = 50.1%.

2.18. Analysis.

Comparison 2 Higher versus lower amino acid intake at commencement of parenteral nutrition: subgrouped by commencement intake, Outcome 18 Head circumference change z‐score post discharge.

Days to full enteral feeds (Analysis 2.19): Data show no difference by commencement intake in days to full enteral feeds (MD ‐0.22, 95% CI ‐1.60 to 1.17; participants = 196; studies = 4); testing for subgroup differences: P = 0.88, I² = 0%.

2.19. Analysis.

Comparison 2 Higher versus lower amino acid intake at commencement of parenteral nutrition: subgrouped by commencement intake, Outcome 19 Days to full enteral feeds.

Late‐onset sepsis (Analysis 2.20): Data show no difference in late‐onset sepsis (typical RR 0.94, 95% CI 0.65 to 1.38; participants = 319; studies = 5) and no subgroup difference by commencement intake; testing for subgroup differences: P = 0.93, I² = 0%.

2.20. Analysis.

Comparison 2 Higher versus lower amino acid intake at commencement of parenteral nutrition: subgrouped by commencement intake, Outcome 20 Late‐onset sepsis.

Necrotising enterocolitis (Analysis 2.21): Data show no difference in necrotising enterocolitis (RR 0.96, 95% CI 0.45 to 2.03; participants = 340; studies = 5) and no subgroup difference by commencement intake; testing for subgroup differences: P = 0.18, I² = 44%.

2.21. Analysis.

Comparison 2 Higher versus lower amino acid intake at commencement of parenteral nutrition: subgrouped by commencement intake, Outcome 21 Necrotising enterocolitis.

Chronic lung disease (Analysis 2.22): Data show no difference in chronic lung disease (RR 1.32, 95% CI 0.86 to 2.02; participants = 202; studies = 4) and no subgroup difference by commencement intake; testing for subgroup differences: P = 0.90, I² = 0%.

2.22. Analysis.

Comparison 2 Higher versus lower amino acid intake at commencement of parenteral nutrition: subgrouped by commencement intake, Outcome 22 Chronic lung disease at ≥ 36 weeks' PMA.

Patent ductus arteriosus (Analysis 2.23): Data show no difference in patent ductus arteriosus (RR 0.73, 95% CI 0.50 to 1.07; participants = 244; studies = 4) and no subgroup difference by commencement intake; testing for subgroup differences: P = 0.11, I² = 54.9%. Meta‐analysis of two studies on high amino acid intake (> 2 to ≤ 3 g/kg/d) found a reduction in patent ductus arteriosus (RR 0.42, 95% CI 0.20 to 0.89; participants = 173; studies = 2) (Balasubramanian 2013; Can 2012), whereas the other studies reported no difference from low amino acid intake (2 g/kg/d) ‐ Pappoe 2009 (RR 1.05, 95% CI 0.63 to 1.74; participants = 42) ‐ or very high amino acid intake (3.5 g/kg/d) ‐ Ibrahim 2004 (RR 1.07, 95% CI 0.50 to 2.28; participants = 29).

2.23. Analysis.

Comparison 2 Higher versus lower amino acid intake at commencement of parenteral nutrition: subgrouped by commencement intake, Outcome 23 Patent ductus arteriosus.

Intraventricular haemorrhage (Analysis 2.24): A single study reported no difference in intraventricular haemorrhage (RR 1.26, 95% CI 0.41 to 3.91; participants = 123) (Balasubramanian 2013).

2.24. Analysis.

Comparison 2 Higher versus lower amino acid intake at commencement of parenteral nutrition: subgrouped by commencement intake, Outcome 24 Intraventricular haemorrhage.

Severe intraventricular haemorrhage (Analysis 2.25): Data show no difference in severe intraventricular haemorrhage (RR 1.44, 95% CI 0.66 to 3.17; participants = 261; studies = 5) and no subgroup difference by commencement intake; testing for subgroup differences: P = 0.59, I² = 0%.

2.25. Analysis.

Comparison 2 Higher versus lower amino acid intake at commencement of parenteral nutrition: subgrouped by commencement intake, Outcome 25 Severe intraventricular haemorrhage.

Periventricular leukomalacia (Analysis 2.26): Data show only one infant with periventricular leukomalacia in the lower amino acid group (two studies, 146 infants).

2.26. Analysis.

Comparison 2 Higher versus lower amino acid intake at commencement of parenteral nutrition: subgrouped by commencement intake, Outcome 26 Periventricular leukomalacia.

Retinopathy of prematurity (Analysis 2.27): Data show a reduction in retinopathy of prematurity (RR 0.44, 95% CI 0.21 to 0.93; participants = 269; studies = 4) and no subgroup difference by commencement intake; testing for subgroup differences: P = 0.76, I² = 0%. Meta‐analysis of studies commencing with high amino acid intake (> 2 to ≤ 3 g/kg/d) found a reduction in retinopathy of prematurity (RR 0.36, 95% CI 0.14 to 0.95; participants = 198; studies = 2). A single trial commencing at low amino acid intake (> 1 to ≤ 2 g/kg/d) reported no difference in retinopathy of prematurity (RR 0.55, 95% CI 0.10 to 2.96; participants = 42) (Pappoe 2009). A single trial commencing at very high amino acid intake (3.5 g/kg/d) also reported no difference (RR 0.71, 95% CI 0.14 to 3.66; participants = 29) (Ibrahim 2004).

2.27. Analysis.

Comparison 2 Higher versus lower amino acid intake at commencement of parenteral nutrition: subgrouped by commencement intake, Outcome 27 Retinopathy of prematurity.

Severe retinopathy of prematurity (Analysis 2.28): Data show no difference in severe retinopathy of prematurity (RR 0.47, 95% CI 0.20 to 1.11; participants = 265; studies = 4) and no subgroup difference by commencement intake; testing for subgroup differences: P = 0.17, I² = 43%. Meta‐analysis of high amino acid intake (3 g/kg/d vs 1.5 g/kg/d) at commencement found a reduction in severe retinopathy of prematurity (RR 0.23, 95% CI 0.06 to 0.85; participants = 125; studies = 2). Pappoe 2009 reported no difference from low amino acid intake (2 g/kg/d vs 1 g/kg/d) (RR 0.55, 95% CI 0.10 to 2.96; participants = 42), and Vlaardingerbroek 2013 reported no difference from very high amino acid intake (3.6 g/kg/d vs 2.4 g/kg/d) (RR 5.00, 95% CI 0.25 to 101.53; participants = 98).

2.28. Analysis.

Comparison 2 Higher versus lower amino acid intake at commencement of parenteral nutrition: subgrouped by commencement intake, Outcome 28 Severe retinopathy of prematurity (> stage 2 or treated).

Cerebral palsy (Analysis 2.29): A single study commencing 3.6 g/kg/d versus 2.4 g/kg/d on day 2 to 6 reported no difference in cerebral palsy (RR 5.00, 95% CI 0.61 to 41.11; participants = 90) (Vlaardingerbroek 2013).

2.29. Analysis.

Comparison 2 Higher versus lower amino acid intake at commencement of parenteral nutrition: subgrouped by commencement intake, Outcome 29 Cerebral palsy.

Developmental delay (Analysis 2.30): Data show no difference in developmental delay at ≥ 18 months (RR 1.04, 95% CI 0.35 to 3.11; participants = 201; studies = 2); and no subgroup difference by commencement intake; testing for subgroup differences: P = 0.53, I² = 0%.

2.30. Analysis.

Comparison 2 Higher versus lower amino acid intake at commencement of parenteral nutrition: subgrouped by commencement intake, Outcome 30 Developmental delay at ≥ 18 months.

Blindness (Analysis 2.31): No infant was reported as being blind in a single study (Vlaardingerbroek 2013).

2.31. Analysis.

Comparison 2 Higher versus lower amino acid intake at commencement of parenteral nutrition: subgrouped by commencement intake, Outcome 31 Blindness.

Deafness (Analysis 2.32): No infant was reported as being deaf in a single study (Vlaardingerbroek 2013).

2.32. Analysis.

Comparison 2 Higher versus lower amino acid intake at commencement of parenteral nutrition: subgrouped by commencement intake, Outcome 32 Deafness.

Abnormal serum ammonium (Analysis 2.33): A single study commencing on 3 g/kg/d amino acid intake reported that none of 42 infants had a serum ammonia > 100 μmol/L (Bulbul 2012).

2.33. Analysis.

Comparison 2 Higher versus lower amino acid intake at commencement of parenteral nutrition: subgrouped by commencement intake, Outcome 33 Abnormal serum ammonia (> 100 μmol/L).

Abnormal blood urea nitrogen (Analysis 2.34): Data show an increase in abnormal blood urea nitrogen (RR 2.11, 95% CI 1.44 to 3.08; participants = 138; studies = 2) and no subgroup difference by commencement intake; testing for subgroup differences: P = 0.88, I² = 0%. Individual studies reported no difference in BUN > 14.3 mmol/L among infants commenced on 2 g/kg/d ‐ Pappoe 2009 (RR 2.48, 95% CI 0.28 to 21.93; participants = 42) ‐ and an increase in BUN > 10 mmol/L among infants commencing on 3.6 g/kg/d ‐ Vlaardingerbroek 2013 (RR 2.09, 95% CI 1.43 to 3.04; participants = 96).

2.34. Analysis.

Comparison 2 Higher versus lower amino acid intake at commencement of parenteral nutrition: subgrouped by commencement intake, Outcome 34 Abnormal blood urea nitrogen (various criteria).

Hyperglycaemia (Analysis 2.35): A single study of infants receiving very high amino acid intake (> 3 g/kg/d) reported no difference in hyperglycaemia (RR 1.47, 95% CI 0.85 to 2.53; participants = 42) (Pappoe 2009).

2.35. Analysis.

Comparison 2 Higher versus lower amino acid intake at commencement of parenteral nutrition: subgrouped by commencement intake, Outcome 35 Hyperglycaemia, plasma glucose > 8.3 mmol/L.

Hyperglycaemia treated with insulin (Analysis 2.36): Data show an increase in hyperglycaemia treated with insulin of borderline significance (RR 1.84, 95% CI 0.97 to 3.49; participants = 138; studies = 2) and a subgroup difference of borderline significance by commencement intake; testing for subgroup differences: P = 0.07, I² = 70%. A single study reported an increase in infants commencing on low amino acid intake at 2 g/kg/d versus 1 g/kg/d (RR 4.96, 95% CI 1.26 to 19.47; participants = 42) (Pappoe 2009). Another single study reported no difference among infants commencing on very high amino acid intake (3.6 g/kg/d vs 2.4 g/kg/d) (RR 1.15, 95% CI 0.54 to 2.45; participants = 96) (Vlaardingerbroek 2013).

2.36. Analysis.

Comparison 2 Higher versus lower amino acid intake at commencement of parenteral nutrition: subgrouped by commencement intake, Outcome 36 Hyperglycaemia treated with insulin.

Hypoglycaemia (Analysis 2.37): A single study reported no difference in hypoglycaemia among infants commencing on high amino acid intake at 3 g/kg/d (RR 1.68, 95% CI 0.83 to 3.41; participants = 123) (Balasubramanian 2013).

2.37. Analysis.

Comparison 2 Higher versus lower amino acid intake at commencement of parenteral nutrition: subgrouped by commencement intake, Outcome 37 Hypoglycaemia.

Metabolic acidosis (Analysis 2.38): No infant was reported as having metabolic acidosis in a single study commencing on low amino acid intake at 1.15 g/kg/d (van Goudoever 1995).

2.38. Analysis.

Comparison 2 Higher versus lower amino acid intake at commencement of parenteral nutrition: subgrouped by commencement intake, Outcome 38 Metabolic acidosis.

Higher versus lower amino acid intake at maximal intake of parenteral nutrition, subgrouped by maximal intake

Two studies compared high amino acid intake (> 3 to ≤ 4 g/kg/d) versus low amino acid intake (> 2 to ≤ 3 g/kg/d) at maximal intake of PN (Morgan 2014; Tan 2008). Tests for subgroup differences are not applicable.

Primary outcomes

Mortality (Analysis 3.1): Data show no difference in mortality (RR 0.94, 95% CI 0.57 to 1.55; participants = 292; studies = 2).

3.1. Analysis.

Comparison 3 Higher versus lower amino acid intake at maximal intake of parenteral nutrition: subgrouped by maximal intake, Outcome 1 Mortality before hospital discharge.

Neurodevelopmental disability and postnatal growth failure: Trials provided no data.

Secondary outcomes

Head circumference growth to one month (Analysis 3.2): Morgan 2014 reported an increase in head circumference growth to one month (MD 0.13 cm/week, 95% CI 0.05 to 0.20; participants = 135).

3.2. Analysis.

Comparison 3 Higher versus lower amino acid intake at maximal intake of parenteral nutrition: subgrouped by maximal intake, Outcome 2 Head circumference growth cm/week to 1 month.

Head circumference change z‐score to one month (Analysis 3.3): Morgan 2014 reported an increase in head circumference change z‐score to one month (MD 0.37, 95% CI 0.15 to 0.59; participants = 135).

3.3. Analysis.

Comparison 3 Higher versus lower amino acid intake at maximal intake of parenteral nutrition: subgrouped by maximal intake, Outcome 3 Head circumference change z‐score to 1 month.

Days to regain birth weight (Analysis 3.4): Tan 2008 reported a reduction in days to regain birth weight (MD ‐3.60 days, 95% CI ‐5.88 to ‐1.32; participants = 114).

3.4. Analysis.

Comparison 3 Higher versus lower amino acid intake at maximal intake of parenteral nutrition: subgrouped by maximal intake, Outcome 4 Days to regain birth weight.

Days to full enteral feeds (Analysis 3.5): Tan 2008 reported an increase in days to full enteral feeds (MD 4.00 days, 95% CI 1.01 to 6.99; participants = 114).

3.5. Analysis.

Comparison 3 Higher versus lower amino acid intake at maximal intake of parenteral nutrition: subgrouped by maximal intake, Outcome 5 Days to full enteral feeds.

Late‐onset sepsis (Analysis 3.6): Morgan 2014 reported no difference in late‐onset sepsis (RR 0.94, 95% CI 0.63 to 1.41; participants = 127).

3.6. Analysis.

Comparison 3 Higher versus lower amino acid intake at maximal intake of parenteral nutrition: subgrouped by maximal intake, Outcome 6 Late‐onset sepsis.

Necrotising enterocolitis (Analysis 3.7): Data show no difference in necrotising enterocolitis (typical RR 0.76, 95% CI 0.37 to 1.59; participants = 241; studies = 2).

3.7. Analysis.

Comparison 3 Higher versus lower amino acid intake at maximal intake of parenteral nutrition: subgrouped by maximal intake, Outcome 7 Necrotising enterocolitis.

Chronic lung disease (Analysis 3.8): Data show no difference in chronic lung disease (typical RR 1.10, 95% CI 0.92 to 1.31; participants = 241; studies = 2).

3.8. Analysis.

Comparison 3 Higher versus lower amino acid intake at maximal intake of parenteral nutrition: subgrouped by maximal intake, Outcome 8 Chronic lung disease at ≥ 36 weeks' PMA.

Patent ductus arteriosus (Analysis 3.9): Morgan 2014 reported no difference in patent ductus arteriosus (RR 1.02, 95% CI 0.66 to 1.56; participants = 127).

3.9. Analysis.

Comparison 3 Higher versus lower amino acid intake at maximal intake of parenteral nutrition: subgrouped by maximal intake, Outcome 9 Patent ductus arteriosus.

Severe intraventricular haemorrhage (Analysis 3.10): Data show no difference in severe intraventricular haemorrhage (typical RR 1.16, 95% CI 0.51 to 2.63; studies = 2).

3.10. Analysis.

Comparison 3 Higher versus lower amino acid intake at maximal intake of parenteral nutrition: subgrouped by maximal intake, Outcome 10 Severe intraventricular haemorrhage.

Periventricular leukomalacia (Analysis 3.11): Morgan 2014 reported no difference in periventricular leukomalacia (RR 2.03, 95% CI 0.39 to 10.70; participants = 127).

3.11. Analysis.

Comparison 3 Higher versus lower amino acid intake at maximal intake of parenteral nutrition: subgrouped by maximal intake, Outcome 11 Periventricular leukomalacia.

Severe retinopathy of prematurity (Analysis 3.12): Morgan 2014 reported no difference in severe retinopathy of prematurity (RR 2.71, 95% CI 0.75 to 9.75; participants = 127).

3.12. Analysis.

Comparison 3 Higher versus lower amino acid intake at maximal intake of parenteral nutrition: subgrouped by maximal intake, Outcome 12 Severe retinopathy of prematurity (> stage 2 or treated).

Hyperglycaemia treated with insulin (Analysis 3.13): Tan 2008 reported an increase in hyperglycaemia treated with insulin (RR 1.69, 95% CI 1.12 to 2.53; participants = 114).

3.13. Analysis.

Comparison 3 Higher versus lower amino acid intake at maximal intake of parenteral nutrition: subgrouped by maximal intake, Outcome 13 Hyperglycaemia treated with insulin.

Cholestasis (Analysis 3.14): Data show no difference in cholestasis (typical RR 1.21, 95% CI 0.76 to 1.94; participants = 241; studies = 2).

3.14. Analysis.

Comparison 3 Higher versus lower amino acid intake at maximal intake of parenteral nutrition: subgrouped by maximal intake, Outcome 14 Cholestasis.

Higher versus lower amino acid intake at commencement and maximal intake of parenteral nutrition, subgrouped by commencement intake

Nine studies compared higher versus lower amino acid intake at commencement and maximal intake of PN (Black 1981; Blanco 2008; Burattini 2013; Clark 2007; Liu 2015; Scattolin 2013; Tang 2009; Uthaya 2016; Vaidya 1995).

Primary outcomes

Mortality to discharge (Analysis 4.1): Data show no difference in mortality (typical RR 0.97, 95% CI 0.66 to 1.42; participants = 567; studies = 5) and no subgroup difference by commencement intake; testing for subgroup differences: P = 0.32, I² = 13.8%.

4.1. Analysis.

Comparison 4 Higher versus lower amino acid intake at commencement and maximal intake of parenteral nutrition: subgrouped by commencement intake, Outcome 1 Mortality to hospital discharge.

Neurodevelopmental disability and postnatal growth failure: Trials provided no data.

Secondary outcomes

Days to regain birth weight (Analysis 4.2): Data show a reduction in days to regain birth weight (MD ‐1.86, 95% CI ‐2.79 to ‐0.93; participants = 496; studies = 5) and no subgroup difference by commencement intake; testing for subgroup differences: P = 0.80, I² = 0%.

4.2. Analysis.

Comparison 4 Higher versus lower amino acid intake at commencement and maximal intake of parenteral nutrition: subgrouped by commencement intake, Outcome 2 Days to regain birth weight.

Maximal weight loss in grams (Analysis 4.3): Studies commencing on high amino acid intake (> 2 to ≤ 3 g/kg/d) reported a reduction in maximal weight loss in grams (MD ‐29.79, 95% CI ‐41.58 to ‐17.99; participants = 185; studies = 2).

4.3. Analysis.

Comparison 4 Higher versus lower amino acid intake at commencement and maximal intake of parenteral nutrition: subgrouped by commencement intake, Outcome 3 Maximal weight loss (grams).

Maximal weight loss per cent (Analysis 4.4): Data show no difference in maximal weight loss per cent (MD 0.22, 95% CI ‐1.20 to 1.64; participants = 229; studies = 2) and no subgroup difference by commencement intake; testing for subgroup differences: P = 0.73, I² = 0%.

4.4. Analysis.

Comparison 4 Higher versus lower amino acid intake at commencement and maximal intake of parenteral nutrition: subgrouped by commencement intake, Outcome 4 Maximal weight loss %.

Weight gain to 1 month (Analysis 4.5): Studies commencing on low amino acid intake (> 1 to ≤ 2 g/kg/d) reported no difference in weight gain to one month (MD 1.48 g/kg/d, 95% CI ‐0.29 to 3.25; participants = 154; studies = 2).

4.5. Analysis.

Comparison 4 Higher versus lower amino acid intake at commencement and maximal intake of parenteral nutrition: subgrouped by commencement intake, Outcome 5 Weight gain g/kg/day up to 1 month age.

Weight gain to discharge (Analysis 4.6): Burattini 2013 commencing on high amino acid intake (> 2 to ≤ 3 g/kg/d) reported no difference in weight gain to discharge (MD 0.60 g/kg/d, 95% CI ‐0.34 to 1.54; participants = 114).

4.6. Analysis.

Comparison 4 Higher versus lower amino acid intake at commencement and maximal intake of parenteral nutrition: subgrouped by commencement intake, Outcome 6 Weight gain g/kg/day to discharge.

Linear growth to one month (Analysis 4.7): Clark 2007 commencing on low amino acid intake (> 1 to ≤ 2 g/kg/d) reported no difference in linear growth to one month (MD 0.00 cm/week, 95% CI ‐0.15 to 0.15; participants = 122).

4.7. Analysis.

Comparison 4 Higher versus lower amino acid intake at commencement and maximal intake of parenteral nutrition: subgrouped by commencement intake, Outcome 7 Linear growth cm/week up to 1 month age.

Head circumference to one month (Analysis 4.8): Clark 2007 commencing on low amino acid intake (> 1 to ≤ 2 g/kg/d) reported no difference in head circumference growth to one month (MD 0.00 cm/week, 95% CI ‐0.12 to 0.12; participants = 122).

4.8. Analysis.

Comparison 4 Higher versus lower amino acid intake at commencement and maximal intake of parenteral nutrition: subgrouped by commencement intake, Outcome 8 Head circumference growth cm/week up to 1 month age.

Head circumference change to discharge (Analysis 4.9): Studies commencing on high amino acid intake (> 2 to ≤ 3 g/kg/d) reported an increase in head circumference change to discharge (MD 0.11 cm/week, 95% CI 0.07 to 0.15; participants = 182; studies = 2).

4.9. Analysis.

Comparison 4 Higher versus lower amino acid intake at commencement and maximal intake of parenteral nutrition: subgrouped by commencement intake, Outcome 9 Head circumference growth cm/week to discharge.

Days to full enteral feeds (Analysis 4.10): Data show a reduction in days to full enteral feeds with a significant subgroup effect by commencement intake (MD ‐1.08, 95% CI ‐2.42 to 0.25; participants = 431; studies = 5) and no significant subgroup difference by commencement intake; testing for subgroup differences: P = 0.01, I² = 76.9%. For subgroups, studies commencing with low amino acid intake (> 1 to ≤ 2 g/kg/d) reported no difference in days to full enteral feeds (MD 2.47, 95% CI ‐1.73 to 6.68; participants = 147; studies = 2). Studies commencing on high amino acid intake (> 2 to ≤ 3 g/kg/d) reported a reduction in days to full enteral feeds (MD ‐3.32, 95% CI ‐5.39 to ‐1.25; participants = 158; studies = 2). Uthaya 2016 commenced on very high amino acid intake (> 3 g/kg/d) and reported no difference in days to full enteral feeds (MD 0.09, 95% CI ‐1.83 to 2.01; participants = 126).

4.10. Analysis.

Comparison 4 Higher versus lower amino acid intake at commencement and maximal intake of parenteral nutrition: subgrouped by commencement intake, Outcome 10 Days to full enteral feeds.

Late onset sepsis (Analysis 4.11): Data show no difference in late‐onset sepsis (typical RR 0.96, 95% CI 0.72 to 1.29; participants = 772; studies = 8) and no subgroup difference by commencement intake; testing for subgroup differences: P = 0.70, I² = 0%.

4.11. Analysis.

Comparison 4 Higher versus lower amino acid intake at commencement and maximal intake of parenteral nutrition: subgrouped by commencement intake, Outcome 11 Late‐onset sepsis.

Necrotising enterocolitis (Analysis 4.12): Data show no difference in necrotising enterocolitis (typical RR 1.14, 95% CI 0.63 to 2.07; participants = 683; studies = 6) and no subgroup difference by commencement intake; testing for subgroup differences: P = 0.43, I² = 0%.

4.12. Analysis.

Comparison 4 Higher versus lower amino acid intake at commencement and maximal intake of parenteral nutrition: subgrouped by commencement intake, Outcome 12 Necrotising enterocolitis.

Chronic lung disease (Analysis 4.13): Data show no difference in chronic lung disease (typical RR 0.81, 95% CI 0.55 to 1.19; participants = 376; studies = 4) and no subgroup difference by commencement intake; testing for subgroup differences: P = 0.13, I² = 58%.

4.13. Analysis.

Comparison 4 Higher versus lower amino acid intake at commencement and maximal intake of parenteral nutrition: subgrouped by commencement intake, Outcome 13 Chronic lung disease at ≥ 36 weeks' PMA.

Patent ductus arteriosus (Analysis 4.14): Data show no differences in patent ductus arteriosus (typical RR 0.81, 95% CI 0.60 to 1.10; participants = 236; studies = 2) and no subgroup difference by commencement intake; testing for subgroup differences: P = 0.22, I² = 32%.

4.14. Analysis.

Comparison 4 Higher versus lower amino acid intake at commencement and maximal intake of parenteral nutrition: subgrouped by commencement intake, Outcome 14 Patent ductus arteriosus.

Intraventricular haemorrhage (Analysis 4.15): Data show no differences in intraventricular haemorrhage (typical RR 1.09, 95% CI 0.70 to 1.70; participants = 218; studies = 2) and no subgroup difference by commencement intake; testing for subgroup differences: P = 0.79, I² = 0%.

4.15. Analysis.

Comparison 4 Higher versus lower amino acid intake at commencement and maximal intake of parenteral nutrition: subgrouped by commencement intake, Outcome 15 Intraventricular haemorrhage.

Severe intraventricular haemorrhage (Analysis 4.16): Data show no differences in severe intraventricular haemorrhage (typical RR 0.96, 95% CI 0.46 to 2.02; participants = 402; studies = 4) and no subgroup difference by commencement intake; testing for subgroup differences: P = 0.58, I² = 0%.

4.16. Analysis.

Comparison 4 Higher versus lower amino acid intake at commencement and maximal intake of parenteral nutrition: subgrouped by commencement intake, Outcome 16 Severe intraventricular haemorrhage.

Periventricular leukomalacia (Analysis 4.17): Data show a reduction in periventricular leukomalacia (typical RR 0.32, 95% CI 0.10 to 1.00; participants = 447; studies = 4) and no significant subgroup difference of borderline significance by commencement intake; testing for subgroup differences: P = 0.09, I² = 66.1%. For subgroups, data show a reduction in periventricular leukomalacia for infants commenced on low amino acid intake (1.5 to 2 g/kg/d) (typical RR 0.14, 95% CI 0.03 to 0.79; participants = 237; studies = 2) and no reduction in infants commenced on high amino acid intake (2.4 to 2.5 g/kg/d) (typical RR 1.37, 95% CI 0.20 to 9.33; participants = 210; studies = 2).

4.17. Analysis.

Comparison 4 Higher versus lower amino acid intake at commencement and maximal intake of parenteral nutrition: subgrouped by commencement intake, Outcome 17 Periventricular leukomalacia.

Severe retinopathy of prematurity (Analysis 4.18): Data show no difference in severe retinopathy of prematurity in infants commencing on low amino acid intake (2 g/kg/d) (typical RR 1.24, 95% CI 0.49 to 3.09; participants = 166; studies = 2). Burattini 2013 commencing with high amino acid intake (2.5 g/kg/d) reported no cases of severe retinopathy of prematurity (114 infants).

4.18. Analysis.

Comparison 4 Higher versus lower amino acid intake at commencement and maximal intake of parenteral nutrition: subgrouped by commencement intake, Outcome 18 Severe retinopathy of prematurity (> stage 2 or treated).

Cerebral palsy (Analysis 4.19): A single study reported no difference in cerebral palsy (RR 3.00, 95% CI 0.35 to 25.87; participants = 32) (Blanco 2008).

4.19. Analysis.

Comparison 4 Higher versus lower amino acid intake at commencement and maximal intake of parenteral nutrition: subgrouped by commencement intake, Outcome 19 Cerebral palsy.

Developmental delay (Analysis 4.20): A single study reported no difference in developmental delay (RR 3.25, 95% CI 0.35 to 30.19; participants = 100) (Burattini 2013).

4.20. Analysis.

Comparison 4 Higher versus lower amino acid intake at commencement and maximal intake of parenteral nutrition: subgrouped by commencement intake, Outcome 20 Developmental delay at ≥ 18 months.

Blindness (Analysis 4.21): A single study reported no difference in blindness (RR 2.00, 95% CI 0.20 to 19.91; participants = 32) (Blanco 2008).

4.21. Analysis.

Comparison 4 Higher versus lower amino acid intake at commencement and maximal intake of parenteral nutrition: subgrouped by commencement intake, Outcome 21 Blindness.

Abnormal serum ammonia (Analysis 4.22): A single study reported an abnormal serum ammonia > 122 μmol/L in one infant commencing on low amino acid intake (2 g/kg/d) (Blanco 2008).

4.22. Analysis.

Comparison 4 Higher versus lower amino acid intake at commencement and maximal intake of parenteral nutrition: subgrouped by commencement intake, Outcome 22 Abnormal serum ammonia.

Abnormal blood urea nitrogen (Analysis 4.23): Data show an increase in abnormal blood urea nitrogen (various criteria) (typical RR 3.19, 95% CI 2.24 to 4.53; participants = 550; studies = 5) and no subgroup difference by commencement intake; testing for subgroup differences: P = 0.25, I² = 27.2% (Vaidya 1995). For subgroups, a single study commencing with very low amino acid intake (≤ 1 g/kg/d) reported an increase in abnormal blood urea nitrogen (RR 10.74, 95% CI 1.45 to 79.59; participants = 85). For studies commencing low amino acid intake (> 1 to ≤ 2 g/kg/d), data show an increase in abnormal blood urea nitrogen (typical RR 12.29, 95% CI 1.66 to 90.79; participants = 183; studies = 2). A single study commencing on high amino acid intake (> 2 to ≤ 3 g/kg/d) reported an increase in abnormal blood urea nitrogen (RR 2.44, 95% CI 1.47 to 4.05; participants = 114) (Burattini 2013). Another single study commencing on very high amino acid intake (> 3 g/kg/d) reported an increase in abnormal blood urea nitrogen (RR 2.73, 95% CI 1.64 to 4.54; participants = 168) (Uthaya 2016).

4.23. Analysis.

Comparison 4 Higher versus lower amino acid intake at commencement and maximal intake of parenteral nutrition: subgrouped by commencement intake, Outcome 23 Abnormal blood urea nitrogen (various criteria).

Hyperglycaemia (Analysis 4.24): Data show a reduction in hyperglycaemia (typical RR 0.54, 95% CI 0.36 to 0.82; participants = 463; studies = 4) and no subgroup difference by commencement intake; testing for subgroup differences: P = 0.55, I² = 0%. For subgroups, a single study commencing infants on very low amino acid intake (0.5 g/kg/d) reported no difference in hyperglycaemia (RR 1.95, 95% CI 0.18 to 20.74; participants = 85) (Vaidya 1995). Data show a reduction in hyperglycaemia in studies commencing infants on high amino acid intake (2.4 to 2.5 g/kg/d) (typical RR 0.51, 95% CI 0.30 to 0.87; participants = 210; studies = 2) and no difference in hyperglycaemia in studies commencing infants on very high amino acid intake (> 3 g/kg/d) (RR 0.53, 95% CI 0.26 to 1.06; participants = 168).

4.24. Analysis.

Comparison 4 Higher versus lower amino acid intake at commencement and maximal intake of parenteral nutrition: subgrouped by commencement intake, Outcome 24 Hyperglycaemia, plasma glucose > 8.3 mmol/L.

Hyperglycaemia treated with insulin (Analysis 4.25): Data show no difference in hyperglycaemia treated with insulin (typical RR 0.62, 95% CI 0.35 to 1.08; participants = 282; studies = 2) and no subgroup difference by commencement intake; testing for subgroup differences: P = 0.59, I² = 0%.

4.25. Analysis.

Comparison 4 Higher versus lower amino acid intake at commencement and maximal intake of parenteral nutrition: subgrouped by commencement intake, Outcome 25 Hyperglycaemia treated with insulin.

Hypoglycaemia (Analysis 4.26): Data show no difference in hypoglycaemia (typical RR 1.03, 95% CI 0.70 to 1.50; participants = 253; studies = 2) and no subgroup difference by commencement intake; testing for subgroup differences: P = 0.76, I² = 0%.

4.26. Analysis.

Comparison 4 Higher versus lower amino acid intake at commencement and maximal intake of parenteral nutrition: subgrouped by commencement intake, Outcome 26 Hypoglycaemia.

Metabolic acidosis (Analysis 4.27): Data show no difference in metabolic acidosis (typical RR 2.05, 95% CI 0.94 to 4.47; participants = 253; studies = 2) and no subgroup difference by commencement intake; testing for subgroup differences: P = 0.27, I² = 17.4%.

4.27. Analysis.

Comparison 4 Higher versus lower amino acid intake at commencement and maximal intake of parenteral nutrition: subgrouped by commencement intake, Outcome 27 Metabolic acidosis.

Cholestasis (Analysis 4.28): Data show no difference in cholestasis (typical RR 1.34, 95% CI 0.71 to 2.50; participants = 375; studies = 3) and no subgroup difference by commencement intake; testing for subgroup differences: P = 0.13, I² = 50.4%.

4.28. Analysis.

Comparison 4 Higher versus lower amino acid intake at commencement and maximal intake of parenteral nutrition: subgrouped by commencement intake, Outcome 28 Cholestasis.

Higher versus lower amino acid intake at commencement and maximal intake of parenteral nutrition subgrouped by maximal intake

Nine studies compared higher versus lower amino acid intake at commencement and maximal intake of PN (Black 1981; Blanco 2008; Burattini 2013; Clark 2007; Liu 2015; Scattolin 2013; Tang 2009; Uthaya 2016; Vaidya 1995) .

Primary outcomes

Mortality to discharge (Analysis 5.1): Data show no difference in mortality (typical RR 0.97, 95% CI 0.66 to 1.42; participants = 567; studies = 5) and no subgroup difference according to maximal intake; testing for subgroup differences: P = 0.40, I² = 0%.

5.1. Analysis.

Comparison 5 Higher versus lower amino acid intake at commencement and maximal intake of parenteral nutrition: subgrouped by maximal intake, Outcome 1 Mortality before hospital discharge.

Neurodevelopmental disability or postnatal growth failure: Trials provided no data.

Secondary outcomes

Days to regain birth weight (Analysis 5.2): Data show a reduction in days to regain birth weight (MD ‐1.86, 95% CI ‐2.79 to ‐0.93; participants = 496; studies = 5) and no subgroup difference according to maximal intake; testing for subgroup differences: P = 0.67, I² = 0%. For subgroups, Vaidya 1995 compared low maximal amino acid intake (3 g/kg/d) versus no amino acid intake and reported no difference in days to regain birth weight (MD ‐1.00, 95% CI ‐5.03 to 3.03; participants = 85). Studies of infants receiving high maximal amino acid intake (> 3 to ≤ 4 g/kg/d) reported a reduction in days to regain birth weight (MD ‐1.91, 95% CI ‐2.87 to ‐0.95; participants = 411; studies = 4).

5.2. Analysis.

Comparison 5 Higher versus lower amino acid intake at commencement and maximal intake of parenteral nutrition: subgrouped by maximal intake, Outcome 2 Days to regain birth weight.

Maximal weight loss in gram (Analysis 5.3): Studies of high maximal amino acid intake (> 3 to ≤ 4 g/kg/d) reported a reduction in maximal weight loss in grams (MD ‐29.79, 95% CI ‐41.58 to ‐17.99; participants = 185; studies = 2).

5.3. Analysis.

Comparison 5 Higher versus lower amino acid intake at commencement and maximal intake of parenteral nutrition: subgrouped by maximal intake, Outcome 3 Maximal weight loss (grams).

Maximal weight loss per cent (Analysis 5.4): Studies of infants receiving high amino acid intake (> 3 to ≤ 4 g/kg/d) reported no difference in maximal weight loss per cent (MD 0.22, 95% CI ‐1.20 to 1.64; participants = 229; studies = 2).

5.4. Analysis.

Comparison 5 Higher versus lower amino acid intake at commencement and maximal intake of parenteral nutrition: subgrouped by maximal intake, Outcome 4 Maximal weight loss %.

Weight gain to one month (Analysis 5.5): Studies of infants receiving high amino acid intake (> 3 to ≤ 4 g/kg/d) reported no difference in weight gain to one month (MD 1.48 g/kg/d, 95% CI ‐0.29 to 3.25; participants = 154; studies = 2).

5.5. Analysis.

Comparison 5 Higher versus lower amino acid intake at commencement and maximal intake of parenteral nutrition: subgrouped by maximal intake, Outcome 5 Weight gain g/kg/day up to 1 month.

Weight gain to discharge (Analysis 5.6): A single study reported no difference in weight gain to discharge (MD 0.60 g/kg/d, 95% CI ‐0.34 to 1.54; participants = 114) (Burattini 2013).

5.6. Analysis.

Comparison 5 Higher versus lower amino acid intake at commencement and maximal intake of parenteral nutrition: subgrouped by maximal intake, Outcome 6 Weight gain g/kg/day to discharge.

Linear growth to one month (Analysis 5.7): A single study reported no difference in weight gain to discharge (MD 0.00 cm/week, 95% CI ‐0.15 to 0.15; participants = 122) (Clark 2007).

5.7. Analysis.

Comparison 5 Higher versus lower amino acid intake at commencement and maximal intake of parenteral nutrition: subgrouped by maximal intake, Outcome 7 Linear growth cm/week up to 1 month.

Head circumference growth to one month (Analysis 5.8): A single study reported no difference in weight gain to discharge (MD 0.00, 95% CI ‐0.12 to 0.12; participants = 122) (Clark 2007).

5.8. Analysis.

Comparison 5 Higher versus lower amino acid intake at commencement and maximal intake of parenteral nutrition: subgrouped by maximal intake, Outcome 8 Head circumference growth cm/week up to 1 month.

Head circumference growth to discharge (Analysis 5.9): Studies of high maximal amino acid intake (> 3 to ≤ 4 g/kg/d) reported an increase in head circumference growth to discharge (MD 0.11, 95% CI 0.07 to 0.15; participants = 182; studies = 2).

5.9. Analysis.

Comparison 5 Higher versus lower amino acid intake at commencement and maximal intake of parenteral nutrition: subgrouped by maximal intake, Outcome 9 Head circumference growth cm/week to discharge.

Days to full enteral feeds (Analysis 5.10): Studies of high maximal amino acid intake (> 3 to ≤ 4 g/kg/d) reported a reduction in days to full enteral feeds (MD ‐1.08, 95% CI ‐2.42 to 0.25; participants = 431; studies = 5).

5.10. Analysis.

Comparison 5 Higher versus lower amino acid intake at commencement and maximal intake of parenteral nutrition: subgrouped by maximal intake, Outcome 10 Days to full enteral feeds.

Late‐onset sepsis (Analysis 5.11): Data show no difference in late‐onset sepsis (typical RR 0.96, 95% CI 0.72 to 1.29; participants = 772; studies = 8) and no subgroup difference according to maximal intake; testing for subgroup differences: P = 0.55, I² = 0%.

5.11. Analysis.

Comparison 5 Higher versus lower amino acid intake at commencement and maximal intake of parenteral nutrition: subgrouped by maximal intake, Outcome 11 Late‐onset sepsis.

Necrostising enterocolitis (Analysis 5.12): Studies of high maximal amino acid intake (> 3 to ≤ 4 g/kg/d) reported no difference in necrotising enterocolitis (typical RR 1.14, 95% CI 0.63 to 2.07; participants = 683; studies = 6).

5.12. Analysis.

Comparison 5 Higher versus lower amino acid intake at commencement and maximal intake of parenteral nutrition: subgrouped by maximal intake, Outcome 12 Necrotising enterocolitis.

Chronic lung disease (Analysis 5.13): Studies of high maximal amino acid intake (> 3 to ≤ 4 g/kg/d) reported no difference in chronic lung disease (typical RR 0.81, 95% CI 0.55 to 1.19; participants = 376; studies = 4).

5.13. Analysis.

Comparison 5 Higher versus lower amino acid intake at commencement and maximal intake of parenteral nutrition: subgrouped by maximal intake, Outcome 13 Chronic lung disease at ≥ 36 weeks' PMA.

Patent ductus arteriosus (Analysis 5.14): Studies of high maximal amino acid intake (> 3 to ≤ 4 g/kg/d) reported no difference in patent ductus arteriosus (typical RR 0.81, 95% CI 0.60 to 1.10; participants = 236; studies = 2).

5.14. Analysis.

Comparison 5 Higher versus lower amino acid intake at commencement and maximal intake of parenteral nutrition: subgrouped by maximal intake, Outcome 14 Patent ductus arteriosus.

Intraventricular haemorrhage (Analysis 5.15): Studies of high maximal amino acid intake (> 3 to ≤ 4 g/kg/d) reported no difference in intraventricular haemorrhage (typical RR 1.09, 95% CI 0.70 to 1.70; participants = 218; studies = 2).

5.15. Analysis.

Comparison 5 Higher versus lower amino acid intake at commencement and maximal intake of parenteral nutrition: subgrouped by maximal intake, Outcome 15 Intraventricular haemorrhage.

Severe intraventricular haemorrhage (Analysis 5.16): Studies of high maximal amino acid intake (> 3 to ≤ 4 g/kg/d) reported no difference in severe intraventricular haemorrhage (typical RR 0.96, 95% CI 0.46 to 2.02; participants = 402; studies = 4).

5.16. Analysis.

Comparison 5 Higher versus lower amino acid intake at commencement and maximal intake of parenteral nutrition: subgrouped by maximal intake, Outcome 16 Severe intraventricular haemorrhage.

Periventricular leukomalacia (Analysis 5.17): Studies of high maximal amino acid intake (> 3 to ≤ 4 g/kg/d) reported a reduction in periventricular leukomalacia (typical RR 0.32, 95% CI 0.10 to 1.00; RD ‐0.04, 95% CI ‐0.07, ‐0.00; P = 0.05; participants = 447; studies = 4).

5.17. Analysis.

Comparison 5 Higher versus lower amino acid intake at commencement and maximal intake of parenteral nutrition: subgrouped by maximal intake, Outcome 17 Periventricular leukomalacia.

Severe retinopathy of prematurity (Analysis 5.18): Studies of high maximal amino acid intake (> 3 to ≤ 4 g/kg/d) reported no difference in severe retinopathy of prematurity (typical RR 1.24, 95% CI 0.49 to 3.09; participants = 280; studies = 3).

5.18. Analysis.

Comparison 5 Higher versus lower amino acid intake at commencement and maximal intake of parenteral nutrition: subgrouped by maximal intake, Outcome 18 Severe retinopathy of prematurity (> stage 2 or treated).

Cerebral palsy (Analysis 5.19): In infants receiving high maximal amino acid intake (4 g/kg/d), Blanco 2008 reported no difference in cerebral palsy (RR 3.00, 95% CI 0.35 to 25.87; participants = 32).

5.19. Analysis.

Comparison 5 Higher versus lower amino acid intake at commencement and maximal intake of parenteral nutrition: subgrouped by maximal intake, Outcome 19 Cerebral palsy.

Developmental delay (Analysis 5.20): In infants receiving high maximal amino acid intake (4 g/kg/d), Burattini 2013 reported no difference in developmental delay (RR 3.25, 95% CI 0.35 to 30.19; participants = 100).

5.20. Analysis.

Comparison 5 Higher versus lower amino acid intake at commencement and maximal intake of parenteral nutrition: subgrouped by maximal intake, Outcome 20 Developmental delay at ≥ 18 months.

Blindness (Analysis 5.21): In infants receiving high maximal amino acid intake (4 g/kg/d), Blanco 2008 reported no difference in blindness (RR 2.00, 95% CI 0.20 to 19.91; participants = 32).

5.21. Analysis.

Comparison 5 Higher versus lower amino acid intake at commencement and maximal intake of parenteral nutrition: subgrouped by maximal intake, Outcome 21 Blindness.

Abnormal serum ammonia (Analysis 5.22): Blanco 2008 reported an abnormal serum ammonia > 122 μmol/L in one infant receiving high maximal amino acid intake (4 g/kg/d).

5.22. Analysis.

Comparison 5 Higher versus lower amino acid intake at commencement and maximal intake of parenteral nutrition: subgrouped by maximal intake, Outcome 22 Abnormal serum ammonia.

Abnormal blood urea nitrogen (Analysis 5.23): Data show an increase in abnormal blood urea nitrogen (various criteria) (typical RR 3.19, 95% CI 2.24 to 4.53; participants = 550; studies = 5) and no subgroup difference according to maximal intake; testing for subgroup differences: P = 0.21, I² = 36.2%. For subgroups, a single study of low maximal amino acid intake (3.0 g/kg/d) reported an increase in abnormal blood urea nitrogen (criteria not reported) (RR 10.74, 95% CI 1.45 to 79.59; participants = 85) (Vaidya 1995). Studies of high maximal amino acid intake (3.5 to 4 g/kg/d) reported an increase in abnormal blood urea nitrogen (typical RR 2.93, 95% CI 2.05 to 4.18; participants = 465; studies = 4).

5.23. Analysis.

Comparison 5 Higher versus lower amino acid intake at commencement and maximal intake of parenteral nutrition: subgrouped by maximal intake, Outcome 23 Abnormal blood urea nitrogen (various criteria).

Hyperglycaemia (Analysis 5.24): Data show a reduction in hyperglycaemia (typical RR 0.54, 95% CI 0.36 to 0.82; participants = 463; studies = 4) and no subgroup difference according to maximal intake; testing for subgroup differences: P = 0.28, I² = 15.8%. For subgroups, a single study of low maximal amino acid intake (3.0 g/kg/d) reported no difference in hyperglycaemia (85 infants, RR 1.95, 95% CI 0.18, 20.74) (Vaidya 1995). Studies of infants on high maximal amino acid intake (> 3 to ≤ 4 g/kg/d) reported a reduction in hyperglycaemia (typical RR 0.51, 95% CI 0.34 to 0.79; participants = 378; studies = 3).

5.24. Analysis.

Comparison 5 Higher versus lower amino acid intake at commencement and maximal intake of parenteral nutrition: subgrouped by maximal intake, Outcome 24 Hyperglycaemia, plasma glucose > 8.3 mmol/L.

Hyperglycaemia treated with insulin (Analysis 5.25): Data show no difference in hyperglycaemia treated with insulin (typical RR 0.62, 95% CI 0.35 to 1.08; participants = 282; studies = 2) and no subgroup difference according to maximal intake; testing for subgroup differences: P = 0.59, I² = 0%.

5.25. Analysis.

Comparison 5 Higher versus lower amino acid intake at commencement and maximal intake of parenteral nutrition: subgrouped by maximal intake, Outcome 25 Hyperglycaemia treated with insulin.

Hypoglycaemia (Analysis 5.26): Data show no difference in hypoglycaemia (typical RR 1.03, 95% CI 0.70 to 1.50; participants = 253; studies = 2) and no subgroup difference according to maximal intake; testing for subgroup differences: P = 0.76, I² = 0%.

5.26. Analysis.

Comparison 5 Higher versus lower amino acid intake at commencement and maximal intake of parenteral nutrition: subgrouped by maximal intake, Outcome 26 Hypoglycaemia.

Metabolic acidosis (Analysis 5.27): Data show no difference in metabolic acidosis (typical RR 2.05, 95% CI 0.94 to 4.47; participants = 253; studies = 2) and no subgroup difference according to maximal intake; testing for subgroup differences: P = 0.27, I² = 17.4%.

5.27. Analysis.

Comparison 5 Higher versus lower amino acid intake at commencement and maximal intake of parenteral nutrition: subgrouped by maximal intake, Outcome 27 Metabolic acidosis.

Cholestasis (Analysis 5.28): Data show no difference in cholestasis (typical RR 1.34, 95% CI 0.71 to 2.50; participants = 375; studies = 3) and no subgroup difference according to maximal intake; testing for subgroup differences: P = 0.11, I² = 66.6%.

5.28. Analysis.

Comparison 5 Higher versus lower amino acid intake at commencement and maximal intake of parenteral nutrition: subgrouped by maximal intake, Outcome 28 Cholestasis.

Higher versus lower amino acid intake in parenteral nutrition, subgrouped according to management of caloric balance

Studies included in this review had two principle strategies for management of caloric balance.

• To increase amino acids and provide isocaloric non‐protein intake (Anderson 1979; Balasubramanian 2013; Blanco 2008; Burattini 2013; Clark 2007; Hata 2002; Heimler 2010; Kashyap 2007; Liu 2015; Pildes 1973; Rivera 1993; Scattolin 2013; Tang 2009; te Braake 2005; Thureen 2003; Uthaya 2016; van Goudoever 1995; van Lingen 1992; Vlaardingerbroek 2013; Xie 2014; Weiler 2006).

• To increase amino acids and non‐protein caloric intake (Black 1981; Bulbul 2012; Can 2012; Can 2013; Ibrahim 2004; Makay 2007; Morgan 2014; Murdock 1995; Pappoe 2009; Tan 2008; Vaidya 1995). All studies that provided additional non‐protein energy intake provided additional parenteral lipid intake.

Primary outcomes

Mortality to discharge (Analysis 6.1): Data show no difference in mortality (typical RR 0.90, 95% CI 0.69 to 1.17; participants = 1407; studies = 14) and no significant subgroup difference according to management of caloric balance; testing for subgroup differences: P = 0.39, I² = 0%.

6.1. Analysis.

Comparison 6 Higher versus lower amino acid intake in parenteral nutrition: subgrouped according to management of caloric balance, Outcome 1 Mortality to hospital discharge.

Neurodevelopmental disability (Analysis 6.2): Studies that increased amino acids and provided isocaloric non‐protein intake reported no difference in neurodevelopmental disability (typical RR 1.04, 95% CI 0.48 to 2.23; participants = 201; studies = 2).

6.2. Analysis.

Comparison 6 Higher versus lower amino acid intake in parenteral nutrition: subgrouped according to management of caloric balance, Outcome 2 Neurodevelopmental disability.

Postnatal growth failure at discharge (Analysis 6.3): Data show a reduction in postnatal growth failure at discharge (typical RR 0.74, 95% CI 0.56 to 0.97; participants = 203; studies = 3) and no significant subgroup difference according to management of caloric balance; testing for subgroup differences: P = 0.93, I² = 0%. Studies that increase amino acids and non‐protein caloric intake reported a reduction in postnatal growth failure at discharge (typical RR 0.73, 95% CI 0.55 to 0.98; participants = 92; studies = 2).

6.3. Analysis.

Comparison 6 Higher versus lower amino acid intake in parenteral nutrition: subgrouped according to management of caloric balance, Outcome 3 Postnatal growth failure at discharge.

Secondary outcomes

Days to regain birth weight (Analysis 6.4): Data show a reduction in days to regain birth weight overall (MD ‐1.14, 95% CI ‐1.73 to ‐0.56; participants = 950; studies = 13) with no significant subgroup difference according to management of caloric balance; testing for subgroup differences: P = 0.68, I² = 0%. Studies that increased amino acids and provided isocaloric non‐protein intake reported a reduction in days to regain birth weight (MD ‐1.06, 95% CI ‐1.77 to ‐0.34; participants = 615; studies = 8). Studies that increased amino acids and non‐protein caloric intake reported a reduction in days to regain birth weight (MD ‐1.32, 95% CI ‐2.33 to ‐0.31; participants = 335; studies = 5).

6.4. Analysis.

Comparison 6 Higher versus lower amino acid intake in parenteral nutrition: subgrouped according to management of caloric balance, Outcome 4 Days to regain birth weight.

Maximal weight loss grams (Analysis 6.5): Data show a significant reduction in maximal weight loss overall (MD ‐22.71, 95% CI ‐33.68 to ‐11.74; participants = 235; studies = 3) and a significant subgroup difference according to management of caloric balance; testing for subgroup differences: P = 0.001, I² = 90.2%. Studies that increased amino acids and provided isocaloric non‐protein intake reported a reduction in maximal weight loss (MD ‐29.79, 95% CI ‐41.58 to ‐17.99; participants = 185; studies = 2). A single study that increased amino acids and non‐protein calorie intake reported no differences (50 infants; MD 22.60 g, 95% CI ‐7.25 to 52.45) (Can 2012).

6.5. Analysis.

Comparison 6 Higher versus lower amino acid intake in parenteral nutrition: subgrouped according to management of caloric balance, Outcome 5 Maximal weight loss (grams).

Maximal weight loss per cent (Analysis 6.6): Data show no difference in maximal weight loss per cent overall (MD ‐0.33, 95% CI ‐1.61 to 0.96; participants = 288; studies = 4) and a significant subgroup difference according to management of caloric balance; testing for subgroup differences: P = 0.03, I² = 78.7%. Studies that increased amino acids and provided isocaloric non‐protein intake reported no difference in maximal weight loss per cent (MD 0.25, 95% CI ‐1.13 to 1.64; participants = 246; studies = 3). A single study that increased amino acids and non‐protein caloric intake reported a reduction in maximal weight loss per cent (MD ‐3.80, 95% CI ‐7.20 to ‐0.40; participants = 42) (Pappoe 2009).

6.6. Analysis.

Comparison 6 Higher versus lower amino acid intake in parenteral nutrition: subgrouped according to management of caloric balance, Outcome 6 Maximal weight loss %.

Weight gain to one month (Analysis 6.7): Studies that increased amino acids and provided isocaloric non‐protein intake reported a reduction in weight gain (g/kg/d) to one month (MD ‐1.50, 95% CI ‐2.56 to ‐0.44; participants = 373; studies = 4).

6.7. Analysis.

Comparison 6 Higher versus lower amino acid intake in parenteral nutrition: subgrouped according to management of caloric balance, Outcome 7 Weight gain g/kg/day up to 1 month.

Weight gain to discharge (Analysis 6.8): Data show no difference overall in weight gain (g/kg/d) to discharge (MD 0.76, 95% CI ‐0.02 to 1.54; participants = 291; studies = 4) and no significant subgroup difference according to management of caloric balance; testing for subgroup differences: P = 0.72, I² = 0%.

6.8. Analysis.

Comparison 6 Higher versus lower amino acid intake in parenteral nutrition: subgrouped according to management of caloric balance, Outcome 8 Weight gain g/kg/day to discharge.

Linear growth to one month (Analysis 6.9): A single study that increased amino acids and provided isocaloric non‐protein intake reported a reduction in linear growth to one month (MD ‐0.00 cm/week, 95% CI ‐0.15, ‐0.15; participants = 122) (Clark 2007).

6.9. Analysis.

Comparison 6 Higher versus lower amino acid intake in parenteral nutrition: subgrouped according to management of caloric balance, Outcome 9 Linear growth cm/week up to 1 month.

Linear growth to discharge (Analysis 6.10): Another single study that increased amino acids and provided isocaloric non‐protein intake reported a reduction in linear growth to discharge (MD ‐0.27 cm/week, 95% CI ‐0.40, ‐0.14; participants = 123) (Balasubramanian 2013).

6.10. Analysis.

Comparison 6 Higher versus lower amino acid intake in parenteral nutrition: subgrouped according to management of caloric balance, Outcome 10 Linear growth cm/week to discharge.

Head circumference growth to one month (Analysis 6.11): Data show no difference overall in head circumference growth up to one month (MD 0.01 cm/week, 95% CI ‐0.05 to 0.07; participants = 380; studies = 3) and a significant subgroup difference according to management of caloric balance; testing for subgroup differences: P < 0.00001, I² = 95%. Studies that increased amino acids and provided isocaloric non‐protein intake reported a decrease in head growth to one month (MD ‐0.16, 95% CI ‐0.25 to ‐0.07; participants = 245; studies = 2). A single study that increased amino acids and non‐protein caloric intake reported an increase in head circumference growth to one month (MD 0.13 cm/week, 95% CI 0.05, 0.20; participants 135) (Morgan 2014).

6.11. Analysis.

Comparison 6 Higher versus lower amino acid intake in parenteral nutrition: subgrouped according to management of caloric balance, Outcome 11 Head circumference growth cm/week up to 1 month.

Head circumference growth to discharge (Analysis 6.12): Studies that increased amino acids and provided isocaloric non‐protein intake reported an increase in head growth to discharge (MD 0.09, 95% CI 0.06 to 0.13; participants = 315; studies = 4).

6.12. Analysis.

Comparison 6 Higher versus lower amino acid intake in parenteral nutrition: subgrouped according to management of caloric balance, Outcome 12 Head circumference growth cm/week to discharge.

Weight change z‐score to discharge (Analysis 6.13): Studies that increased amino acids and provided isocaloric non‐protein intake reported no difference in weight change z‐score to discharge (MD 0.01, 95% CI ‐0.33 to 0.36; participants = 207; studies = 2).

6.13. Analysis.

Comparison 6 Higher versus lower amino acid intake in parenteral nutrition: subgrouped according to management of caloric balance, Outcome 13 Weight change z‐score to discharge.

Head circumference change z‐score to one month (Analysis 6.14): Data show an increase in head circumference change z‐score to one month (MD 0.27, 95% CI 0.08 to 0.46; participants = 231; studies = 2) and subgroup differences according to management of caloric balance that was borderline significant; testing for subgroup differences: P = 0.09, I² = 66%. For subgroups, a single study that increased amino acids and provided isocaloric non‐protein intake reported no difference in head circumference change z‐score to one month (RR 0.00, 95% CI ‐0.36 to 0.36; participants = 96) (Vlaardingerbroek 2013). Another single study that increased amino acids and non‐protein intake reported an increase in head circumference change z‐score to one month (RR 0.37, 95% CI 0.15, 0.59; participants = 135) (Morgan 2014).

6.14. Analysis.

Comparison 6 Higher versus lower amino acid intake in parenteral nutrition: subgrouped according to management of caloric balance, Outcome 14 Head circumference change z‐score to 1 month.

Head circumference change z‐score to discharge (Analysis 6.15): Studies that increased amino acids and provided isocaloric non‐protein intake found no difference in head circumference change z‐score to discharge (MD 0.18, 95% CI ‐0.15 to 0.50; participants = 207; studies = 2).

6.15. Analysis.

Comparison 6 Higher versus lower amino acid intake in parenteral nutrition: subgrouped according to management of caloric balance, Outcome 15 Head circumference change z‐score to discharge.

Days to full enteral feeds (Analysis 6.16): Data show no difference in days to full enteral feeds (MD ‐0.19, 95% CI ‐1.07 to 0.70; participants = 778; studies = 11) and no significant subgroup difference according to management of caloric balance; testing for subgroup differences: P = 0.11, I² = 60.9%. Studies that increased amino acids and provided isocaloric non‐protein intake reported no difference in days to full enteral feeds (MD ‐0.90, 95% CI ‐2.14 to 0.35; participants = 495; studies = 7). Studies that increased amino acids and non‐protein caloric intake reported no difference in days to full enteral feeds (MD 0.56, 95% CI ‐0.71 to 1.83; participants = 283; studies = 4).

6.16. Analysis.

Comparison 6 Higher versus lower amino acid intake in parenteral nutrition: subgrouped according to management of caloric balance, Outcome 16 Days to full enteral feeds.

Late‐onset sepsis (Analysis 6.17): Data show no difference in late‐onset sepsis (typical RR 0.96, 95% CI 0.79 to 1.18; participants = 1255; studies = 15) and no significant subgroup difference according to management of caloric balance; testing for subgroup differences: P = 0.66, I² = 0%.

6.17. Analysis.

Comparison 6 Higher versus lower amino acid intake in parenteral nutrition: subgrouped according to management of caloric balance, Outcome 17 Late‐onset sepsis.

Necrotising enterocolitis (Analysis 6.18): Data show no difference in necrotising enterocolitis (typical RR 1.00, 95% CI 0.68 to 1.47; participants = 1301; studies = 14) and no significant subgroup difference according to management of caloric balance; testing for subgroup differences: P = 0.44, I² = 0%.

6.18. Analysis.

Comparison 6 Higher versus lower amino acid intake in parenteral nutrition: subgrouped according to management of caloric balance, Outcome 18 Necrotising enterocolitis.

Chronic lung disease (Analysis 6.19): Data show no difference in chronic lung disease (typical RR 1.04, 95% CI 0.89 to 1.23; participants = 819; studies = 10) and no significant subgroup difference according to management of caloric balance; testing for subgroup differences: P = 0.43, I² = 0%.

6.19. Analysis.

Comparison 6 Higher versus lower amino acid intake in parenteral nutrition: subgrouped according to management of caloric balance, Outcome 19 Chronic lung disease ≥ 36 weeks' PMA.

Intraventricular haemorrhage (Analysis 6.20): Data show no difference in intraventricular haemorrhage (typical RR 1.08, 95% CI 0.73 to 1.59; participants = 370; studies = 4) and no significant subgroup difference according to management of caloric balance; testing for subgroup differences: P = 0.66, I² = 0%.

6.20. Analysis.

Comparison 6 Higher versus lower amino acid intake in parenteral nutrition: subgrouped according to management of caloric balance, Outcome 20 Intraventricular haemorrhage.

Severe intraventricular haemorrhage (Analysis 6.21): Data show no difference in severe intraventricular haemorrhage (typical RR 1.16, 95% CI 0.74 to 1.82; participants = 904; studies = 11) and no significant subgroup difference according to management of caloric balance; testing for subgroup differences: P = 0.44, I² = %.

6.21. Analysis.

Comparison 6 Higher versus lower amino acid intake in parenteral nutrition: subgrouped according to management of caloric balance, Outcome 21 Severe intraventricular haemorrhage.

Periventricular leukomalacia (Analysis 6.22): Data show no difference in periventricular leukomalacia (typical RR 0.55, 95% CI 0.24 to 1.25; participants = 720; studies = 7) and no significant subgroup difference according to management of caloric balance; testing for subgroup differences: P = 0.12, I² = 58%. For subgroups, data show a reduction in periventricular leukomalacia in studies that increased amino acids and provided isocaloric non‐protein intake of borderline significance (typical RR 0.32, 95% CI 0.10 to 1.00; participants = 543; studies = 5).

6.22. Analysis.

Comparison 6 Higher versus lower amino acid intake in parenteral nutrition: subgrouped according to management of caloric balance, Outcome 22 Periventricular leukomalacia.

Retinopathy of prematurity (Analysis 6.23): Data show a reduction in retinopathy of prematurity (typical RR 0.44, 95% CI 0.21 to 0.93; participants = 269; studies = 4) and no significant subgroup difference according to management of caloric balance; testing for subgroup differences: P = 0.11, I² = 61%. The single study that increased amino acids and provided isocaloric non‐protein intake reported no difference in retinopathy of prematurity (123 infants; RR 1.58, 95% CI 0.27 to 9.10). Studies that increased amino acids and non‐protein caloric intake reported a reduction in retinopathy of prematurity (typical RR 0.32, 95% CI 0.13 to 0.77; participants = 146; studies = 3).

6.23. Analysis.

Comparison 6 Higher versus lower amino acid intake in parenteral nutrition: subgrouped according to management of caloric balance, Outcome 23 Retinopathy of prematurity.

Severe retinopathy of prematurity (Analysis 6.24): Data show no difference in severe retinopathy of prematurity (typical RR 0.96, 95% CI 0.56 to 1.63; participants = 672; studies = 8) and no significant subgroup difference according to management of caloric balance; testing for subgroup differences: P = 0.20, I² = 38%.

6.24. Analysis.

Comparison 6 Higher versus lower amino acid intake in parenteral nutrition: subgrouped according to management of caloric balance, Outcome 24 Severe retinopathy of prematurity (> stage 2 or treated).

Cerebral palsy (Analysis 6.25): Data show no difference in cerebral palsy (typical RR 4.00, 95% CI 0.89 to 17.97; participants = 122; studies = 2) for studies that increased amino acids and provided isocaloric non‐protein intake

6.25. Analysis.

Comparison 6 Higher versus lower amino acid intake in parenteral nutrition: subgrouped according to management of caloric balance, Outcome 25 Cerebral palsy.

Developmental delay at ≥ 18 months (Analysis 6.26): Studies that increased amino acids and provided isocaloric non‐protein intake reported no difference in developmental delay at ≥ 18 months (typical RR 1.35, 95% CI 0.52 to 3.53; participants = 301; studies = 3).

6.26. Analysis.

Comparison 6 Higher versus lower amino acid intake in parenteral nutrition: subgrouped according to management of caloric balance, Outcome 26 Developmental delay at ≥ 18 months.

Blindness (Analysis 6.27): Data show no difference in blindness (typical RR 2.00, 95% CI 0.20 to 19.91; participants = 122; studies = 2) for studies that increased amino acids and provided isocaloric non‐protein intake.

6.27. Analysis.

Comparison 6 Higher versus lower amino acid intake in parenteral nutrition: subgrouped according to management of caloric balance, Outcome 27 Blindness.

Deafness (Analysis 6.28): A single study that increased amino acids and provided isocaloric non‐protein intake reported that no infants were deaf (Vlaardingerbroek 2013).

6.28. Analysis.

Comparison 6 Higher versus lower amino acid intake in parenteral nutrition: subgrouped according to management of caloric balance, Outcome 28 Deafness.

Abnormal serum ammonia (Analysis 6.29): A single study that increased amino acids and provided isocaloric non‐protein intake reported an abnormal serum ammonia > 122 μmol/L in one infant on higher amino acid intake (Blanco 2008).

6.29. Analysis.

Comparison 6 Higher versus lower amino acid intake in parenteral nutrition: subgrouped according to management of caloric balance, Outcome 29 Abnormal serum ammonia.

Abnormal blood urea nitrogen (Analysis 6.30): Data show an increase in abnormal blood urea nitrogen overall (typical RR 2.77, 95% CI 2.13 to 3.61; participants = 688; studies = 7) with no significant subgroup differences according to management of caloric balance; testing for subgroup differences: P = 0.22, I² = 33.3%. Data show a significant increase in abnormal blood urea nitrogen in studies that increased amino acids and provided isocaloric non‐protein intake (typical RR 2.60, 95% CI 2.00 to 3.40; participants = 561; studies = 5) and in studies that increased both amino acids and non‐protein calorie intake (typical RR 6.45, 95% CI 1.55 to 26.84; participants = 127; studies = 2).

6.30. Analysis.

Comparison 6 Higher versus lower amino acid intake in parenteral nutrition: subgrouped according to management of caloric balance, Outcome 30 Abnormal blood urea nitrogen (various criteria).

Hyperglycaemia (Analysis 6.31): Data show no difference in hyperglycaemia overall (typical RR 0.51, 95% CI 0.34 to 0.79; participants = 378; studies = 3) and a significant subgroup difference according to management of caloric balance; testing for subgroup differences: P = 0.002, I² = 89.3%. For subgroups, studies that increased amino acids and provided isocaloric non‐protein intake reported a reduction in hyperglycaemia (typical RR 0.51, 95% CI 0.34 to 0.79; participants = 378; studies = 3). Studies that increased amino acids and non‐protein calorie nutrition reported no difference (typical RR 1.51, 95% CI 0.88 to 2.62; participants = 127; studies = 2).

6.31. Analysis.

Comparison 6 Higher versus lower amino acid intake in parenteral nutrition: subgrouped according to management of caloric balance, Outcome 31 Hyperglycaemia, plasma glucose > 8.3 mmol/L.

Hyperglycaemia treated with insulin (Analysis 6.32): Data show an increase in hyperglycaemia treated with insulin overall (typical RR 1.24, 95% CI 0.93 to 1.66; participants = 534; studies = 5) and a significant subgroup difference according to management of caloric balance; tests for subgroup differences: P = 0.001, I² = 90.1%. For subgroups, studies that increased amino acids and provided isocaloric non‐protein intake reported no difference in hyperglycaemia treated with insulin (typical RR 0.76, 95% CI 0.49 to 1.19; participants = 378; studies = 3). Studies that increased amino acids and non‐protein calorie nutrition reported an increase (typical RR 2.00, 95% CI 1.35 to 2.98; participants = 156; studies = 2).

6.32. Analysis.

Comparison 6 Higher versus lower amino acid intake in parenteral nutrition: subgrouped according to management of caloric balance, Outcome 32 Hyperglycaemia treated with insulin.

Hypoglycaemia (Analysis 6.33): Data show no significant effect overall in hypoglycaemia (typical RR 1.17, 95% CI 0.84 to 1.63; participants = 376; studies = 3) and no significant subgroup difference according to management of caloric balance; testing for subgroup differences: P = 0.94, I² = 0%.

6.33. Analysis.

Comparison 6 Higher versus lower amino acid intake in parenteral nutrition: subgrouped according to management of caloric balance, Outcome 33 Hypoglycaemia.

Metabolic acidosis (Analysis 6.34): Data show no significant effect overall in metabolic acidosis (typical RR 2.05, 95% CI 0.94 to 4.47; participants = 305; studies = 4) and no significant subgroup difference according to management of caloric balance; testing for subgroup differences: P = 0.27, I² = 17.4%.

6.34. Analysis.

Comparison 6 Higher versus lower amino acid intake in parenteral nutrition: subgrouped according to management of caloric balance, Outcome 34 Metabolic acidosis.

Cholestasis (Analysis 6.35): Data show no difference in cholestasis (typical RR 1.26, 95% CI 0.86 to 1.84; participants = 616; studies = 5) and no significant subgroup difference according to management of caloric balance; testing for subgroup differences: P = 0.33, I² = 0%.

6.35. Analysis.

Comparison 6 Higher versus lower amino acid intake in parenteral nutrition: subgrouped according to management of caloric balance, Outcome 35 Cholestasis.

Higher versus lower amino acid intake in parenteral nutrition, very preterm or low birth weight infants

This analysis is restricted to studies that enrolled infants ≤ 1500 grams and/or at ≤ 32 weeks' gestation (Balasubramanian 2013; Blanco 2008; Bulbul 2012; Burattini 2013; Can 2012; Can 2013; Clark 2007; Ibrahim 2004; Morgan 2014; Pappoe 2009; Pildes 1973; Scattolin 2013; Tan 2008; te Braake 2005; Thureen 2003; Uthaya 2016; Vaidya 1995; Vlaardingerbroek 2013; Weiler 2006). Variable enrolment criteria and reporting of gestational and birth weight strata prevents further subgroup analysis.

Primary outcomes

Mortality to discharge (Analysis 7.1): Data show no difference in mortality (typical RR 0.90, 95% CI 0.69 to 1.17; participants = 1407; studies = 14).

7.1. Analysis.

Comparison 7 Higher versus lower amino acid intake in parenteral nutrition: very preterm or very low birth weight infants, Outcome 1 Mortality before hospital discharge.

Neurodevelopmental disability at two years (Analysis 7.2): Data show no difference in neurodevelopmental disability at two years (typical RR 1.04, 95% CI 0.48 to 2.23; participants = 201; studies = 2).

7.2. Analysis.

Comparison 7 Higher versus lower amino acid intake in parenteral nutrition: very preterm or very low birth weight infants, Outcome 2 Neurodevelopmental disability.

Postnatal growth failure (Analysis 7.3): Data show a reduction in postnatal growth failure at discharge (typical RR 0.74, 95% CI 0.56 to 0.97; participants = 203; studies = 3). A single study reported no difference in growth failure at two years (RR 0.66, 95% CI 0.33 to 1.32; participants = 111) (te Braake 2005).

7.3. Analysis.

Comparison 7 Higher versus lower amino acid intake in parenteral nutrition: very preterm or very low birth weight infants, Outcome 3 Postnatal growth failure.

Secondary outcomes

Days to regain birth weight (Analysis 7.4): Data show a significant reduction in days to regain birth weight (MD ‐0.78, 95% CI ‐1.46 to ‐0.11; participants = 800; studies = 10).

7.4. Analysis.

Comparison 7 Higher versus lower amino acid intake in parenteral nutrition: very preterm or very low birth weight infants, Outcome 4 Days to regain birth weight.

Maximal weight loss in grams (Analysis 7.5): Data show a reduction in maximal weight loss in grams (MD ‐20.37, 95% CI ‐32.68 to ‐8.05; participants = 139; studies = 2).

7.5. Analysis.

Comparison 7 Higher versus lower amino acid intake in parenteral nutrition: very preterm or very low birth weight infants, Outcome 5 Maximal weight loss (grams).

Maximal weight loss per cent (Analysis 7.6): Data show no difference in maximal weight loss per cent (MD ‐0.38, 95% CI ‐1.69 to 0.93; participants = 271; studies = 3).

7.6. Analysis.

Comparison 7 Higher versus lower amino acid intake in parenteral nutrition: very preterm or very low birth weight infants, Outcome 6 Maximal weight loss %.

Weight gain (Analysis 7.7): Data show a reduction in weight gain to one month (MD ‐1.50, 95% CI ‐2.56 to ‐0.44; participants = 373; studies = 4) and no difference in weight gain to discharge (MD 0.72, 95% CI ‐0.09 to 1.52; participants = 254; studies = 3).

7.7. Analysis.

Comparison 7 Higher versus lower amino acid intake in parenteral nutrition: very preterm or very low birth weight infants, Outcome 7 Weight gain g/kg/day.

Linear growth (Analysis 7.8): Data show a reduction in linear growth to one month (MD ‐0.16, 95% CI ‐0.26 to ‐0.06; participants = 245; studies = 2).

7.8. Analysis.

Comparison 7 Higher versus lower amino acid intake in parenteral nutrition: very preterm or very low birth weight infants, Outcome 8 Linear growth cm/week.

Head circumference growth (Analysis 7.9): Data show no difference in head circumference growth to one month (MD 0.01, 95% CI ‐0.04 to 0.06; participants = 476; studies = 4) and an increase in head circumference growth to discharge (MD 0.08, 95% CI 0.05 to 0.12; participants = 182; studies = 2).

7.9. Analysis.

Comparison 7 Higher versus lower amino acid intake in parenteral nutrition: very preterm or very low birth weight infants, Outcome 9 Head circumference growth cm/week.

Weight change in z‐score (Analysis 7.10): A single study reported no difference in weight change in z‐score to one month (MD ‐0.20, 95% CI ‐0.62 to 0.22; participants = 96) (Vlaardingerbroek 2013). Data show no difference in weight change in z‐score to discharge (MD 0.01, 95% CI ‐0.33 to 0.36; participants = 207; studies = 2) and no difference in weight change in z‐score post discharge (MD 0.13, 95% CI ‐0.26 to 0.52; participants = 201; studies = 2).

7.10. Analysis.

Comparison 7 Higher versus lower amino acid intake in parenteral nutrition: very preterm or very low birth weight infants, Outcome 10 Weight change z‐score.

Head circumference change in z‐score (Analysis 7.11): Data show an increase in head circumference change in z‐score to one month (MD 0.27, 95% CI 0.08 to 0.46; participants = 231; studies = 2). Meta‐analysis revealed no difference in head circumference change in z‐score to discharge (MD 0.18, 95% CI ‐0.15 to 0.50; participants = 207; studies = 2) and no difference in head circumference change in z‐score post discharge (MD 0.25, 95% CI ‐0.14 to 0.64; participants = 201; studies = 2).

7.11. Analysis.

Comparison 7 Higher versus lower amino acid intake in parenteral nutrition: very preterm or very low birth weight infants, Outcome 11 Head circumference change z‐score.

Days to full enteral feeds (Analysis 7.12): Data show no difference in days to full enteral feeds (MD ‐0.19, 95% CI ‐1.07 to 0.70; participants = 778; studies = 11).

7.12. Analysis.

Comparison 7 Higher versus lower amino acid intake in parenteral nutrition: very preterm or very low birth weight infants, Outcome 12 Days to full enteral feeds.

Late‐onset sepsis (Analysis 7.13): Data show no difference in late‐onset sepsis (typical RR 0.96, 95% CI 0.79 to 1.18; participants = 1255; studies = 15).

7.13. Analysis.

Comparison 7 Higher versus lower amino acid intake in parenteral nutrition: very preterm or very low birth weight infants, Outcome 13 Late‐onset sepsis.

Necrotising enterocolitis (Analysis 7.14): Data show no difference in necrotising enterocolitis (typical RR 1.00, 95% CI 0.68 to 1.47; participants = 1301; studies = 14).

7.14. Analysis.

Comparison 7 Higher versus lower amino acid intake in parenteral nutrition: very preterm or very low birth weight infants, Outcome 14 Necrotising enterocolitis.

Chronic lung disease (Analysis 7.15): Data show no difference in chronic lung disease (typical RR 1.04, 95% CI 0.89 to 1.23; participants = 819; studies = 10).

7.15. Analysis.

Comparison 7 Higher versus lower amino acid intake in parenteral nutrition: very preterm or very low birth weight infants, Outcome 15 Chronic lung disease ≥ 36 weeks' PMA.

Intraventricular haemorrhage (Analysis 7.16): Data show no difference in intraventricular haemorrhage (typical RR 1.12, 95% CI 0.74 to 1.69; participants = 341; studies = 3).

7.16. Analysis.

Comparison 7 Higher versus lower amino acid intake in parenteral nutrition: very preterm or very low birth weight infants, Outcome 16 Intraventricular haemorrhage.

Severe intraventricular haemorrhage (Analysis 7.17): Data show no difference in severe intraventricular haemorrhage (typical RR 1.16, 95% CI 0.74 to 1.82; participants = 904; studies = 11).

7.17. Analysis.

Comparison 7 Higher versus lower amino acid intake in parenteral nutrition: very preterm or very low birth weight infants, Outcome 17 Severe intraventricular haemorrhage.

Periventricular leukomalacia (Analysis 7.18): Data show no difference in periventricular leukomalacia (typical RR 0.48, 95% CI 0.20 to 1.17; participants = 624; studies = 6).

7.18. Analysis.

Comparison 7 Higher versus lower amino acid intake in parenteral nutrition: very preterm or very low birth weight infants, Outcome 18 Periventricular leukomalacia.

Retinopathy of prematurity (Analysis 7.19): Data show a reduction in retinopathy of prematurity (typical RR 0.44, 95% CI 0.21 to 0.93; participants = 269; studies = 4).

7.19. Analysis.

Comparison 7 Higher versus lower amino acid intake in parenteral nutrition: very preterm or very low birth weight infants, Outcome 19 Retinopathy of prematurity.

Severe retinopathy of prematurity (Analysis 7.20): Data show no difference in severe retinopathy of prematurity (typical RR 0.96, 95% CI 0.56 to 1.63; participants = 672; studies = 8).

7.20. Analysis.

Comparison 7 Higher versus lower amino acid intake in parenteral nutrition: very preterm or very low birth weight infants, Outcome 20 Severe retinopathy of prematurity (> stage 2 or treated).

Cerebral palsy (Analysis 7.21): Data show no difference in cerebral palsy (typical RR 4.00, 95% CI 0.89 to 17.97; participants = 122; studies = 2).

7.21. Analysis.

Comparison 7 Higher versus lower amino acid intake in parenteral nutrition: very preterm or very low birth weight infants, Outcome 21 Cerebral palsy.

Developmental delay (Analysis 7.22): Data show no difference in developmental delay (typical RR 1.35, 95% CI 0.52 to 3.53; participants = 301; studies = 3).

7.22. Analysis.

Comparison 7 Higher versus lower amino acid intake in parenteral nutrition: very preterm or very low birth weight infants, Outcome 22 Developmental delay at ≥ 18 months.

Blindness (Analysis 7.23): Data show no difference in blindness (typical RR 2.00, 95% CI 0.20 to 19.91; participants = 122; studies = 2).

7.23. Analysis.

Comparison 7 Higher versus lower amino acid intake in parenteral nutrition: very preterm or very low birth weight infants, Outcome 23 Blindness.

Deafness (Analysis 7.24): A single study reported no difference in infants with deafness in either group (Vlaardingerbroek 2013).

7.24. Analysis.

Comparison 7 Higher versus lower amino acid intake in parenteral nutrition: very preterm or very low birth weight infants, Outcome 24 Deafness.

Abnormal serum ammonia (Analysis 7.25): A single study reported no difference in abnormal serum ammonia >122 μmol/L (RR 3.10, 95% CI 0.13 to 73.16; participants = 61) (Blanco 2008).

7.25. Analysis.

Comparison 7 Higher versus lower amino acid intake in parenteral nutrition: very preterm or very low birth weight infants, Outcome 25 Abnormal serum ammonia > 122 μmol/L.

Abnormal blood urea nitrogen (Analysis 7.26): Data show an increase in abnormal blood urea nitrogen (typical RR 2.77, 95% CI 2.13 to 3.61; participants = 688; studies = 7).

7.26. Analysis.

Comparison 7 Higher versus lower amino acid intake in parenteral nutrition: very preterm or very low birth weight infants, Outcome 26 Abnormal blood urea nitrogen > 21.4 mmol/L.

Hyperglycaemia (Analysis 7.27): Data show a reduction in hyperglycaemia (typical RR 0.66, 95% CI 0.45 to 0.96; participants = 409; studies = 4).

7.27. Analysis.

Comparison 7 Higher versus lower amino acid intake in parenteral nutrition: very preterm or very low birth weight infants, Outcome 27 Hyperglycaemia, plasma glucose > 8.3 mmol/L.

Hyperglycaemia treated with insulin (Analysis 7.28): Data show no difference in hyperglycaemia treated with insulin (typical RR 1.24, 95% CI 0.93 to 1.66; participants = 534; studies = 5).

7.28. Analysis.

Comparison 7 Higher versus lower amino acid intake in parenteral nutrition: very preterm or very low birth weight infants, Outcome 28 Hyperglycaemia treated with insulin.

Hypoglycaemia (Analysis 7.29): Data show no difference in hypoglycaemia (typical RR 1.17, 95% CI 0.84 to 1.63; participants = 376; studies = 3).

7.29. Analysis.

Comparison 7 Higher versus lower amino acid intake in parenteral nutrition: very preterm or very low birth weight infants, Outcome 29 Hypoglycaemia.

Metabolic acidosis (Analysis 7.30): Data show no difference in metabolic acidosis (typical RR 2.05, 95% CI 0.94 to 4.47; participants = 253; studies = 2).

7.30. Analysis.

Comparison 7 Higher versus lower amino acid intake in parenteral nutrition: very preterm or very low birth weight infants, Outcome 30 Metabolic acidosis.

Cholestasis (Analysis 7.31): Data show no difference in cholestasis (typical RR 1.26, 95% CI 0.86 to 1.84; participants = 616; studies = 5).

7.31. Analysis.

Comparison 7 Higher versus lower amino acid intake in parenteral nutrition: very preterm or very low birth weight infants, Outcome 31 Cholestasis.

Higher versus lower amino acid intake in parenteral nutrition, subgrouped according to age at commencement

Studies included in this review commenced parenteral amino acid intake at the following time points.

• < 24 hours (Anderson 1979; Balasubramanian 2013; Blanco 2008; Bulbul 2012; Burattini 2013; Can 2012; Can 2013; Ibrahim 2004; Makay 2007; Morgan 2014; Murdock 1995; Pappoe 2009; Rivera 1993; Scattolin 2013; Tan 2008; Tang 2009; te Braake 2005; Thureen 2003; van Goudoever 1995; Uthaya 2016; Weiler 2006; Xie 2014).

• ≥ 24 hours to < 48 hours (Clark 2007; Pildes 1973; Vlaardingerbroek 2013).

• ≥ 48 hours to < 72 hours (Black 1981; Vaidya 1995).

• ≥ 72 hours (Hata 2002).

Primary outcomes

Mortality to discharge (Analysis 8.1): Data show no difference in mortality (typical RR 0.90, 95% CI 0.69 to 1.17; participants = 1407; studies = 14) and no significant subgroup difference according to age at commencement of amino acid; testing for subgroup differences: P = 0.45, I² = 0%.

8.1. Analysis.

Comparison 8 Higher versus lower amino acid intake in parenteral nutrition: subgrouped according to age at commencement, Outcome 1 Mortality before hospital discharge.

Neurodevelopmental disability (Analysis 8.2): Studies that commenced amino acids at < 24 hours' age reported no difference in neurodevelopmental disability (typical RR 1.04, 95% CI 0.48 to 2.23; participants = 201; studies = 2).

8.2. Analysis.

Comparison 8 Higher versus lower amino acid intake in parenteral nutrition: subgrouped according to age at commencement, Outcome 2 Neurodevelopmental disability.

Postnatal growth failure at discharge (Analysis 8.3): Studies that commenced amino acids at < 24 hours' age reported a significant reduction in postnatal growth failure at discharge (typical RR 0.74, 95% CI 0.56 to 0.97; participants = 203; studies = 3).

8.3. Analysis.

Comparison 8 Higher versus lower amino acid intake in parenteral nutrition: subgrouped according to age at commencement, Outcome 3 Postnatal growth failure at discharge.

Secondary outcomes

Days to regain birth weight (Analysis 8.4): Data show a reduction in days to regain birth weight overall (MD ‐1.14, 95% CI ‐1.73 to ‐0.56; participants = 950; studies = 13) and no significant subgroup difference according to age at commencement of amino acid; testing for subgroup differences: P = 0.94, I² = 0%. Data show a reduction in days to regain birth weight in studies that commenced higher amino acid intakes at < 24 hours (MD ‐1.15, 95% CI ‐1.74 to ‐0.56; participants = 865; studies = 12). A single study that commenced higher amino acid intakes at ≥ 24 to 48 hours age reported no difference (MD ‐1.00, 95% CI ‐5.03 to 3.03; participants = 85) (Vaidya 1995).

8.4. Analysis.

Comparison 8 Higher versus lower amino acid intake in parenteral nutrition: subgrouped according to age at commencement, Outcome 4 Days to regain birth weight.

Weight loss in grams (Analysis 8.5): Data show a reduction in weight loss in grams in studies that commenced higher amino acids at < 24 hours (MD ‐22.71, 95% CI ‐33.68 to ‐11.74; participants = 235; studies = 3).

8.5. Analysis.

Comparison 8 Higher versus lower amino acid intake in parenteral nutrition: subgrouped according to age at commencement, Outcome 5 Maximal weight loss (grams).

Weight loss per cent (Analysis 8.6): Data show no difference in weight loss per cent in studies that commenced higher amino acids at < 24 hours (MD ‐0.33, 95% CI ‐1.61 to 0.96; participants = 288; studies = 4).

8.6. Analysis.

Comparison 8 Higher versus lower amino acid intake in parenteral nutrition: subgrouped according to age at commencement, Outcome 6 Maximal weight loss %.

Weight gain to one month (Analysis 8.7): A single study that commenced higher amino acid intakes at ≥ 24 to 48 hours age reported no difference in weight gain to one month (MD 1.50, 95% CI ‐0.27 to 3.27; participants = 122) (Clark 2007).

8.7. Analysis.

Comparison 8 Higher versus lower amino acid intake in parenteral nutrition: subgrouped according to age at commencement, Outcome 7 Weight gain g/kg/day up to 1 month.

Weight gain to discharge (Analysis 8.8): Data show no difference in weight gain (g/kg/d) to discharge overall (MD ‐0.16, 95% CI ‐0.87 to 0.54; participants = 446; studies = 6) and no significant subgroup difference according to age at commencement of amino acid; testing for subgroup differences: P = 0.08, I² = 67.8%.

8.8. Analysis.

Comparison 8 Higher versus lower amino acid intake in parenteral nutrition: subgrouped according to age at commencement, Outcome 8 Weight gain g/kg/day to discharge.

Linear growth to one month (Analysis 8.9): Data show a reduction in linear growth to one month overall (MD ‐0.16, 95% CI ‐0.26 to ‐0.06; participants = 245; studies = 2) with significant subgroup differences according to age at commencement of amino acid; testing for subgroup differences: P = 0.007, I² = 86.2%. A single study that commenced amino acids at < 24 hours reported a reduction in linear growth to one month (MD ‐0.27, 95% CI ‐0.40 to ‐0.14; participants = 123) (Balasubramanian 2013). Another single study that commenced amino acids at ≥ 24 to 48 hours' age reported no difference in linear growth to one month (MD 0.00, 95% CI ‐0.15 to 0.15; participants = 122) (Clark 2007).

8.9. Analysis.

Comparison 8 Higher versus lower amino acid intake in parenteral nutrition: subgrouped according to age at commencement, Outcome 9 Linear growth cm/week up to 1 month.

Head circumference growth to one month (Analysis 8.10): Data show no difference in head circumference growth to one month (MD 0.01, 95% CI ‐0.04 to 0.06; participants = 476; studies = 4) and no significant subgroup difference according to age at commencement of amino acid; testing for subgroup differences: P = 1.00, I² = 0. Studies that commenced amino acids at < 24 hours reported no difference in head circumference growth to one month (MD 0.01, 95% CI ‐0.06 to 0.08; participants = 258; studies = 2). Studies that commenced amino acids at ≥ 24 to 48 hours reported no difference in head circumference growth to one month (MD 0.01, 95% CI ‐0.07 to 0.09; participants = 218; studies = 2).

8.10. Analysis.

Comparison 8 Higher versus lower amino acid intake in parenteral nutrition: subgrouped according to age at commencement, Outcome 10 Head circumference growth cm/week up to 1 month age.

Head circumference growth to discharge (Analysis 8.11): Data show an increase in head circumference growth to discharge (MD 0.09, 95% CI 0.06 to 0.13; participants = 315; studies = 4) and a significant subgroup difference according to age at commencement of amino acid; testing for subgroup differences: P = 0.007, I² = 86.2. Studies that commenced amino acids at < 24 hours reported an increase in head circumference growth to discharge (MD 0.12, 95% CI 0.08 to 0.17; participants = 219; studies = 3). A single study that commenced amino acids at ≥ 24 to 48 hours' age reported no difference (MD 0.03, 95% CI ‐0.03 to 0.09; participants = 96) (Vlaardingerbroek 2013).

8.11. Analysis.

Comparison 8 Higher versus lower amino acid intake in parenteral nutrition: subgrouped according to age at commencement, Outcome 11 Head circumference growth cm/week to discharge.

Weight gain change in z‐score (Analysis 8.12): Data show no difference in weight gain change in z‐score to discharge (MD 0.01, 95% CI ‐0.33 to 0.36; participants = 207; studies = 2) and no significant subgroup difference according to age at commencement of amino acid; testing for subgroup differences: P = 0.17, I² = 48.1%.

8.12. Analysis.

Comparison 8 Higher versus lower amino acid intake in parenteral nutrition: subgrouped according to age at commencement, Outcome 12 Weight change z‐score to discharge.

Head circumference change in z‐score to one month (Analysis 8.13): Data show an increase in head circumference change in z‐score up to one month of age (MD 0.27, 95% CI 0.08 to 0.46; participants = 231; studies = 2) and no significant subgroup difference according to age at commencement of amino acid; testing for subgroup differences: P = 0.09, I² = 66%. A single study that commenced amino acids at < 24 hours' age reported an increase in head circumference change z‐score up to one month (MD 0.37, 95% CI 0.15 to 0.59; participants = 135) (Morgan 2014). Another single study that commenced amino acids at ≥ 24 to 48 hours reported no difference (MD 0.00, 95% CI ‐0.36 to 0.36; participants = 96) (Vlaardingerbroek 2013).

8.13. Analysis.

Comparison 8 Higher versus lower amino acid intake in parenteral nutrition: subgrouped according to age at commencement, Outcome 13 Head circumference change z‐score to 1 month age.

Head circumference change in z‐score to discharge (Analysis 8.14): Data show no difference in head circumference change in z‐score to discharge (MD 0.18, 95% CI ‐0.15 to 0.50; participants = 207; studies = 2) and no significant subgroup difference according to age at commencement of amino acid; testing for subgroup differences: P = 0.10, I² = 62.7%.

8.14. Analysis.

Comparison 8 Higher versus lower amino acid intake in parenteral nutrition: subgrouped according to age at commencement, Outcome 14 Head circumference change z‐score to discharge.

Days to full enteral feeds (Analysis 8.15): All studies commenced amino acids at < 24 hours. Data show no difference in days to full enteral feeds (MD ‐0.19, 95% CI ‐1.07 to 0.70; participants = 778; studies = 11).

8.15. Analysis.

Comparison 8 Higher versus lower amino acid intake in parenteral nutrition: subgrouped according to age at commencement, Outcome 15 Days to full enteral feeds.

Late‐onset sepsis (Analysis 8.16): Data who no difference in late‐onset sepsis (typical RR 0.96, 95% CI 0.79 to 1.18; participants = 1255; studies = 15) and no significant subgroup difference according to age at commencement of amino acid; testing for subgroup differences: P = 0.72, I² = 0%.

8.16. Analysis.

Comparison 8 Higher versus lower amino acid intake in parenteral nutrition: subgrouped according to age at commencement, Outcome 16 Late‐onset sepsis.

Necrotising enterocolitis (Analysis 8.17): Data show no difference in necrotising enterocolitis (typical RR 1.00, 95% CI 0.68 to 1.47; participants = 1301; studies = 14) and no significant subgroup difference according to age at commencement of amino acid; testing for subgroup differences: P = 0.85, I² = 0%.

8.17. Analysis.

Comparison 8 Higher versus lower amino acid intake in parenteral nutrition: subgrouped according to age at commencement, Outcome 17 Necrotising enterocolitis.

Chronic lung disease (Analysis 8.18): Data show no difference in chronic lung disease (typical RR 1.04, 95% CI 0.89 to 1.23; participants = 819; studies = 10) and no significant subgroup difference according to age at commencement of amino acid; testing for subgroup differences: P = 0.23, I² = 29.5%.

8.18. Analysis.

Comparison 8 Higher versus lower amino acid intake in parenteral nutrition: subgrouped according to age at commencement, Outcome 18 Chronic lung disease ≥ 36 weeks' PMA.

Intraventricular haemorrhage (Analysis 8.19): Data show no difference in intraventricular haemorrhage (typical RR 1.12, 95% CI 0.74 to 1.69; participants = 341; studies = 3) and no significant subgroup difference according to age at commencement of amino acid; testing for subgroup differences: P = 0.72, I² = 0%.

8.19. Analysis.

Comparison 8 Higher versus lower amino acid intake in parenteral nutrition: subgrouped according to age at commencement, Outcome 19 Intraventricular haemorrhage.

Severe intraventricular haemorrhage (Analysis 8.20): Data show no difference in severe intraventricular haemorrhage (typical RR 1.16, 95% CI 0.74 to 1.82; participants = 904; studies = 11) and no significant subgroup difference according to age at commencement of amino acid; testing for subgroup differences: P = 0.97, I² = 0%.

8.20. Analysis.

Comparison 8 Higher versus lower amino acid intake in parenteral nutrition: subgrouped according to age at commencement, Outcome 20 Severe intraventricular haemorrhage.

Periventricular leukomalacia (Analysis 8.21): Data show no difference in periventricular leukomalacia (typical RR 0.55, 95% CI 0.24 to 1.25; participants = 720; studies = 7) and no significant subgroup difference according to age at commencement of amino acid; testing for subgroup differences: P = 0.20, I² = 40.3%.

8.21. Analysis.

Comparison 8 Higher versus lower amino acid intake in parenteral nutrition: subgrouped according to age at commencement, Outcome 21 Periventricular leukomalacia.

Retinopathy of prematurity (Analysis 8.22): All four studies reporting retinopathy of prematurity commenced amino acids at < 24 hours. Data show a reduction in retinopathy of prematurity (typical RR 0.44, 95% CI 0.21 to 0.93; participants = 269; studies = 4).

8.22. Analysis.

Comparison 8 Higher versus lower amino acid intake in parenteral nutrition: subgrouped according to age at commencement, Outcome 22 Retinopathy of prematurity.

Severe retinopathy of prematurity (Analysis 8.23): Data show no difference in severe retinopathy of prematurity (typical RR 0.96, 95% CI 0.56 to 1.63; participants = 672; studies = 8) and no significant subgroup difference according to age at commencement of amino acid; testing for subgroup differences: P = 0.26, I² = 20%.

8.23. Analysis.

Comparison 8 Higher versus lower amino acid intake in parenteral nutrition: subgrouped according to age at commencement, Outcome 23 Severe retinopathy of prematurity (> stage 2 or treated).

Cerebral palsy (Analysis 8.24): Studies that commenced amino acids at < 24 hours reported no difference in cerebral palsy (typical RR 4.00, 95% CI 0.89 to 17.97; participants = 122; studies = 2).

8.24. Analysis.

Comparison 8 Higher versus lower amino acid intake in parenteral nutrition: subgrouped according to age at commencement, Outcome 24 Cerebral palsy.

Developmental delay at ≥ 18 months (Analysis 8.25): Studies that commenced amino acids at < 24 hours reported no difference in developmental delay at ≥ 18 months (typical RR 1.35, 95% CI 0.52 to 3.53; participants = 301; studies = 3).

8.25. Analysis.

Comparison 8 Higher versus lower amino acid intake in parenteral nutrition: subgrouped according to age at commencement, Outcome 25 Developmental delay at ≥ 18 months.

Blindness (Analysis 8.26): Studies that commenced amino acids at < 24 hours reported no difference in blindness (typical RR 2.00, 95% CI 0.20 to 19.91; participants = 122; studies = 2).

8.26. Analysis.

Comparison 8 Higher versus lower amino acid intake in parenteral nutrition: subgrouped according to age at commencement, Outcome 26 Blindness.

Deafness (Analysis 8.27): A single study that commenced amino acids at ≥ 24 to < 48 hours reported no infants with deafness in either group (Vlaardingerbroek 2013).

8.27. Analysis.

Comparison 8 Higher versus lower amino acid intake in parenteral nutrition: subgrouped according to age at commencement, Outcome 27 Deafness.

Abnormal serum ammonia (Analysis 8.28): A single study that commenced amino acids at < 24 hours reported an abnormal serum ammonia > 122 μmol/L in one infant on higher amino acid intake (Blanco 2008).

8.28. Analysis.

Comparison 8 Higher versus lower amino acid intake in parenteral nutrition: subgrouped according to age at commencement, Outcome 28 Abnormal serum ammonia > 122 μmol/L.

Abnormal blood urea nitrogen (Analysis 8.29): Data show an increase in abnormal blood urea nitrogen overall (typical RR 2.77, 95% CI 2.13 to 3.61; participants = 688; studies = 7) and no significant subgroup difference according to age at commencement of amino acid; testing for subgroup differences: P = 0.23, I² = 31.4%. Data show increases in abnormal blood urea nitrogen in studies commencing amino acid at < 24 hours (typical RR 2.85, 95% CI 2.00 to 4.06; participants = 385; studies = 4); studies commencing amino acid at ≥ 24 to 48 hours (typical RR 2.20, 95% CI 1.50 to 3.23; participants = 218; studies = 2); and one study commencing amino acid at ≥ 48 to 72 hours (RR 10.74, 95% CI 1.45 to 79.59; participants = 85) (Vaidya 1995).

8.29. Analysis.

Comparison 8 Higher versus lower amino acid intake in parenteral nutrition: subgrouped according to age at commencement, Outcome 29 Abnormal blood urea nitrogen (various criteria).

Hyperglycaemia (Analysis 8.30): Data show a reduction in hyperglycaemia overall (typical RR 0.69, 95% CI 0.49 to 0.96; participants = 505; studies = 5) and no significant subgroup difference according to age at commencement of amino acid; testing for subgroup differences: P = 0.38, I² = 0%.

8.30. Analysis.

Comparison 8 Higher versus lower amino acid intake in parenteral nutrition: subgrouped according to age at commencement, Outcome 30 Hyperglycaemia, plasma glucose > 8.3 mmol/L.

Hyperglycaemia treated with insulin (Analysis 8.31): Data show no difference in hyperglycaemia treated with insulin (typical RR 1.24, 95% CI 0.93 to 1.66; participants = 534; studies = 5) and no significant subgroup difference according to age at commencement of amino acid; testing for subgroup differences: P = 0.82, I² = 0%. Subgroup analysis of studies that commenced amino acids at < 24 hours revealed no difference in hyperglycaemia treated with insulin (typical RR 1.26, 95% CI 0.92 to 1.72; participants = 438; studies = 4). A single study that commenced amino acids at ≥ 24 to < 48 hours reported no difference (RR 1.15, 95% CI 0.54 to 2.45; participants = 96) (Vlaardingerbroek 2013).

8.31. Analysis.

Comparison 8 Higher versus lower amino acid intake in parenteral nutrition: subgrouped according to age at commencement, Outcome 31 Hyperglycaemia treated with insulin.

Hypoglycaemia (Analysis 8.32): Data show no difference in hypoglycaemia overall (typical RR 1.17, 95% CI 0.84 to 1.63; participants = 376; studies = 3) and no significant subgroup difference according to age at commencement of amino acid; testing for subgroup differences: P = 0.94, I² = 0%.

8.32. Analysis.

Comparison 8 Higher versus lower amino acid intake in parenteral nutrition: subgrouped according to age at commencement, Outcome 32 Hypoglycaemia.

Metabolic acidosis (Analysis 8.33): Data show no difference in metabolic acidosis overall (typical RR 2.05, 95% CI 0.94 to 4.47; participants = 305; studies = 4) and no significant subgroup difference according to age at commencement of amino acid; testing for subgroup differences: P = 0.27, I² = 17.4%.

8.33. Analysis.

Comparison 8 Higher versus lower amino acid intake in parenteral nutrition: subgrouped according to age at commencement, Outcome 33 Metabolic acidosis.

Cholestasis (Analysis 8.34): Data show no difference in cholestasis overall (typical RR 1.26, 95% CI 0.86 to 1.84; participants = 616; studies = 5) and no significant subgroup difference according to age at commencement of amino acid; testing for subgroup differences: P = 0.22, I² = 34.5%.

8.34. Analysis.

Comparison 8 Higher versus lower amino acid intake in parenteral nutrition: subgrouped according to age at commencement, Outcome 34 Cholestasis.

Higher versus lower amino acid intake in parenteral nutrition, subgrouped according to lipid intake

We did not prespecify this subgroup analysis. Studies included in this review used differing strategies for lipid infusion, so we had to perform a subgroup analysis to determine an effect of lipid intake.

• Early lipid infusion (Black 1981; Blanco 2008; Bulbul 2012; Can 2012; Can 2013; Clark 2007; Heimler 2010; Ibrahim 2004; Liu 2015; Makay 2007; Morgan 2014; Murdock 1995; Pappoe 2009; Tan 2008; Tang 2009; te Braake 2005; Thureen 2003; Uthaya 2016; Vaidya 1995; van Goudoever 1995; van Lingen 1992; Vlaardingerbroek 2013; Weiler 2006; Xie 2014).

• Delayed lipid infusion ≥ 5 days (Burattini 2013; Vaidya 1995).

• No lipid infusion (Anderson 1979; Balasubramanian 2013; Hata 2002; Pildes 1973; Rivera 1993; van Goudoever 1995).

Primary outcomes

Mortality to discharge (Analysis 9.1): Data show no difference in mortality (typical RR 0.90, 95% CI 0.69 to 1.17; participants = 1407; studies = 14) and no significant subgroup difference according to age at commencement of lipid; testing for subgroup differences: P = 0.79, I² = 0%.

9.1. Analysis.

Comparison 9 Higher versus lower amino acid intake in parenteral nutrition: subgrouped according to lipid intake, Outcome 1 Mortality before hospital discharge.

Neurodevelopmental disability (Analysis 9.2): Studies that provided early lipid intake reported no difference in neurodevelopmental disability (typical RR 1.04, 95% CI 0.48 to 2.23; participants = 201; studies = 2).

9.2. Analysis.

Comparison 9 Higher versus lower amino acid intake in parenteral nutrition: subgrouped according to lipid intake, Outcome 2 Neurodevelopmental disability.

Postnatal growth failure at discharge (Analysis 9.3): All studies reporting postnatal growth failure commenced early lipid. Data show a significant reduction in postnatal growth failure at discharge (typical RR 0.74, 95% CI 0.56 to 0.97; participants = 203; studies = 3).

9.3. Analysis.

Comparison 9 Higher versus lower amino acid intake in parenteral nutrition: subgrouped according to lipid intake, Outcome 3 Postnatal growth failure at discharge.

Secondary outcomes

Days to regain birth weight (Analysis 9.4): Data show a reduction in days to regain birth weight overall (MD ‐1.14, 95% CI ‐1.73 to ‐0.56; participants = 950; studies = 13) and no significant subgroup difference according to age at commencement of lipid; testing for subgroup differences: P < 0.00001, I² = 92%. Studies commencing early lipid infusion reported a reduction in days to regain birth weight (MD ‐2.02, 95% CI ‐2.73 to ‐1.31; participants = 513; studies = 9). Studies with delayed lipid infusion ≥ 5 days reported no difference in days to regain birth weight (MD ‐0.57, 95% CI ‐2.04 to 0.91; participants = 199; studies = 2). Studies with no lipid reported an increase in days to regain birth weight (MD 2.04, 95% CI 0.58 to 3.50; participants = 238; studies = 2).

9.4. Analysis.

Comparison 9 Higher versus lower amino acid intake in parenteral nutrition: subgrouped according to lipid intake, Outcome 4 Days to regain birth weight.

Maximal weight loss grams (Analysis 9.5): All studies reporting maximal weight loss in grams commenced early lipid infusion. Data show a decrease in maximal weight loss (MD ‐22.71, 95% CI ‐33.68 to ‐11.74; participants = 235; studies = 3).

9.5. Analysis.

Comparison 9 Higher versus lower amino acid intake in parenteral nutrition: subgrouped according to lipid intake, Outcome 5 Maximal weight loss (grams).

Maximal weight loss per cent (Analysis 9.6): Data show no difference in maximal weight loss per cent overall (MD ‐0.33, 95% CI ‐1.61 to 0.96; participants = 288; studies = 4) and no significant subgroup difference according to age at commencement of lipid; testing for subgroup differences: P = 0.20, I² = 37%.

9.6. Analysis.

Comparison 9 Higher versus lower amino acid intake in parenteral nutrition: subgrouped according to lipid intake, Outcome 6 Maximal weight loss %.

Weight gain to one month (Analysis 9.7): Data show a reduction in weight gain to one month overall (MD ‐1.50, 95% CI ‐2.56 to ‐0.44; participants = 373; studies = 4) with a significant subgroup difference according to age at commencement of lipid; testing for subgroup differences: P < 0.00001, I² = 94.9%. Studies commencing early lipid infusion reported no difference in weight gain to one month (MD 0.42, 95% CI ‐0.94 to 1.78; participants = 250; studies = 3). A single study with no lipid reported a reduction in weight gain to one month (MD ‐4.48, 95% CI ‐6.17 to ‐2.79; participants = 123) (Balasubramanian 2013).

9.7. Analysis.

Comparison 9 Higher versus lower amino acid intake in parenteral nutrition: subgrouped according to lipid intake, Outcome 7 Weight gain g/kg/day to 1 month.

Weight gain to discharge (Analysis 9.8): Data show no difference in weight gain to discharge overall (MD 0.76, 95% CI ‐0.02 to 1.54; participants = 291; studies = 4) and no significant subgroup difference according to age at commencement of lipid; testing for subgroup differences: P = 0.55, I² = 0%.

9.8. Analysis.

Comparison 9 Higher versus lower amino acid intake in parenteral nutrition: subgrouped according to lipid intake, Outcome 8 Weight gain g/kg/day to discharge.

Linear growth to one month (Analysis 9.9): Data show a reduction in linear growth to one month overall (MD ‐0.16, 95% CI ‐0.26 to ‐0.06; participants = 245; studies = 2) with a significant subgroup difference according to age at commencement of lipid; testing for subgroup differences: P = 0.007, I² = 86.2%. A single study commencing early lipid infusion reported no difference in linear growth to one month (MD 0.00, 95% CI ‐0.15 to 0.15; participants = 122) (Clark 2007). A single study of no lipid reported a reduction in linear growth to one month (MD ‐0.27, 95% CI ‐0.40 to ‐0.14; participants = 123) (Balasubramanian 2013).

9.9. Analysis.

Comparison 9 Higher versus lower amino acid intake in parenteral nutrition: subgrouped according to lipid intake, Outcome 9 Linear growth cm/week up to 1 month age.

Head circumference growth to one month (Analysis 9.10): Data show no difference in head circumference growth to one month overall (MD 0.01, 95% CI ‐0.04 to 0.06; participants = 476; studies = 4) with a significant subgroup difference according to age at commencement of lipid; testing for subgroup differences: P < 0.00001, I² = 97%. Studies commencing early lipid infusion reported an increase in head circumference growth to one month (MD 0.07, 95% CI 0.02 to 0.13; participants = 353; studies = 3). A single study of no lipid reported a reduction in head circumference growth to one month (MD ‐0.38, 95% CI ‐0.51 to ‐0.24; participants = 123) (Balasubramanian 2013).

9.10. Analysis.

Comparison 9 Higher versus lower amino acid intake in parenteral nutrition: subgrouped according to lipid intake, Outcome 10 Head circumference growth cm/week up to 1 month age.

Head circumference growth to discharge (Analysis 9.11): All studies reporting head circumference growth to discharge commenced early lipid infusion. Studies that commenced early lipid infusion reported an increase in head circumference growth to discharge (MD 0.09, 95% CI 0.06 to 0.13; participants = 315; studies = 4).

9.11. Analysis.

Comparison 9 Higher versus lower amino acid intake in parenteral nutrition: subgrouped according to lipid intake, Outcome 11 Head circumference growth cm/week to discharge.

Only studies that commenced early lipid infusion reported change in z scores.

Weight change z‐score to one month (Analysis 9.12): A single study that commenced early lipid infusion reported no difference in weight change z‐score to one month (MD ‐0.20, 95% CI ‐0.62 to 0.22; participants = 96) (Vlaardingerbroek 2013).

9.12. Analysis.

Comparison 9 Higher versus lower amino acid intake in parenteral nutrition: subgrouped according to lipid intake, Outcome 12 Weight change z‐score to 1 month.

Weight change z‐score to discharge (Analysis 9.13): Studies that commenced early lipid infusion reported no difference in weight change z‐score to discharge (MD 0.01, 95% CI ‐0.33 to 0.36; participants = 207; studies = 2).

9.13. Analysis.

Comparison 9 Higher versus lower amino acid intake in parenteral nutrition: subgrouped according to lipid intake, Outcome 13 Weight change z‐score to discharge.

Weight change z‐score post discharge (Analysis 9.14): Studies that commenced early lipid infusion reported no difference in weight change z‐score post discharge (MD 0.13, 95% CI ‐0.26 to 0.52; participants = 201; studies = 2).

9.14. Analysis.

Comparison 9 Higher versus lower amino acid intake in parenteral nutrition: subgrouped according to lipid intake, Outcome 14 Weight change z‐score post discharge.

Head circumference change z‐score to one month (Analysis 9.15): Studies that commenced early lipid infusion reported an increase in head circumference change z‐score to one month (MD 0.27, 95% CI 0.08 to 0.46; participants = 231; studies = 2).

9.15. Analysis.

Comparison 9 Higher versus lower amino acid intake in parenteral nutrition: subgrouped according to lipid intake, Outcome 15 Head circumference change z‐score to 1 month.

Head circumference change z‐score to discharge (Analysis 9.16): Studies that commenced early lipid infusion reported no difference in head circumference change z‐score to discharge (MD 0.18, 95% CI ‐0.15 to 0.50; participants = 207; studies = 2).

9.16. Analysis.

Comparison 9 Higher versus lower amino acid intake in parenteral nutrition: subgrouped according to lipid intake, Outcome 16 Head circumference change z‐score to discharge.

Head circumference change z‐score post discharge (Analysis 9.17): Studies that commenced early lipid infusion reported no difference in head circumference change z‐score post discharge (MD 0.25, 95% CI ‐0.14 to 0.64; participants = 201; studies = 2).

9.17. Analysis.

Comparison 9 Higher versus lower amino acid intake in parenteral nutrition: subgrouped according to lipid intake, Outcome 17 Head circumference change z‐score post discharge.

Days to full enteral feeds (Analysis 9.18): Studies reported no differences overall (MD ‐0.19, 95% CI ‐1.07 to 0.70; participants = 778; studies = 11) and no significant subgroup difference in days to full enteral feeds; testing for subgroup differences: P = 0.44; I² = 0%.

9.18. Analysis.

Comparison 9 Higher versus lower amino acid intake in parenteral nutrition: subgrouped according to lipid intake, Outcome 18 Days to full enteral feeds.

Late‐onset sepsis (Analysis 9.19): Data show no differences overall (typical RR 0.96, 95% CI 0.79 to 1.18; participants = 1255; studies = 15), no differences for subgroups, and no significant subgroup difference in late‐onset sepsis; testing for subgroup differences: P = 0.90, I² = 0%.

9.19. Analysis.

Comparison 9 Higher versus lower amino acid intake in parenteral nutrition: subgrouped according to lipid intake, Outcome 19 Late‐onset sepsis.

Necrotising enterocolitis (Analysis 9.20): Data show no differences overall, no differences for subgroups, and no significant subgroup difference in necrotising enterocolitis (typical RR 1.00, 95% CI 0.68 to 1.47; participants = 1301; studies = 14); testing for subgroup differences: P = 0.72, I² = 0%.

9.20. Analysis.

Comparison 9 Higher versus lower amino acid intake in parenteral nutrition: subgrouped according to lipid intake, Outcome 20 Necrotising enterocolitis.

Chronic lung disease (Analysis 9.21): Data show no differences in chronic lung disease (typical RR 1.04, 95% CI 0.89 to 1.23; participants = 819; studies = 10) and no significant subgroup difference according to age at commencement of lipid; testing for subgroup differences: P = 0.07, I² = 63.1%.

9.21. Analysis.

Comparison 9 Higher versus lower amino acid intake in parenteral nutrition: subgrouped according to lipid intake, Outcome 21 Chronic lung disease ≥ 36 weeks' PMA.

Patent ductus arteriosus (Analysis 9.22): Data show a reduction in patent ductus arteriosus (typical RR 0.78, 95% CI 0.61 to 0.99; participants = 480; studies = 6) and no significant subgroup difference according to age at commencement of lipid; testing for subgroup differences: P = 0.26, I² = 25.5%.

9.22. Analysis.

Comparison 9 Higher versus lower amino acid intake in parenteral nutrition: subgrouped according to lipid intake, Outcome 22 Patent ductus arteriosus.

Intraventricular haemorrhage (Analysis 9.23): Data show no differences in intraventricular haemorrhage (typical RR 1.12, 95% CI 0.74 to 1.69; participants = 341; studies = 3) and no significant subgroup difference according to age at commencement of lipid; testing for subgroup differences: P = 0.81, I² = 0%.

9.23. Analysis.

Comparison 9 Higher versus lower amino acid intake in parenteral nutrition: subgrouped according to lipid intake, Outcome 23 Intraventricular haemorrhage.

Severe intraventricular haemorrhage (Analysis 9.24): Data show no differences in severe intraventricular haemorrhage (typical RR 1.16, 95% CI 0.74 to 1.82; participants = 904; studies = 11) and no significant subgroup difference according to age at commencement of lipid; testing for subgroup differences: P = 0.54, I² = 0%.

9.24. Analysis.

Comparison 9 Higher versus lower amino acid intake in parenteral nutrition: subgrouped according to lipid intake, Outcome 24 Severe intraventricular haemorrhage.

Periventricular leukomalacia (Analysis 9.25): Data show no difference in periventricular leukomalacia (typical RR 0.55, 95% CI 0.24 to 1.25; participants = 720; studies = 7) and no significant subgroup difference according to age at commencement of lipid; testing for subgroup differences: P = 0.48, I² = 0%.

9.25. Analysis.

Comparison 9 Higher versus lower amino acid intake in parenteral nutrition: subgrouped according to lipid intake, Outcome 25 Periventricular leukomalacia.

Retinopathy of prematurity (Analysis 9.26): Data show a reduction in retinopathy of prematurity (typical RR 0.44, 95% CI 0.21 to 0.93; participants = 269; studies = 4) and no significant subgroup difference according to age at commencement of lipid; testing for subgroup differences: P = 0.11, I² = 60.6%. Subgroup analysis showed a reduction for studies commencing early lipid infusion (typical RR 0.32, 95% CI 0.13 to 0.77; participants = 146; studies = 3). A single study of infants who did not receive lipid infusion reported no difference (RR 1.58, 95% CI 0.27 to 9.10; participants = 123) (Balasubramanian 2013).

9.26. Analysis.

Comparison 9 Higher versus lower amino acid intake in parenteral nutrition: subgrouped according to lipid intake, Outcome 26 Retinopathy of prematurity.

Severe retinopathy of prematurity (Analysis 9.27): Data show no difference in severe retinopathy of prematurity (typical RR 0.96, 95% CI 0.56 to 1.63; participants = 672; studies = 8) and no significant subgroup difference according to age at commencement of lipid; testing for subgroup differences: P = 0.58, I² = 0%.

9.27. Analysis.

Comparison 9 Higher versus lower amino acid intake in parenteral nutrition: subgrouped according to lipid intake, Outcome 27 Severe retinopathy of prematurity > stage 2 or treated.

Cerebral palsy (Analysis 9.28): Studies that commenced early lipid infusion reported no difference in cerebral palsy (typical RR 4.00, 95% CI 0.89 to 17.97; participants = 122; studies = 2).

9.28. Analysis.

Comparison 9 Higher versus lower amino acid intake in parenteral nutrition: subgrouped according to lipid intake, Outcome 28 Cerebral palsy.

Developmental delay at ≥ 18 months (Analysis 9.29): Data show no difference overall in developmental delay at ≥ 18 months (typical RR 1.35, 95% CI 0.52 to 3.53; participants = 301; studies = 3) and no significant subgroup difference according to age at commencement of lipid; testing for subgroup differences: P = 0.37, I² = 0%.

9.29. Analysis.

Comparison 9 Higher versus lower amino acid intake in parenteral nutrition: subgrouped according to lipid intake, Outcome 29 Developmental delay at ≥ 18 months.

Blindness (Analysis 9.30): Studies that commenced early lipid infusion reported no difference in blindness (typical RR 2.00, 95% CI 0.20 to 19.91; participants = 122; studies = 2).

9.30. Analysis.

Comparison 9 Higher versus lower amino acid intake in parenteral nutrition: subgrouped according to lipid intake, Outcome 30 Blindness.

Deafness (Analysis 9.31): A single study that commenced early lipid infusion reported no infant with deafness in either group (Vlaardingerbroek 2013).

9.31. Analysis.

Comparison 9 Higher versus lower amino acid intake in parenteral nutrition: subgrouped according to lipid intake, Outcome 31 Deafness.

Abnormal serum ammonia (Analysis 9.32): A single study that commenced early lipid infusion reported an abnormal serum ammonia > 122 μmol/L in one infant on higher amino acid intake (Blanco 2008).

9.32. Analysis.

Comparison 9 Higher versus lower amino acid intake in parenteral nutrition: subgrouped according to lipid intake, Outcome 32 Abnormal serum ammonia.

Abnormal blood urea nitrogen (Analysis 9.33): Data show an increase in abnormal blood urea nitrogen overall (typical RR 2.77, 95% CI 2.13 to 3.61; participants = 688; studies = 7) with no significant subgroup difference according to age at commencement of lipid; testing for subgroup differences: P = 0.68, I² = 0%. Data show an increase in abnormal blood urea nitrogen in studies commencing early lipid infusion (typical RR 2.66, 95% CI 1.95 to 3.64; participants = 489; studies = 5). Studies that commenced lipid at ≥ 5 days reported a significant increase in abnormal blood urea nitrogen (typical RR 3.01, 95% CI 1.83 to 4.95; participants = 199; studies = 2).

9.33. Analysis.

Comparison 9 Higher versus lower amino acid intake in parenteral nutrition: subgrouped according to lipid intake, Outcome 33 Abnormal blood urea nitrogen.

Hyperglycaemia (Analysis 9.34): Data show a reduction in hyperglycaemia overall (typical RR 0.69, 95% CI 0.49 to 0.96; participants = 505; studies = 5) and no significant subgroup difference according to age at commencement of lipid; testing for subgroup differences: P = 0.08, I² = 68.1%. Studies that commenced early lipid infusion reported no difference in hyperglycaemia (typical RR 0.84, 95% CI 0.57 to 1.22; participants = 306; studies = 3). Studies that delayed lipid infusion ≥ 5 days reported a reduction in hyperglycaemia (typical RR 0.39, 95% CI 0.18 to 0.83; participants = 199; studies = 2).

9.34. Analysis.

Comparison 9 Higher versus lower amino acid intake in parenteral nutrition: subgrouped according to lipid intake, Outcome 34 Hyperglycaemia, plasma glucose > 8.3 mmol/L.

Hyperglycaemia treated with insulin (Analysis 9.35): Data show no difference in hyperglycaemia treated with insulin (typical RR 1.24, 95% CI 0.93 to 1.66; participants = 534; studies = 5) and no significant subgroup difference according to age at commencement of lipid; testing for subgroup differences: P = 0.25, I² = 24%. Studies that commenced early lipid infusion reported no difference in hyperglycaemia treated with insulin (typical RR 1.29, 95% CI 0.96 to 1.73; participants = 420; studies = 4). A single study that delayed lipid infusion ≥ 5 days reported no difference in hyperglycaemia treated with insulin (RR 0.35, 95% CI 0.04 to 3.22; participants = 114) (Burattini 2013).

9.35. Analysis.

Comparison 9 Higher versus lower amino acid intake in parenteral nutrition: subgrouped according to lipid intake, Outcome 35 Hyperglycaemia treated with insulin.

Hypoglycaemia (Analysis 9.36): Data show no difference in hypoglycaemia overall (typical RR 1.17, 95% CI 0.84 to 1.63; participants = 376; studies = 3) and no significant subgroup difference according to age at commencement of lipid; testing for subgroup differences: P = 0.45, I² = 0%.

9.36. Analysis.

Comparison 9 Higher versus lower amino acid intake in parenteral nutrition: subgrouped according to lipid intake, Outcome 36 Hypoglycaemia.

Metabolic acidosis (Analysis 9.37): Data show no difference in metabolic acidosis (typical RR 2.05, 95% CI 0.94 to 4.47; participants = 305; studies = 4) and no significant subgroup difference according to age at commencement of lipid; testing for subgroup differences: P = 0.27, I² = 17.4%.

9.37. Analysis.

Comparison 9 Higher versus lower amino acid intake in parenteral nutrition: subgrouped according to lipid intake, Outcome 37 Metabolic acidosis.

Cholestasis (Analysis 9.38): Data show no difference in cholestasis overall (typical RR 1.26, 95% CI 0.86 to 1.84; participants = 616; studies = 5) and no significant subgroup difference according to age at commencement of lipid; testing for subgroup differences: P = 0.11, I² = 63.7%. No study reported cholestasis in the absence of parenteral lipid administration.

9.38. Analysis.

Comparison 9 Higher versus lower amino acid intake in parenteral nutrition: subgrouped according to lipid intake, Outcome 38 Cholestasis.

Higher versus lower amino acid intake in parenteral nutrition: sensitivity analysis (allocation concealment, adequate randomisation, blinding of treatment, less than 10% loss to follow‐up)

Primary outcomes

Mortality to discharge (Analysis 10.1): High‐quality studies reported no difference in mortality (typical RR 0.74, 95% CI 0.42 to 1.29; participants = 568; studies = 5).

10.1. Analysis.

Comparison 10 Higher versus lower amino acid intake in parenteral nutrition: sensitivity analysis (allocation concealment, adequate randomisation, blinding of treatment, less than 10% loss to follow‐up), Outcome 1 Mortality before hospital discharge.

Neurodevelopmental disability (Analysis 10.2): Both studies reporting neurodevelopmental disability had methodological concerns.

10.2. Analysis.

Comparison 10 Higher versus lower amino acid intake in parenteral nutrition: sensitivity analysis (allocation concealment, adequate randomisation, blinding of treatment, less than 10% loss to follow‐up), Outcome 2 Neurodevelopmental disability.

Postnatal growth failure at discharge (Analysis 10.3): A single study at low risk of bias reported a reduction in postnatal growth failure at discharge (RR 0.59, 95% CI 0.39 to 0.88; participants = 50) (Can 2012).

10.3. Analysis.

Comparison 10 Higher versus lower amino acid intake in parenteral nutrition: sensitivity analysis (allocation concealment, adequate randomisation, blinding of treatment, less than 10% loss to follow‐up), Outcome 3 Postnatal growth failure at discharge.

Postnatal growth failure post discharge (Analysis 10.4): A single study reporting postnatal growth failure post discharge did not report the method of sequence generation and had imbalances between groups (te Braake 2005).

10.4. Analysis.

Comparison 10 Higher versus lower amino acid intake in parenteral nutrition: sensitivity analysis (allocation concealment, adequate randomisation, blinding of treatment, less than 10% loss to follow‐up), Outcome 4 Postnatal growth failure post discharge.

Secondary outcomes

Days to regain birth weight (Analysis 10.5): High‐quality studies reported no difference in days to regain birth weight (MD ‐0.49, 95% CI ‐1.87 to 0.89; participants = 94; studies = 2).

10.5. Analysis.

Comparison 10 Higher versus lower amino acid intake in parenteral nutrition: sensitivity analysis (allocation concealment, adequate randomisation, blinding of treatment, less than 10% loss to follow‐up), Outcome 5 Days to regain birth weight.

Maximal weight loss grams (Analysis 10.6): A single study at low risk of bias reported no difference in maximal weight loss in grams (MD 22.60, 95% CI ‐7.25 to 52.45; participants = 50) (Can 2012).

10.6. Analysis.

Comparison 10 Higher versus lower amino acid intake in parenteral nutrition: sensitivity analysis (allocation concealment, adequate randomisation, blinding of treatment, less than 10% loss to follow‐up), Outcome 6 Maximal weight loss (grams).

Maximal weight loss in per cent (Analysis 10.7): No high‐quality studies reported maximal weight loss in per cent.

10.7. Analysis.

Comparison 10 Higher versus lower amino acid intake in parenteral nutrition: sensitivity analysis (allocation concealment, adequate randomisation, blinding of treatment, less than 10% loss to follow‐up), Outcome 7 Maximal weight loss %.

Weight gain to one month (Analysis 10.8): A single study at low risk of bias reported no difference in weight gain to one month (MD 1.50, 95% CI ‐0.27 to 3.27; participants = 122) (Clark 2007).

10.8. Analysis.

Comparison 10 Higher versus lower amino acid intake in parenteral nutrition: sensitivity analysis (allocation concealment, adequate randomisation, blinding of treatment, less than 10% loss to follow‐up), Outcome 8 Weight gain g/kg/day up to 1 month age.

Weight gain to discharge (Analysis 10.9): No high‐quality studies reported weight gain to discharge.

10.9. Analysis.

Comparison 10 Higher versus lower amino acid intake in parenteral nutrition: sensitivity analysis (allocation concealment, adequate randomisation, blinding of treatment, less than 10% loss to follow‐up), Outcome 9 Weight gain g/kg/day to discharge.

Linear growth to one month (Analysis 10.10): A single study at low risk of bias reported no difference in linear growth to one month (MD 0.00, 95% CI ‐0.15 to 0.15; participants = 122) (Clark 2007).

10.10. Analysis.

Comparison 10 Higher versus lower amino acid intake in parenteral nutrition: sensitivity analysis (allocation concealment, adequate randomisation, blinding of treatment, less than 10% loss to follow‐up), Outcome 10 Linear growth cm/week up to 1 month age.

Head circumference growth to one month (Analysis 10.11): High‐quality studies reported an increase in head circumference growth at one month (MD 0.09, 95% CI 0.02 to 0.15; participants = 257; studies = 2).

10.11. Analysis.

Comparison 10 Higher versus lower amino acid intake in parenteral nutrition: sensitivity analysis (allocation concealment, adequate randomisation, blinding of treatment, less than 10% loss to follow‐up), Outcome 11 Head circumference growth cm/week up to 1 month age.

Head circumference growth to discharge (Analysis 10.12): No study at low risk of bias reported head circumference growth to discharge.

10.12. Analysis.

Comparison 10 Higher versus lower amino acid intake in parenteral nutrition: sensitivity analysis (allocation concealment, adequate randomisation, blinding of treatment, less than 10% loss to follow‐up), Outcome 12 Head circumference growth cm/week to discharge.

Weight change in z‐score (Analysis 10.13; Analysis 10.14; Analysis 10.15): No high‐quality studies reported weight change in z‐score at any time point.

10.13. Analysis.

Comparison 10 Higher versus lower amino acid intake in parenteral nutrition: sensitivity analysis (allocation concealment, adequate randomisation, blinding of treatment, less than 10% loss to follow‐up), Outcome 13 Weight change z‐score up to 1 month age.

10.14. Analysis.

Comparison 10 Higher versus lower amino acid intake in parenteral nutrition: sensitivity analysis (allocation concealment, adequate randomisation, blinding of treatment, less than 10% loss to follow‐up), Outcome 14 Weight change z‐score to discharge.

10.15. Analysis.

Comparison 10 Higher versus lower amino acid intake in parenteral nutrition: sensitivity analysis (allocation concealment, adequate randomisation, blinding of treatment, less than 10% loss to follow‐up), Outcome 15 Weight change z‐score post discharge.

Head circumference change z‐score (Analysis 10.16): A single study reported an increase in head circumference change z‐score at one month (MD 0.37, 95% CI 0.15 to 0.59; participants = 135) (Morgan 2014). No study at low risk of bias reported head circumference change z‐score at any other time point (Analysis 10.17; Analysis 10.18).

10.16. Analysis.

Comparison 10 Higher versus lower amino acid intake in parenteral nutrition: sensitivity analysis (allocation concealment, adequate randomisation, blinding of treatment, less than 10% loss to follow‐up), Outcome 16 Head circumference change z‐score up to 1 month.

10.17. Analysis.

Comparison 10 Higher versus lower amino acid intake in parenteral nutrition: sensitivity analysis (allocation concealment, adequate randomisation, blinding of treatment, less than 10% loss to follow‐up), Outcome 17 Head circumference change z‐score to discharge.

10.18. Analysis.

Comparison 10 Higher versus lower amino acid intake in parenteral nutrition: sensitivity analysis (allocation concealment, adequate randomisation, blinding of treatment, less than 10% loss to follow‐up), Outcome 18 Head circumference change z‐score post discharge.

Days to full enteral feeds (Analysis 10.19): High‐quality studies reported no difference in days to full enteral feeds (MD ‐0.20, 95% CI ‐1.60 to 1.20; participants = 169; studies = 3).

10.19. Analysis.

Comparison 10 Higher versus lower amino acid intake in parenteral nutrition: sensitivity analysis (allocation concealment, adequate randomisation, blinding of treatment, less than 10% loss to follow‐up), Outcome 19 Days to full enteral feeds.

Late‐onset sepsis (Analysis 10.20): High‐quality studies reported no difference in late‐onset sepsis (typical RR 1.03, 95% CI 0.72 to 1.46; participants = 293; studies = 3).

10.20. Analysis.

Comparison 10 Higher versus lower amino acid intake in parenteral nutrition: sensitivity analysis (allocation concealment, adequate randomisation, blinding of treatment, less than 10% loss to follow‐up), Outcome 20 Late‐onset sepsis.

Necrotising enterocolitis (Analysis 10.21): Studies at low risk of bias reported no difference in necrotising enterocolitis (typical RR 0.89, 95% CI 0.50 to 1.60; participants = 511; studies = 5).

10.21. Analysis.

Comparison 10 Higher versus lower amino acid intake in parenteral nutrition: sensitivity analysis (allocation concealment, adequate randomisation, blinding of treatment, less than 10% loss to follow‐up), Outcome 21 Necrotising enterocolitis.

Chronic lung disease (Analysis 10.22): Studies at low risk of bias reported no difference in chronic lung disease (typical RR 1.02, 95% CI 0.79 to 1.31; participants = 177; studies = 2).

10.22. Analysis.

Comparison 10 Higher versus lower amino acid intake in parenteral nutrition: sensitivity analysis (allocation concealment, adequate randomisation, blinding of treatment, less than 10% loss to follow‐up), Outcome 22 Chronic lung disease at ≥ 36 weeks' PMA.

Intraventricular haemorrhage (Analysis 10.23): A single study at low risk of bias reported no difference in intraventricular haemorrhage (RR 1.05, 95% CI 0.64 to 1.73; participants = 122) (Clark 2007).

10.23. Analysis.

Comparison 10 Higher versus lower amino acid intake in parenteral nutrition: sensitivity analysis (allocation concealment, adequate randomisation, blinding of treatment, less than 10% loss to follow‐up), Outcome 23 Intraventricular haemorrhage.

Severe intraventricular haemorrhage (Analysis 10.24): Studies at low risk of bias reported no difference in severe intraventricular haemorrhage (typical RR 1.42, 95% CI 0.66 to 3.03; participants = 343; studies = 4).

10.24. Analysis.

Comparison 10 Higher versus lower amino acid intake in parenteral nutrition: sensitivity analysis (allocation concealment, adequate randomisation, blinding of treatment, less than 10% loss to follow‐up), Outcome 24 Severe intraventricular haemorrhage.

Periventricular leukomalacia (Analysis 10.25): Studies at low risk of bias reported no difference in periventricular leukomalacia (typical RR 0.61, 95% CI 0.21 to 1.81; participants = 299; studies = 3).

10.25. Analysis.

Comparison 10 Higher versus lower amino acid intake in parenteral nutrition: sensitivity analysis (allocation concealment, adequate randomisation, blinding of treatment, less than 10% loss to follow‐up), Outcome 25 Periventricular leukomalacia.

Retinopathy of prematurity (Analysis 10.26): A single study at low risk of bias reported a reduction in retinopathy of prematurity (RR 0.16, 95% CI 0.04 to 0.67; participants = 75) (Can 2012).

10.26. Analysis.

Comparison 10 Higher versus lower amino acid intake in parenteral nutrition: sensitivity analysis (allocation concealment, adequate randomisation, blinding of treatment, less than 10% loss to follow‐up), Outcome 26 Retinopathy of prematurity.

Severe retinopathy of prematurity (Analysis 10.27): Studies at low risk of bias reported no difference in severe retinopathy of prematurity (typical RR 0.77, 95% CI 0.36 to 1.66; participants = 252; studies = 3).

10.27. Analysis.

Comparison 10 Higher versus lower amino acid intake in parenteral nutrition: sensitivity analysis (allocation concealment, adequate randomisation, blinding of treatment, less than 10% loss to follow‐up), Outcome 27 Severe retinopathy of prematurity (> stage 2 or treated).

Neurodevelopment (Analysis 10.28; Analysis 10.29; Analysis 10.30; Analysis 10.31): No study at low risk of bias reported neurodevelopmental outcomes (cerebral palsy, developmental delay, blindness or deafness).

10.28. Analysis.

Comparison 10 Higher versus lower amino acid intake in parenteral nutrition: sensitivity analysis (allocation concealment, adequate randomisation, blinding of treatment, less than 10% loss to follow‐up), Outcome 28 Cerebral palsy.

10.29. Analysis.

Comparison 10 Higher versus lower amino acid intake in parenteral nutrition: sensitivity analysis (allocation concealment, adequate randomisation, blinding of treatment, less than 10% loss to follow‐up), Outcome 29 Developmental delay at ≥ 18 months.

10.30. Analysis.

Comparison 10 Higher versus lower amino acid intake in parenteral nutrition: sensitivity analysis (allocation concealment, adequate randomisation, blinding of treatment, less than 10% loss to follow‐up), Outcome 30 Blindness.

10.31. Analysis.

Comparison 10 Higher versus lower amino acid intake in parenteral nutrition: sensitivity analysis (allocation concealment, adequate randomisation, blinding of treatment, less than 10% loss to follow‐up), Outcome 31 Deafness.

Abnormal serum ammonia (Analysis 10.32): A single study at low risk of bias for biochemical outcomes reported an abnormal serum ammonia > 122 μmol/L in one infant on higher amino acid intake (Blanco 2008).

10.32. Analysis.

Comparison 10 Higher versus lower amino acid intake in parenteral nutrition: sensitivity analysis (allocation concealment, adequate randomisation, blinding of treatment, less than 10% loss to follow‐up), Outcome 32 Abnormal serum ammonia > 122 μmol/L.

Abnormal blood urea nitrogen (Analysis 10.33): Studies at low risk of bias reported an increase in abnormal blood urea nitrogen (typical RR 12.29, 95% CI 1.66 to 90.79; participants = 183; studies = 2).

10.33. Analysis.

Comparison 10 Higher versus lower amino acid intake in parenteral nutrition: sensitivity analysis (allocation concealment, adequate randomisation, blinding of treatment, less than 10% loss to follow‐up), Outcome 33 Abnormal blood urea nitrogen.

Hyperglycaemia (Analysis 10.34): No studies at low risk of bias reported hyperglycaemia.

10.34. Analysis.

Comparison 10 Higher versus lower amino acid intake in parenteral nutrition: sensitivity analysis (allocation concealment, adequate randomisation, blinding of treatment, less than 10% loss to follow‐up), Outcome 34 Hyperglycaemia, plasma glucose > 8.3 mmol/L.

Hyperglycaemia treated with insulin (Analysis 10.35): No studies at low risk of bias reported hyperglycaemia treated with insulin.

10.35. Analysis.

Comparison 10 Higher versus lower amino acid intake in parenteral nutrition: sensitivity analysis (allocation concealment, adequate randomisation, blinding of treatment, less than 10% loss to follow‐up), Outcome 35 Hyperglycaemia treated with insulin.

Hypoglycaemia (Analysis 10.36): No studies at low risk of bias reported hypoglycaemia.

10.36. Analysis.

Comparison 10 Higher versus lower amino acid intake in parenteral nutrition: sensitivity analysis (allocation concealment, adequate randomisation, blinding of treatment, less than 10% loss to follow‐up), Outcome 36 Hypoglycaemia.

Metabolic acidosis (Analysis 10.37): No studies at low risk of bias reported metabolic acidosis.

10.37. Analysis.

Comparison 10 Higher versus lower amino acid intake in parenteral nutrition: sensitivity analysis (allocation concealment, adequate randomisation, blinding of treatment, less than 10% loss to follow‐up), Outcome 37 Metabolic acidosis.

Cholestasis (Analysis 10.38): Studies at low risk of bias reported no difference in cholestasis (typical RR 1.21, 95% CI 0.67 to 2.17; participants = 249; studies = 2).

10.38. Analysis.

Comparison 10 Higher versus lower amino acid intake in parenteral nutrition: sensitivity analysis (allocation concealment, adequate randomisation, blinding of treatment, less than 10% loss to follow‐up), Outcome 38 Cholestasis.

Discussion

Summary of main results

Primary outcomes

Higher amino acid intake in parenteral nutrition did not affect mortality (GRADE level of evidence: low ‐ see grading of evidence summary (Table 1. We downgraded the quality of evidence owing to imprecision and potential for publication or reporting bias. We found no significant mortality differences in subgroup analyses according to amino acid intake at commencement, at maximal intake, or at commencement and maximal intake; according to management of caloric balance (non‐protein caloric intake); in very preterm or very low birth weight infants; according to age of commencement; or according to timing of lipid intake. We found insufficient evidence to determine an effect on neurodevelopment and found no reported benefit (GRADE level of evidence: very low). We downgraded the quality of evidence owing to risk of bias, inconsistency, imprecision, and potential for publication or reporting bias.

We found that higher amino acid intake in parenteral nutrition was associated with a reduction in postnatal growth failure at discharge (number needed to treat for an additional beneficial outcome (NNTB) 7, 95% confidence interval (CI) 4 to 50) (GRADE level of evidence: very low). We downgraded the quality of evidence owing to risk of bias, imprecision, and potential for publication or reporting bias. Subgroup analyses revealed a significant reduction in postnatal growth failure at discharge for infants commenced on high amino acid intake (> 2 to ≤ 3 g/kg/d); with increased amino acid and non‐protein caloric intake; commenced on intake at < 24 hours' age; and given an early lipid infusion.

Secondary outcomes

Growth outcomes

Higher amino acid intake in parenteral nutrition was associated with a reduction in days to regain birth weight. Subgroup analysis showed that the reduction in days to regain birth weight was consistent for studies that commenced on high amino acid intake (> 2 to ≤ 3 g/kg/d); that reported high maximal amino acid intake (> 3 to ≤ 4 g/kg/d); that provided isocaloric non‐protein intake; that reported increased non‐protein intake with higher amino acid intake; that commenced amino acids early (at < 24 hours' age); and that provided an early lipid infusion.

Growth effects were variable at other time points. Higher amino acid intake in parenteral nutrition reduced maximal weight loss in studies reporting effects in grams but not in studies reporting per cent. Analyses of weight loss in grams and per cent incorporated different studies. Results showed a reduction in weight gain up to one month but no significant difference to discharge (GRADE level of evidence: very low). For weight gain to one month, studies that commenced higher amino acid with an early lipid infusion reported no difference. A single study that provided no lipid infusion reported reduced weight and length gain to one month in infants who received higher amino acids (Balasubramanian 2013). In contrast, analyses revealed no difference in head circumference growth at one month but an increase in head circumference growth to discharge among infants receiving higher amino acid intake (GRADE level of evidence: very low). Subgroup analyses showed a significant increase in head circumference growth to discharge for infants on high amino acid intake (> 2 to ≤ 3 g/kg/d) at commencement; and for infants on high amino acid intake (> 3 to ≤ 4 g/kg/d) at maximal intake. Effects on anthropometric z‐scores were not consistent at any time point.

Clinical outcomes

Analysis revealed no effect from higher amino acid intake in parenteral nutrition on days to full enteral feeds, late‐onset sepsis, necrotising enterocolitis, chronic lung disease, intraventricular haemorrhage, severe intraventricular haemorrhage, or periventricular leukomalacia. Higher amino acid intake in parenteral nutrition was associated with a reduction in retinopathy of prematurity (NNTB 12.5, 95% CI 6.7 to 100) (GRADE level of evidence: very low). Heterogeneity between studies was high. Subgroup analyses that found a significant reduction in retinopathy of prematurity included studies commencing high amino acid intake (> 2 to ≤ 3 g/kg/d); that increased both amino acids and non‐protein energy intake; commencing amino acid intake early; and commencing early lipid infusion. However, analyses revealed no difference in severe retinopathy of prematurity.

Although we found no significant difference overall in periventricular leukomalacia, we did find a reduction in periventricular leukomalacia when performing subgroup analyses of studies that commenced low amino acid intake (> 1 to ≤ 2 g/kg/d); that reported high maximal amino acid intake (> 3 to ≤ 4 g/kg/d); and that increased amino acids and provided isocaloric non‐protein intake.

Biochemical outcomes

Higher amino acid intake in parenteral nutrition was associated with an increase in protein and nitrogen balance, which increased with increasing amino acid intake. Trials reported potential biochemical intolerances. All nine infants with a serum ammonia > 69 μmol/L and the only infant with ammonia > 122 μmol/L were included in the higher amino acid group. Data show a substantially increased risk of abnormal blood urea nitrogen (typical risk ratio (RR) 2.77, 95% CI 2.13 to 3.61; participants = 688; studies = 7; I² = 6%; risk difference (RD) 0.26, 95% CI 0.20 to 0.32; number needed to treat for an additional harmful outcome (NNTH) 4, 95% CI 3 to 5) (GRADE level of evidence: high). Studies had variable reporting levels for abnormal blood urea levels. However, when analysis is restricted to studies reporting blood urea levels above those reported in foetuses (Ridout 2005: > 14.3 mmol/L), the effect remains significant.

Higher amino acid intake in parenteral nutrition was associated with a reduction in hyperglycaemia (> 8.3 mmol/L), although the incidence of hyperglycaemia treated with insulin was not significantly different. Subgroup analyses found reduced hyperglycaemia in studies that commenced high amino acid intake (> 2 to ≤ 3 g/kg/d); that had high amino acid intake (> 3 to ≤ 4 g/kg/d) at maximal intake; that increased amino acids whilst providing isocaloric non‐protein intake; and that delayed lipid infusion for five days or longer. Although the data show no difference in hyperglycaemia treated with insulin overall, subgroup analyses revealed increases in studies that commenced on low amino acid intake (> 1 to ≤ 2 g/kg/d); that reported high amino acid intake (> 3 to ≤ 4 g/kg/d) at maximal intake; that increased amino acids and non‐protein energy intake; that included very preterm or very low birth weight infants; that commenced amino acids early; and that commenced lipid early.

Data show no differences in the incidence of hypoglycaemia or metabolic acidosis or cholestasis.

Overall completeness and applicability of evidence

We report substantial limitations to the overall completeness and applicability of evidence. Of the 31 included studies, six were short‐term biochemical studies (Anderson 1979; Murdock 1995; Rivera 1993; Thureen 2003; van Goudoever 1995; van Lingen 1992), one was a trial that enrolled term surgical infants (Hata 2002), and another included infants at > 35 weeks (Makay 2007) ‐ all without substantial clinical reporting. We could not included in meta‐analysis data from another study (Pildes 1973). One study has not yet published data (Kashyap 2007). The 21 remaining trials assessed various aspects of parenteral nutrition including higher amino acid intake at commencement (nine studies), higher maximal amino acid intake (two studies), higher amino acid intake at commencement and maximal intake (10 studies), and a higher rate of grading (one study).

Of the 21 studies reporting clinical effects included in this review, outcome reporting was variable both for outcomes reported and for timing of reporting. Outcomes reported by more than 50% of studies (≥ 10 of 21) included mortality (14 studies), days to regain birth weight (13 studies), late‐onset sepsis (15 studies), necrotising enterocolitis (14 studies), chronic lung disease (10 studies), and severe intraventricular haemorrhage (11 studies).

A minority of studies reported extremely preterm (< 28 weeks' gestation) or extremely low birth weight infants (< 1000 grams) separately, so we did not undertake subgroup analysis. However, most trials enrolled very low birth weight or very preterm infants (n = 26) and included extremely preterm or extremely low birth weight infants. Concerns related to biochemical tolerance are particularly applicable to these infants.

Studies had differing non‐protein nutritional practices and variously provided isocaloric non‐protein caloric intake to both higher and lower amino acid groups (Anderson 1979; Balasubramanian 2013; Blanco 2008; Burattini 2013; Clark 2007; Hata 2002; Heimler 2010; Kashyap 2007; Liu 2015; Pildes 1973; Rivera 1993; Scattolin 2013; Tang 2009; te Braake 2005; Thureen 2003; van Goudoever 1995; van Lingen 1992; Vlaardingerbroek 2013; Uthaya 2016; Weiler 2006; Xie 2014) or increasing non‐protein caloric intake through a concomitant increase in lipid infusion (Black 1981; Bulbul 2012; Can 2012; Can 2013; Ibrahim 2004; Makay 2007; Murdock 1995; Pappoe 2009; Tan 2008; Vaidya 1995). A single study increased both glucose and lipid intake (Morgan 2014).

Studies also reported variable enteral nutritional practices including commencing early enteral feeds in both groups (Bulbul 2012; Burattini 2013; Can 2012; Can 2013; Clark 2007; Kashyap 2007; Liu 2015; Morgan 2014; Pildes 1973; Scattolin 2013; Tan 2008; te Braake 2005; Uthaya 2016; Vaidya 1995; Weiler 2006) and providing no enteral feeds (Anderson 1979; Hata 2002; Makay 2007; Murdock 1995; Rivera 1993; Thureen 2003; van Goudoever 1995; van Lingen 1992; Vlaardingerbroek 2013) or delayed enteral feeds (Heimler 2010; Ibrahim 2004); three studies did not describe enteral feeding practices (Blanco 2008; Tang 2009; Xie 2014). This review excluded studies that described different enteral feeding regimens between the two groups so does not assess studies that compared effects of higher parenteral and enteral amino acid/protein intake versus lower parenteral and enteral intake.

This review did not assess amino acid profiles, as they are also a reflection of the specific amino acid solution given. Biochemical safety in terms of hyper‐aminoacidaemia cannot be assumed from this review, and the safety of specific preparations must be assessed.

This review did not perform a subgroup analysis according to specific amino acid solution used. It is possible that clinical and biochemical effects may vary with the specific amino acid solution used.

Quality of the evidence

Review authors expressed substantial concern regarding publication or reporting bias for most outcomes, given that most outcomes were underreported. One potentially eligible study has not published outcomes to date (Kashyap 2007). We assessed only five studies as high quality with low risk of bias from allocation concealment, randomisation, blinding of treatment, and less than 10% loss to follow‐up (Bulbul 2012; Can 2012; Can 2013; Clark 2007; Morgan 2014). Blanco 2008 also met these criteria for mortality and biochemical outcome reporting but not for other clinical and developmental outcomes. Uthaya 2016 was at low risk of bias for reporting mortality, sepsis, and necrotising enterocolitis but was at high risk of attrition bias for other outcomes. All other studies had methodological concerns, which included not reporting method of sequence generation and being at high risk for performance and detection bias and for attrition bias.

Sensitivity analysis restricted to studies at low risk of bias supported the findings of no effect on mortality. No studies at low risk of bias reported neurodevelopmental disability. A single study at low risk of bias reported reduction in postnatal growth failure at discharge (Can 2012). Meta‐analysis of two studies at low risk of bias revealed no difference in days to regain birth weight (Bulbul 2012; Can 2012). A single study at low risk of bias reported no difference in maximal weight loss in grams (Can 2012). Meta‐analysis of two studies at low risk of bias revealed an increase in head circumference growth at one month (Clark 2007; Morgan 2014), and Morgan 2014 reported an increase in head circumference change z‐score at one month. No study at low risk of bias reported head circumference growth to discharge.

Meta‐analysis of studies at low risk of bias showed no difference in days to full enteral feeds; late‐onset sepsis and necrotising enterocolitis; or chronic lung disease. A single study at low risk of bias reported no difference in intraventricular haemorrhage (Clark 2007). Meta‐analysis of studies at low risk of bias revealed no difference in severe intraventricular haemorrhage nor in periventricular leukomalacia. A single study at low risk of bias reported a reduction in retinopathy of prematurity (Can 2012). Meta‐analysis of studies at low risk of bias showed no difference in severe retinopathy of prematurity. No study at low risk of bias reported neurodevelopmental outcomes.

A single study at low risk of bias for biochemical outcomes reported an abnormal serum ammonia > 122 μmol/L in one infant on higher amino acid intake (Blanco 2008). Meta‐analysis of two studies at low risk of bias revealed an increase in abnormal blood urea nitrogen (Blanco 2008; Clark 2007). No studies at low risk of bias reported hyperglycaemia, hyperglycaemia treated with insulin, hypoglycaemia, or metabolic acidosis. Meta‐analysis of studies at low risk of bias showed no difference in cholestasis.

We graded the evidence for no effect on mortality as low quality and downgraded evidence owing to lack of precision, which does not preclude a significant effect, particularly as a substantial number of studies did not report mortality. We graded evidence showing reduction in postnatal growth failure as very low. We downgraded the evidence as only a single study was at low risk of bias (this study reported a significant effect), confidence intervals were wide showing close to no effect, and a substantial number of studies did not report the outcome. We graded evidence for other growth and clinical effects as very low. We graded evidence for an increase in abnormal blood urea nitrogen as high owing to the magnitude and consistency of findings, including those reported by studies at low risk of bias.

Potential biases in the review process

We reported several outcomes in the overall review analysis that were not prespecified, including weight, length, and head circumference; weight, length, and head circumference z‐scores; patent ductus arteriosus; development quotient scores; nitrogen and protein balance; maximal blood urea nitrogen; and hyperkalaemia and discontinued parenteral nutrition (PN) due to biochemical intolerance. As these outcomes were not prespecified, we did not include them in subsequent comparisons and subgroup analyses.

We did not prespecify the additional subgroup analysis according to lipid intake.

We modified data extraction for abnormal blood urea nitrogen to adapt to reported data. Of seven trials that reported abnormal blood urea nitrogen (BUN), one did not document criteria, three were at or above the prespecified level (BUN > 14.3 to 21.4 mmol/L), and three were below the prespecified reporting level (two studies BUN > 10 mmol/L, and one study BUN > 11.6 mmol/L).

For studies that reported non‐parametric data, we calculated means and standard deviations using medians and interquartile ranges, which we did not prespecify.

Agreements and disagreements with other studies or reviews

The findings of this review are largely consistent with those of the Cochrane Review "Early versus late administration of amino acids in preterm infants receiving parenteral nutrition" (Trivedi 2013), which reported that "early administration of amino acids results in positive nitrogen balance. Metabolic acidosis, elevated serum ammonia and hypoglycaemia were not a complication of early administration of amino acids. Elevated blood urea nitrogen is consistently associated with early administration of amino acids." Elevated blood urea nitrogen levels reported in this review are above those reported in normal foetuses from cord blood, as in Gresham 1971, and in newborn infants receiving a mean 1.8 g/kg/d parenteral nutrition, as in Ridout 2005. However, it is unclear what ammonia levels are normal in preterm infants. All six infants with an ammonia > 69 μmol/L ‐ the level seen in infants after the first week ‐ were receiving higher levels of amino acid. The biochemical safety of very high early amino acid intake in parenteral nutrition remains unclear.

The Cochrane Review "Early introduction of lipids to parenterally‐fed preterm infants" reported that "no statistically significant effects of 'early introduction' of lipids on short‐term nutritional or other clinical outcomes, either benefits or adverse effects, were demonstrated in the studies reviewed" (Simmer 2006). That review did not report biochemical tolerance. The findings of our review that early lipid intake may have potential subgroup effects including increased growth, reduced glucose tolerance, reduced retinopathy of prematurity, and increased chronic lung disease are related to the effects of higher amino acid intake in parenteral nutrition in the context of early lipid intake.

Authors' conclusions

Implications for practice.

Low‐quality evidence suggests that higher amino acid (AA) intake in parenteral nutrition does not affect mortality. Very low‐quality evidence suggests that higher AA intake reduces the incidence of postnatal growth failure. Subgroup analysis revealed high commencement of amino acid intake (> 2 to ≤ 3 g/kg/d), increased amino acid and non‐protein caloric intakes, early commencement of intake (< 24 hours' age), and early lipid infusion were associated with reduced postnatal growth failure. We found insufficient evidence to determine an effect on neurodevelopment and discovered that clinical effects of higher commencement or maximal amino acid intake were not consistent. Very low‐quality evidence suggests that higher AA intake reduces retinopathy of prematurity but not severe retinopathy of prematurity. Higher AA intake was associated with potentially adverse biochemical effects including azotaemia.

Implications for research.

Adequately powered trials in very preterm infants are required to determine the effects of optimal intake and balance of amino acids in parenteral nutrition on the brain and on neurodevelopment. Further trials are required to identify effects of higher amino acid intake in parenteral nutrition on retinopathy of prematurity and periventricular leukomalacia. Limited data from this review suggest that higher amino acid intake in parenteral nutrition may be associated with a reduction in retinopathy of prematurity. Subgroup analysis suggests effects from commencing high (> 2 to ≤ 3 g/kg/d) amino acid intake; increasing both amino acid and non‐protein caloric intake; providing intake for very preterm or very low birth weight infants; commencing intake at < 24 hours' age; and providing an early lipid infusion. Subgroup analysis also suggests a possible reduction in periventricular leukomalacia in studies that commenced low amino acid intake (> 1 to ≤ 2 g/kg/d) and in studies that reported high maximal amino acid intake (> 3 to ≤ 4 g/kg/d).

Higher amino acid intake was associated with a reduction in hyperglycaemia (> 8.3 mmol/L), although the incidence of hyperglycaemia treated with insulin was not significantly different. Subgroup analyses showed reduced hyperglycaemia in studies that commenced high amino acid intake (> 2 to ≤ 3 g/kg/d); that had high amino acid intake (> 3 to ≤ 4 g/kg/d) at maximal intake; that increased amino acids whilst providing isocaloric non‐protein intake; and that delayed lipid infusion for five days or longer.

Higher amino acid intake in parenteral nutrition was associated with some evidence of biochemical intolerance, with increasing numbers of infants showing abnormal blood urea nitrogen. Subgroup analysis did not identify a threshold for amino acid intake associated with abnormal blood urea nitrogen. Further trials are required to determine the effects of optimal intake and balance of amino acids, particularly at commencement of parenteral nutrition, on biochemical tolerance, growth, the brain, and neurodevelopment. Trials should use standardised anthropometric measures to facilitate interpretation and meta‐analysis of data.

Given that trials frequently reported failure to achieve target intakes of amino acids (parenteral and enteral), trials examining optimal intake of amino acid at commencement and maximal intake are required.

Appendices

Appendix 1. CENTRAL search strategy September 2016

"amino acid" and "parenteral nutrition" and "newborn" = 140 records

Appendix 2. MEDLINE and Embase search strategy September 2016

#5 #4 AND ('clinical trial'/de OR 'controlled clinical trial'/de OR 'controlled study'/de OR 'randomised controlled trial'/de) = 221 records

#4 #1 AND #2 AND #3 = 877

#3 'parenteral nutrition'/exp OR 'parenteral nutrition' = 42,145

#2 'amino acid'/exp OR 'amino acid' = 1,504,241

#1 'newborn'/exp OR newborn = 570,100

Appendix 3. Updated search strategy June 2017

PubMed: (amino acid OR amino acid[MeSH]) AND (parenteral nutrition OR parenteral nutrition[MeSH])

Other databases: (amino acid) AND (parenteral nutrition)

Plus the following database‐specific terms:

PubMed: ((infant, newborn[MeSH] OR newborn OR neonate OR neonatal OR premature OR low birth weight OR VLBW OR LBW or infan* or neonat*) AND (randomized controlled trial [pt] OR controlled clinical trial [pt] OR Clinical Trial[ptyp] OR randomized [tiab] OR placebo [tiab] OR clinical trials as topic [mesh: noexp] OR randomly [tiab] OR trial [ti]) NOT (animals [mh] NOT humans [mh]))

Embase: (infant, newborn or newborn or neonate or neonatal or premature or very low birth weight or low birth weight or VLBW or LBW or Newborn or infan* or neonat*) AND (human not animal) AND (randomized controlled trial or controlled clinical trial or randomized or placebo or clinical trials as topic or randomly or trial or clinical trial)

CINAHL: (infant, newborn OR newborn OR neonate OR neonatal OR premature OR low birth weight OR VLBW OR LBW or Newborn or infan* or neonat*) AND (randomized controlled trial OR controlled clinical trial OR randomized OR placebo OR clinical trials as topic OR randomly OR trial OR PT clinical trial)

Cochrane Library: (infant or newborn or neonate or neonatal or premature or very low birth weight or low birth weight or VLBW or LBW)

Total Studies Found: 33

Appendix 4. Risk of bias tool

1. RANDOM SEQUENCE GENERATION Selection bias (biased allocation to interventions) due to inadequate generation of a randomised sequence
Criteria for a judgement of ‘low risk’ of bias	The investigators describe a random component in the sequence generation process such as: Referring to a random number table; Using a computer random number generator; Coin tossing; Shuffling cards or envelopes; Throwing dice; Drawing of lots; or Minimisation*. *Minimisation may be implemented without a random element, and this is considered equivalent to being random.
Criteria for a judgement of ‘high risk’ of bias	The investigators describe a non‐random component in the sequence generation process. Usually, the description would involve some systematic, non‐random approach, for example: Sequence generated by odd or even date of birth; Sequence generated by some rule based on date (or day) of admission; or Sequence generated by some rule based on hospital or clinic record number. Other non‐random approaches happen much less frequently than the systematic approaches mentioned above and tend to be obvious. They usually involve judgement or some method of non‐random categorisation of participants, for example: Allocation by judgement of the clinician; Allocation by preference of the participant; Allocation based on the results of a laboratory test or a series of tests; or Allocation by availability of the intervention.
Criteria for a judgement of ‘unclear risk’ of bias	Insufficient information about the sequence generation process to permit judgement of ‘low risk’ or ‘high risk’
2. ALLOCATION CONCEALMENT Selection bias (biased allocation to interventions) due to inadequate concealment of allocations before assignment
Criteria for a judgement of ‘low risk’ of bias	Participants and investigators enrolling participants could not foresee assignment because one of the following, or an equivalent method, was used to conceal allocation: Central allocation (including telephone, Web‐based, and pharmacy‐controlled randomisation); Sequentially numbered drug containers of identical appearance; or Sequentially numbered, opaque, sealed envelopes.
Criteria for a judgement of ‘high risk’ of bias	Participants or investigators enrolling participants could possibly foresee assignments and thus introduce selection bias, such as allocation based on: Using an open random allocation schedule (e.g. a list of random numbers); Using assignment envelopes without appropriate safeguards (e.g. if envelopes were unsealed or non­opaque or were not sequentially numbered); Alternation or rotation; Date of birth; Case record number; or Any other explicitly unconcealed procedure.
Criteria for a judgement of ‘unclear risk’ of bias	Insufficient information to permit judgement of ‘low risk’ or ‘high risk’. This is usually the case if the method of concealment is not described or is not described in sufficient detail to allow a definitive judgement – for example, if use of assignment envelopes is described, but it remains unclear whether envelopes were sequentially numbered, opaque, and sealed.
3. BLINDING OF PARTICIPANTS AND PERSONNEL Performance bias due to knowledge of allocated interventions by participants and personnel during the study
Criteria for a judgement of ‘low risk’ of bias	Any one of the following: No blinding or incomplete blinding, but the review authors judge that the outcome is not likely to be influenced by lack of blinding; or Blinding of participants and key study personnel ensured, and unlikely that the blinding could have been broken.
Criteria for a judgement of ‘high risk’ of bias	Any one of the following: No blinding or incomplete blinding, and the outcome is likely to be influenced by lack of blinding; or Blinding of key study participants and personnel attempted, but likely that the blinding could have been broken, and the outcome is likely to be influenced by lack of blinding.
Criteria for a judgement of ‘unclear risk’ of bias	Any one of the following: Insufficient information to permit judgement of ‘low risk’ or ‘high risk’; or The study did not address this outcome.
4. BLINDING OF OUTCOME ASSESSMENT Detection bias due to knowledge of allocated interventions by outcome assessors
Criteria for a judgement of ‘low risk’ of bias	Any one of the following: No blinding of outcome assessment, but the review authors judge that the outcome measurement is not likely to be influenced by lack of blinding; or Blinding of outcome assessment ensured, and unlikely that the blinding could have been broken.
Criteria for a judgement of ‘high risk’ of bias	Any one of the following: No blinding of outcome assessment, and the outcome measurement is likely to be influenced by lack of blinding; or Blinding of outcome assessment, but likely that the blinding could have been broken, and the outcome measurement is likely to be influenced by lack of blinding.
Criteria for a judgement of ‘unclear risk’ of bias	Any one of the following: Insufficient information to permit judgement of ‘low risk’ or ‘high risk’; or The study did not address this outcome.
5. INCOMPLETE OUTCOME DATA Attrition bias due to quantity, nature, or handling of incomplete outcome data
Criteria for a judgement of ‘low risk’ of bias	Any one of the following: No missing outcome data; Reasons for missing outcome data unlikely to be related to true outcome (for survival data, censoring unlikely to be introducing bias); Missing outcome data balanced in numbers across intervention groups, with similar reasons for missing data across groups; For dichotomous outcome data, the proportion of missing outcomes compared with observed event risk not enough to have a clinically relevant impact on the intervention effect estimate; For continuous outcome data, plausible effect size (difference in means or standardised difference in means) among missing outcomes not enough to have a clinically relevant impact on observed effect size; or Missing data have been imputed using appropriate methods.
Criteria for a judgement of ‘high risk’ of bias	Any one of the following: Reason for missing outcome data likely to be related to true outcome, with either imbalance in numbers or reasons for missing data across intervention groups; For dichotomous outcome data, the proportion of missing outcomes compared with observed event risk enough to induce clinically relevant bias in intervention effect estimate; For continuous outcome data, plausible effect size (difference in means or standardised difference in means) among missing outcomes enough to induce clinically relevant bias in observed effect size; "As‐treated" analysis done with substantial departure of the intervention received from that assigned at randomisation; or Potentially inappropriate application of simple imputation.
Criteria for a judgement of ‘unclear risk’ of bias	Any one of the following: Insufficient reporting of attrition/exclusions to permit judgement of ‘low risk’ or ‘high risk’ (e.g. number randomised not stated, no reasons for missing data provided); or The study did not address this outcome.
6. SELECTIVE REPORTING Reporting bias due to selective outcome reporting
Criteria for a judgement of ‘low risk’ of bias	Any of the following: The study protocol is available and all of the study’s prespecified (primary and secondary) outcomes of interest in the review have been reported in the prespecified way; or The study protocol is not available but it is clear that published reports include all expected outcomes, including those that were prespecified (convincing text of this nature may be uncommon).
Criteria for a judgement of ‘high risk’ of bias	Any one of the following: Not all of the study’s prespecified primary outcomes have been reported; One or more primary outcomes is reported by measurements, analysis methods, or subsets of the data (e.g. subscales) that were not prespecified; One or more reported primary outcomes were not prespecified (unless clear justification for their reporting is provided, such as an unexpected adverse effect); One or more outcomes of interest in the review are reported incompletely so that they cannot be entered in a meta‐analysis; or The study report fails to include results for a key outcome that would be expected to have been reported for such a study.
Criteria for a judgement of ‘unclear risk’ of bias	Insufficient information to permit judgement of ‘low risk’ or ‘high risk’. It is likely that most studies will fall into this category.
7. OTHER BIAS Bias due to problems not covered elsewhere in the table
Criteria for a judgement of ‘low risk’ of bias	The study appears to be free of other sources of bias.
Criteria for a judgement of ‘high risk’ of bias	There is at least one important risk of bias. For example, the study: Had a potential source of bias related to the specific study design used; Has been claimed to have been fraudulent; or Had some other problem.
Criteria for a judgement of ‘unclear risk’ of bias	There may be a risk of bias, but there is either: Insufficient information to assess whether an important risk of bias exists; or Insufficient rationale or evidence that an identified problem will introduce bias.

Data and analyses

Comparison 1. Higher versus lower amino acid intake in parenteral nutrition.

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Mortality to hospital discharge	14	1407	Risk Ratio (M‐H, Fixed, 95% CI)	0.90 [0.69, 1.17]
2 Neurodevelopmental disability	2	201	Risk Ratio (M‐H, Fixed, 95% CI)	1.04 [0.48, 2.23]
3 Postnatal growth failure at discharge (weight < 10th centile)	3	203	Risk Ratio (M‐H, Fixed, 95% CI)	0.74 [0.56, 0.97]
4 Postnatal growth failure at discharge (weight 2 SD below mean)	1	114	Risk Ratio (M‐H, Fixed, 95% CI)	0.96 [0.66, 1.40]
5 Postnatal growth failure post discharge	1	111	Risk Ratio (M‐H, Fixed, 95% CI)	0.66 [0.33, 1.32]
6 Days to regain birth weight	13	950	Mean Difference (IV, Fixed, 95% CI)	‐1.14 [‐1.73, ‐0.56]
7 Maximal weight loss (grams)	3	235	Mean Difference (IV, Fixed, 95% CI)	‐22.71 [‐33.68, ‐11.74]
8 Maximal weight loss %	4	288	Mean Difference (IV, Fixed, 95% CI)	‐0.33 [‐1.61, 0.96]
9 Weight gain g/kg/d	7		Mean Difference (IV, Fixed, 95% CI)	Subtotals only
9.1 To 1 month age	4	373	Mean Difference (IV, Fixed, 95% CI)	‐1.50 [‐2.56, ‐0.44]
9.2 To discharge	4	291	Mean Difference (IV, Fixed, 95% CI)	0.76 [‐0.02, 1.54]
10 Linear growth cm/week	2		Mean Difference (IV, Fixed, 95% CI)	Subtotals only
10.1 To 1 month age	2	245	Mean Difference (IV, Fixed, 95% CI)	‐0.16 [‐0.26, ‐0.06]
11 Head circumference growth cm/week	7		Mean Difference (IV, Fixed, 95% CI)	Subtotals only
11.1 To 1 month age	4	476	Mean Difference (IV, Fixed, 95% CI)	0.01 [‐0.04, 0.06]
11.2 To discharge	4	315	Mean Difference (IV, Fixed, 95% CI)	0.09 [0.06, 0.13]
12 Weight change z‐score	2		Mean Difference (IV, Fixed, 95% CI)	Subtotals only
12.1 To 1 month age	1	96	Mean Difference (IV, Fixed, 95% CI)	‐0.20 [‐0.62, 0.22]
12.2 To discharge	2	207	Mean Difference (IV, Fixed, 95% CI)	0.01 [‐0.33, 0.36]
12.3 Post discharge	2	201	Mean Difference (IV, Fixed, 95% CI)	0.13 [‐0.26, 0.52]
13 Head circumference change z‐score	3		Mean Difference (IV, Fixed, 95% CI)	Subtotals only
13.1 To 1 month age	2	231	Mean Difference (IV, Fixed, 95% CI)	0.27 [0.08, 0.46]
13.2 To discharge	2	207	Mean Difference (IV, Fixed, 95% CI)	0.18 [‐0.15, 0.50]
13.3 Post discharge	2	201	Mean Difference (IV, Fixed, 95% CI)	0.25 [‐0.14, 0.64]
14 Weight (grams)	12		Mean Difference (IV, Fixed, 95% CI)	Subtotals only
14.1 At 1 month age	4	430	Mean Difference (IV, Fixed, 95% CI)	‐18.45 [‐68.42, 31.52]
14.2 At discharge	10	874	Mean Difference (IV, Fixed, 95% CI)	81.07 [36.59, 125.56]
14.3 Post discharge	2	211	Mean Difference (IV, Fixed, 95% CI)	‐11.07 [‐493.31, 471.18]
15 Length (cm)	8		Mean Difference (IV, Fixed, 95% CI)	Subtotals only
15.1 At 1 month age	3	295	Mean Difference (IV, Fixed, 95% CI)	‐0.41 [‐1.03, 0.20]
15.2 At discharge	6	553	Mean Difference (IV, Fixed, 95% CI)	0.57 [0.17, 0.98]
15.3 Post discharge	1	100	Mean Difference (IV, Fixed, 95% CI)	‐0.10 [‐1.81, 1.61]
16 Head circumference (cm)	11		Mean Difference (IV, Fixed, 95% CI)	Subtotals only
16.1 At 1 month age	4	430	Mean Difference (IV, Fixed, 95% CI)	0.19 [‐0.13, 0.51]
16.2 At discharge	9	834	Mean Difference (IV, Fixed, 95% CI)	0.08 [‐0.14, 0.29]
16.3 Post discharge	2	211	Mean Difference (IV, Fixed, 95% CI)	‐0.04 [‐0.52, 0.44]
17 Weight z‐score	3		Mean Difference (IV, Fixed, 95% CI)	Subtotals only
17.1 Up at 1 month age	1	135	Mean Difference (IV, Fixed, 95% CI)	0.14 [‐0.11, 0.39]
17.2 At discharge	3	352	Mean Difference (IV, Fixed, 95% CI)	0.16 [‐0.02, 0.33]
18 Length z‐score	2		Mean Difference (IV, Fixed, 95% CI)	Subtotals only
18.1 At discharge	2	228	Mean Difference (IV, Fixed, 95% CI)	0.12 [‐0.14, 0.38]
19 Head circumference z‐score	3		Mean Difference (IV, Fixed, 95% CI)	Subtotals only
19.1 At 1 month age	1	135	Mean Difference (IV, Fixed, 95% CI)	0.30 [0.01, 0.59]
19.2 At discharge	3	354	Mean Difference (IV, Fixed, 95% CI)	0.04 [‐0.18, 0.26]
19.3 Post discharge	1	100	Mean Difference (IV, Fixed, 95% CI)	‐0.01 [‐0.50, 0.48]
20 Days to full enteral feeds	11	778	Mean Difference (IV, Fixed, 95% CI)	‐0.19 [‐1.07, 0.70]
21 Late‐onset sepsis	15	1255	Risk Ratio (M‐H, Fixed, 95% CI)	0.96 [0.79, 1.18]
22 Necrotising enterocolitis	14	1301	Risk Ratio (M‐H, Fixed, 95% CI)	1.00 [0.68, 1.47]
23 Chronic lung disease at ≥ 36 weeks' PMA	10	819	Risk Ratio (M‐H, Fixed, 95% CI)	1.04 [0.89, 1.23]
24 Patent ductus arteriosus	7	607	Risk Ratio (M‐H, Fixed, 95% CI)	0.83 [0.67, 1.02]
25 Intraventricular haemorrhage	3	341	Risk Ratio (M‐H, Fixed, 95% CI)	1.12 [0.74, 1.69]
26 Severe intraventricular haemorrhage	11	904	Risk Ratio (M‐H, Fixed, 95% CI)	1.16 [0.74, 1.82]
27 Periventricular leukomalacia	7	720	Risk Ratio (M‐H, Fixed, 95% CI)	0.55 [0.24, 1.25]
28 Retinopathy of prematurity	4	269	Risk Ratio (M‐H, Fixed, 95% CI)	0.44 [0.21, 0.93]
29 Severe retinopathy of prematurity (> stage 2 or treated)	8	672	Risk Ratio (M‐H, Fixed, 95% CI)	0.96 [0.56, 1.63]
30 Cerebral palsy	2	122	Risk Ratio (M‐H, Fixed, 95% CI)	4.0 [0.89, 17.97]
31 Developmental delay at ≥ 18 months	3	301	Risk Ratio (M‐H, Fixed, 95% CI)	1.35 [0.52, 3.53]
32 Blindness	2	122	Risk Ratio (M‐H, Fixed, 95% CI)	2.0 [0.20, 19.91]
33 Deafness	1	90	Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
34 Bayley MDI at ≥ 18 months	2	105	Mean Difference (IV, Fixed, 95% CI)	‐4.18 [‐8.53, 0.17]
35 Bayley III score at ≥ 18 months	1	100	Mean Difference (IV, Fixed, 95% CI)	3.0 [‐2.52, 8.52]
36 Bayley PDI at ≥ 18 months	1	32	Mean Difference (IV, Fixed, 95% CI)	3.00 [‐6.41, 12.41]
37 Autism	1	32	Risk Ratio (M‐H, Fixed, 95% CI)	1.0 [0.07, 14.64]
38 Nitrogen balance	6	153	Mean Difference (IV, Fixed, 95% CI)	505.20 [492.01, 518.39]
38.1 AA 1.0 g/kg increase per day vs 0.5 g/kg increase per day	1	37	Mean Difference (IV, Fixed, 95% CI)	31.77 [‐61.98, 125.51]
38.2 AA 1.15 g/kg/day vs 0 g/kg/day	1	15	Mean Difference (IV, Fixed, 95% CI)	120.00 [21.10, 218.90]
38.3 AA 1.5 g/kg/day vs 0 g/kg/day	1	23	Mean Difference (IV, Fixed, 95% CI)	223.0 [182.18, 263.82]
38.4 AA 2.0‐2.5 g/kg/day vs 0‐0.4 g/kg/day	2	49	Mean Difference (IV, Fixed, 95% CI)	280.75 [234.74, 326.76]
38.5 AA 3.5 g/kg/day vs 0 g/kg/day	1	29	Mean Difference (IV, Fixed, 95% CI)	587.9 [572.92, 602.88]
39 Protein balance	3	52	Mean Difference (IV, Fixed, 95% CI)	1.57 [1.47, 1.66]
39.1 AA 1.5 g/kg/day vs 0 g/kg/day	1	12	Mean Difference (IV, Fixed, 95% CI)	1.1 [0.16, 2.04]
39.2 AA 2.3 g/kg/day vs 0 g/kg/day	1	18	Mean Difference (IV, Fixed, 95% CI)	2.0 [1.82, 2.18]
39.3 AA 3 g/kg/day vs 1 g/kg/day	1	22	Mean Difference (IV, Fixed, 95% CI)	1.42 [1.31, 1.53]
40 Abnormal serum ammonia	2		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only
40.1 Ammonia > 69 μmol/L	1	61	Risk Ratio (M‐H, Fixed, 95% CI)	13.42 [0.79, 228.24]
40.2 Ammonia > 100 μmol/L	2	105	Risk Ratio (M‐H, Fixed, 95% CI)	9.29 [0.52, 165.45]
40.3 Ammonia > 122 μmol/L	1	61	Risk Ratio (M‐H, Fixed, 95% CI)	3.10 [0.13, 73.16]
41 Abnormal blood urea nitrogen (various criteria)	7	688	Risk Ratio (M‐H, Fixed, 95% CI)	2.77 [2.13, 3.61]
41.1 AA started 0.5 g/kg/day and graded to 3.0 g/kg/day vs 0 g/kg/day: high BUN criteria not reported	1	85	Risk Ratio (M‐H, Fixed, 95% CI)	10.74 [1.45, 79.59]
41.2 AA started 2 g/kg/day and graded to 3.5 g/kg/day vs started 1.0 g/kg/day and graded to 3.5 g/kg/day: BUN > 14.3 mmol/L	1	42	Risk Ratio (M‐H, Fixed, 95% CI)	2.48 [0.28, 21.93]
41.3 AA started 1.5 g/kg/day and graded to 3.5 g/kg/day vs started 1.0 g/kg/day and graded to 2.5 g/kg/day: BUN > 17.85 mmol/L	1	122	Risk Ratio (M‐H, Fixed, 95% CI)	6.35 [0.34, 120.45]
41.4 AA started 2 g/kg/day and graded to 4.0 g/kg/day vs started 0.5 g/kg/day and graded to 3.0 g/kg/day: BUN > 21.4 mmol/L	1	61	Risk Ratio (M‐H, Fixed, 95% CI)	19.61 [1.19, 322.72]
41.5 AA started 2.5 g/kg/day and graded to 4.0 g/kg/day vs started 1.5 g/kg/day and graded to 2.5 g/kg/day: BUN > 11.6 mmol/L	1	114	Risk Ratio (M‐H, Fixed, 95% CI)	2.44 [1.47, 4.05]
41.6 AA started 3.6 g/kg/day vs started 1.7 g/kg/day amino acids and graded to 2.7 g/kg/day: BUN > 10 mmol/L	1	168	Risk Ratio (M‐H, Fixed, 95% CI)	2.73 [1.64, 4.54]
41.7 AA 3.6 g/kg/day vs 2.4 g/kg/day: BUN > 10 mmol/L	1	96	Risk Ratio (M‐H, Fixed, 95% CI)	2.09 [1.43, 3.04]
42 Maximum blood urea nitrogen mmol/L	2	159	Mean Difference (IV, Fixed, 95% CI)	4.48 [3.43, 5.53]
43 Hyperglycaemia, plasma glucose > 8.3 mmol/L	5	505	Risk Ratio (M‐H, Fixed, 95% CI)	0.69 [0.49, 0.96]
44 Hyperglycaemia treated with insulin	5	534	Risk Ratio (M‐H, Fixed, 95% CI)	1.24 [0.93, 1.66]
45 Hypoglycaemia	3	376	Risk Ratio (M‐H, Fixed, 95% CI)	1.17 [0.84, 1.63]
46 Metabolic acidosis	4	305	Risk Ratio (M‐H, Fixed, 95% CI)	2.05 [0.94, 4.47]
47 Cholestasis	5	616	Risk Ratio (M‐H, Fixed, 95% CI)	1.26 [0.86, 1.84]
48 Hyperkalaemia	1	61	Risk Ratio (M‐H, Fixed, 95% CI)	0.62 [0.16, 2.37]
49 Discontinued PN owing to biochemical intolerance	1	61	Risk Ratio (M‐H, Fixed, 95% CI)	13.42 [0.79, 228.24]

Comparison 2. Higher versus lower amino acid intake at commencement of parenteral nutrition: subgrouped by commencement intake.

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Mortality before hospital discharge	6	433	Risk Ratio (M‐H, Fixed, 95% CI)	0.78 [0.45, 1.36]
1.1 Low amino acid intake (> 1 to ≤ 2 g/kg/day)	1	42	Risk Ratio (M‐H, Fixed, 95% CI)	1.65 [0.16, 16.85]
1.2 High amino acid intake (> 2 to ≤ 3 g/kg/day)	3	263	Risk Ratio (M‐H, Fixed, 95% CI)	0.78 [0.35, 1.76]
1.3 Very high amino acid intake (> 3 g/kg/day)	2	128	Risk Ratio (M‐H, Fixed, 95% CI)	0.69 [0.30, 1.57]
2 Neurodevelopmental disability	2	201	Risk Ratio (M‐H, Fixed, 95% CI)	1.04 [0.48, 2.23]
2.1 High amino acid intake (> 2 to ≤ 3 g/kg/day)	1	111	Risk Ratio (M‐H, Fixed, 95% CI)	0.48 [0.18, 1.29]
2.2 Very high amino acid intake (> 3 g/kg/day)	1	90	Risk Ratio (M‐H, Fixed, 95% CI)	7.0 [0.90, 54.60]
3 Postnatal growth failure at discharge	3	203	Risk Ratio (M‐H, Fixed, 95% CI)	0.74 [0.56, 0.97]
3.1 Low amino acid intake (> 1 to ≤ 2 g/kg/day)	1	42	Risk Ratio (M‐H, Fixed, 95% CI)	0.95 [0.62, 1.46]
3.2 High amino acid intake (> 2 to ≤ 3 g/kg/day)	2	161	Risk Ratio (M‐H, Fixed, 95% CI)	0.67 [0.48, 0.94]
4 Postnatal growth failure post discharge	1	111	Risk Ratio (M‐H, Fixed, 95% CI)	0.66 [0.33, 1.32]
4.1 High amino acid intake (> 2 to ≤ 3 g/kg/day)	1	111	Risk Ratio (M‐H, Fixed, 95% CI)	0.66 [0.33, 1.32]
5 Days to regain birth weight	6	303	Mean Difference (IV, Fixed, 95% CI)	0.43 [‐0.51, 1.37]
5.1 Very low amino acid intake (≤ 1 g/kg/day)	1	27	Mean Difference (IV, Fixed, 95% CI)	‐1.45 [‐4.45, 1.56]
5.2 Low amino acid intake (> 1 to ≤ 2 g/kg/day)	2	59	Mean Difference (IV, Fixed, 95% CI)	‐1.40 [‐3.66, 0.85]
5.3 High amino acid intake (> 2 to ≤ 3 g/kg/day)	3	217	Mean Difference (IV, Fixed, 95% CI)	1.13 [0.02, 2.23]
6 Maximal weight loss (grams)	1	50	Mean Difference (IV, Fixed, 95% CI)	22.60 [‐7.25, 52.45]
6.1 High amino acid intake (> 2 to ≤ 3 g/kg/day)	1	50	Mean Difference (IV, Fixed, 95% CI)	22.60 [‐7.25, 52.45]
7 Maximal weight loss %	2	59	Mean Difference (IV, Fixed, 95% CI)	‐2.73 [‐5.71, 0.25]
7.1 Low amino acid intake (> 1 to ≤ 2 g/kg/day)	2	59	Mean Difference (IV, Fixed, 95% CI)	‐2.73 [‐5.71, 0.25]
8 Weight gain g/kg/day to 1 month age	2	219	Mean Difference (IV, Fixed, 95% CI)	‐3.17 [‐4.49, ‐1.84]
8.1 High amino acid intake (> 2 to ≤ 3 g/kg/day)	1	123	Mean Difference (IV, Fixed, 95% CI)	‐4.48 [‐6.17, ‐2.79]
8.2 Very high amino acid intake (> 3 g/kg/day)	1	96	Mean Difference (IV, Fixed, 95% CI)	‐1.10 [‐3.22, 1.02]
9 Weight gain g/kg/day to discharge	2	140	Mean Difference (IV, Fixed, 95% CI)	1.05 [‐0.55, 2.66]
9.1 Low amino acid intake (> 1 to ≤ 2 g/kg/day)	1	42	Mean Difference (IV, Fixed, 95% CI)	0.40 [‐1.69, 2.49]
9.2 Very high amino acid intake (> 3 g/kg/day)	1	98	Mean Difference (IV, Fixed, 95% CI)	2.0 [‐0.51, 4.51]
10 Linear growth cm/week to 1 month age	1	123	Mean Difference (IV, Fixed, 95% CI)	‐0.27 [‐0.40, ‐0.14]
10.1 High amino acid intake (> 2 to ≤ 3 g/kg/day)	1	123	Mean Difference (IV, Fixed, 95% CI)	‐0.27 [‐0.40, ‐0.14]
11 Head circumference growth cm/week to 1 month age	2	219	Mean Difference (IV, Fixed, 95% CI)	‐0.12 [‐0.21, ‐0.04]
11.1 High amino acid intake (> 2 to ≤ 3 g/kg/day)	1	123	Mean Difference (IV, Fixed, 95% CI)	‐0.38 [‐0.51, ‐0.24]
11.2 Very high amino acid intake (> 3 g/kg/day)	1	96	Mean Difference (IV, Fixed, 95% CI)	0.02 [‐0.09, 0.13]
12 Head circumference growth cm/week to discharge	1	96	Mean Difference (IV, Fixed, 95% CI)	0.03 [‐0.03, 0.09]
12.1 Very high amino acid intake (> 3 g/kg/day)	1	96	Mean Difference (IV, Fixed, 95% CI)	0.03 [‐0.03, 0.09]
13 Weight change z‐score to 1 month age	1	96	Mean Difference (IV, Fixed, 95% CI)	‐0.20 [‐0.62, 0.22]
13.1 Very high amino acid intake (> 3 g/kg/day)	1	96	Mean Difference (IV, Fixed, 95% CI)	‐0.20 [‐0.62, 0.22]
14 Weight change z‐score to discharge	2	207	Mean Difference (IV, Fixed, 95% CI)	0.01 [‐0.33, 0.36]
14.1 High amino acid intake (> 2 to ≤ 3 g/kg/day)	1	111	Mean Difference (IV, Fixed, 95% CI)	‐0.22 [‐0.70, 0.26]
14.2 Very high amino acid intake (> 3 g/kg/day)	1	96	Mean Difference (IV, Fixed, 95% CI)	0.27 [‐0.23, 0.77]
15 Weight change z‐score post discharge	2	201	Mean Difference (IV, Fixed, 95% CI)	0.13 [‐0.26, 0.52]
15.1 High amino acid intake (> 2 to ≤ 3 g/kg/day)	1	111	Mean Difference (IV, Fixed, 95% CI)	‐0.17 [‐0.75, 0.41]
15.2 Very high amino acid intake (> 3 g/kg/day)	1	90	Mean Difference (IV, Fixed, 95% CI)	0.38 [‐0.15, 0.91]
16 Head circumference change z‐score to 1 month age	1	96	Mean Difference (IV, Fixed, 95% CI)	0.0 [‐0.36, 0.36]
16.1 Very high amino acid intake (> 3 g/kg/day)	1	96	Mean Difference (IV, Fixed, 95% CI)	0.0 [‐0.36, 0.36]
17 Head circumference change z‐score to discharge	2	207	Mean Difference (IV, Fixed, 95% CI)	0.18 [‐0.15, 0.50]
17.1 High amino acid intake (> 2 to ≤ 3 g/kg/day)	1	111	Mean Difference (IV, Fixed, 95% CI)	‐0.15 [‐0.66, 0.36]
17.2 Very high amino acid intake (> 3 g/kg/day)	1	96	Mean Difference (IV, Fixed, 95% CI)	0.4 [‐0.02, 0.82]
18 Head circumference change z‐score post discharge	2	201	Mean Difference (IV, Fixed, 95% CI)	0.25 [‐0.14, 0.64]
18.1 High amino acid intake (> 2 to ≤ 3 g/kg/day)	1	111	Mean Difference (IV, Fixed, 95% CI)	0.03 [‐0.46, 0.52]
18.2 Very high amino acid intake (> 3 g/kg/day)	1	90	Mean Difference (IV, Fixed, 95% CI)	0.61 [‐0.02, 1.23]
19 Days to full enteral feeds	4	196	Mean Difference (IV, Fixed, 95% CI)	‐0.22 [‐1.60, 1.17]
19.1 Very low amino acid intake (≤ 1 g/kg/day)	1	27	Mean Difference (IV, Fixed, 95% CI)	‐0.91 [‐9.80, 7.98]
19.2 High amino acid intake (> 2 to ≤ 3 g/kg/day)	3	169	Mean Difference (IV, Fixed, 95% CI)	‐0.20 [‐1.60, 1.20]
20 Late‐onset sepsis	5	319	Risk Ratio (M‐H, Fixed, 95% CI)	0.94 [0.65, 1.38]
20.1 Very low amino acid intake (≤ 1 g/kg/day)	1	27	Risk Ratio (M‐H, Fixed, 95% CI)	1.08 [0.40, 2.88]
20.2 High amino acid intake (> 2 to ≤ 3 g/kg/day)	2	167	Risk Ratio (M‐H, Fixed, 95% CI)	0.84 [0.35, 2.00]
20.3 Very high amino acid intake (> 3 g/kg/day)	2	125	Risk Ratio (M‐H, Fixed, 95% CI)	0.96 [0.61, 1.52]
21 Necrotising enterocolitis	5	340	Risk Ratio (M‐H, Fixed, 95% CI)	0.96 [0.45, 2.03]
21.1 Very low amino acid intake (≤ 1 g/kg/day)	1	27	Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
21.2 High amino acid intake (> 2 to ≤ 3 g/kg/day)	3	217	Risk Ratio (M‐H, Fixed, 95% CI)	1.26 [0.55, 2.92]
21.3 Very high amino acid intake (> 3 g/kg/day)	1	96	Risk Ratio (M‐H, Fixed, 95% CI)	0.26 [0.03, 2.25]
22 Chronic lung disease at ≥ 36 weeks' PMA	4	202	Risk Ratio (M‐H, Fixed, 95% CI)	1.32 [0.86, 2.02]
22.1 Very low amino acid intake (≤ 1 g/kg/day)	1	27	Risk Ratio (M‐H, Fixed, 95% CI)	1.08 [0.34, 3.44]
22.2 High amino acid intake (> 2 to ≤ 3 g/kg/day)	1	50	Risk Ratio (M‐H, Fixed, 95% CI)	1.0 [0.07, 15.12]
22.3 Very high amino acid intake (> 3 g/kg/day)	2	125	Risk Ratio (M‐H, Fixed, 95% CI)	1.39 [0.87, 2.21]
23 Patent ductus arteriosus	4	244	Risk Ratio (M‐H, Fixed, 95% CI)	0.73 [0.50, 1.07]
23.1 Low amino acid intake (> 1 to ≤ 2 g/kg/day)	1	42	Risk Ratio (M‐H, Fixed, 95% CI)	1.05 [0.63, 1.74]
23.2 High amino acid intake (> 2 to ≤ 3 g/kg/day)	2	173	Risk Ratio (M‐H, Fixed, 95% CI)	0.42 [0.20, 0.89]
23.3 Very high amino acid intake (> 3 g/kg/day)	1	29	Risk Ratio (M‐H, Fixed, 95% CI)	1.07 [0.50, 2.28]
24 Intraventricular haemorrhage	1	123	Risk Ratio (M‐H, Fixed, 95% CI)	1.26 [0.41, 3.91]
24.1 High amino acid intake (> 2 to ≤ 3 g/kg/day)	1	123	Risk Ratio (M‐H, Fixed, 95% CI)	1.26 [0.41, 3.91]
25 Severe intraventricular haemorrhage	5	261	Risk Ratio (M‐H, Fixed, 95% CI)	1.44 [0.66, 3.17]
25.1 Low amino acid intake (> 1 to ≤ 2 g/kg/day)	1	42	Risk Ratio (M‐H, Fixed, 95% CI)	3.30 [0.40, 27.13]
25.2 High amino acid intake (> 2 to ≤ 3 g/kg/day)	2	94	Risk Ratio (M‐H, Fixed, 95% CI)	2.0 [0.19, 20.67]
25.3 Very high amino acid intake (> 3 g/kg/day)	2	125	Risk Ratio (M‐H, Fixed, 95% CI)	1.06 [0.42, 2.69]
26 Periventricular leukomalacia	2	146	Risk Ratio (M‐H, Fixed, 95% CI)	0.33 [0.01, 7.81]
26.1 High amino acid intake (> 2 to ≤ 3 g/kg/day)	1	50	Risk Ratio (M‐H, Fixed, 95% CI)	0.33 [0.01, 7.81]
26.2 Very high amino acid intake (> 3 g/kg/day)	1	96	Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
27 Retinopathy of prematurity	4	269	Risk Ratio (M‐H, Fixed, 95% CI)	0.44 [0.21, 0.93]
27.1 Low amino acid intake (> 1 to ≤ 2 g/kg/day)	1	42	Risk Ratio (M‐H, Fixed, 95% CI)	0.55 [0.10, 2.96]
27.2 High amino acid intake (> 2 to ≤ 3 g/kg/day)	2	198	Risk Ratio (M‐H, Fixed, 95% CI)	0.36 [0.14, 0.95]
27.3 Very high amino acid intake (> 3 g/kg/day)	1	29	Risk Ratio (M‐H, Fixed, 95% CI)	0.71 [0.14, 3.66]
28 Severe retinopathy of prematurity (> stage 2 or treated)	4	265	Risk Ratio (M‐H, Fixed, 95% CI)	0.47 [0.20, 1.11]
28.1 Low amino acid intake (> 1 to ≤ 2 g/kg/day)	1	42	Risk Ratio (M‐H, Fixed, 95% CI)	0.55 [0.10, 2.96]
28.2 High amino acid intake (> 2 to ≤ 3 g/kg/day)	2	125	Risk Ratio (M‐H, Fixed, 95% CI)	0.23 [0.06, 0.85]
28.3 Very high amino acid intake (> 3 g/kg/day)	1	98	Risk Ratio (M‐H, Fixed, 95% CI)	5.0 [0.25, 101.53]
29 Cerebral palsy	1	90	Risk Ratio (M‐H, Fixed, 95% CI)	5.0 [0.61, 41.11]
29.1 Very high amino acid intake (> 3 g/kg/day)	1	90	Risk Ratio (M‐H, Fixed, 95% CI)	5.0 [0.61, 41.11]
30 Developmental delay at ≥ 18 months	2	201	Risk Ratio (M‐H, Fixed, 95% CI)	1.04 [0.35, 3.11]
30.1 High amino acid intake (> 2 to ≤ 3 g/kg/day)	1	111	Risk Ratio (M‐H, Fixed, 95% CI)	0.84 [0.24, 2.98]
30.2 Very high amino acid intake (> 3 g/kg/day)	1	90	Risk Ratio (M‐H, Fixed, 95% CI)	2.0 [0.19, 21.28]
31 Blindness	1	90	Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
31.1 Very high amino acid intake (> 3 g/kg/day)	1	90	Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
32 Deafness	1	90	Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
32.1 Very high amino acid intake (> 3 g/kg/day)	1	90	Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
33 Abnormal serum ammonia (> 100 μmol/L)	1		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only
33.1 High amino acid intake (> 2 to ≤ 3 g/kg/day)	1	44	Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
34 Abnormal blood urea nitrogen (various criteria)	2	138	Risk Ratio (M‐H, Fixed, 95% CI)	2.11 [1.44, 3.08]
34.1 Low amino acid intake (> 1 to ≤ 2 g/kg/day)	1	42	Risk Ratio (M‐H, Fixed, 95% CI)	2.48 [0.28, 21.93]
34.2 Very high amino acid intake (> 3 g/kg/day)	1	96	Risk Ratio (M‐H, Fixed, 95% CI)	2.09 [1.43, 3.04]
35 Hyperglycaemia, plasma glucose > 8.3 mmol/L	1	42	Risk Ratio (M‐H, Fixed, 95% CI)	1.47 [0.85, 2.53]
35.1 Low amino acid intake (> 1 to ≤ 2 g/kg/day)	1	42	Risk Ratio (M‐H, Fixed, 95% CI)	1.47 [0.85, 2.53]
36 Hyperglycaemia treated with insulin	2	138	Risk Ratio (M‐H, Fixed, 95% CI)	1.84 [0.97, 3.49]
36.1 Low amino acid intake (> 1 to ≤ 2 g/kg/day)	1	42	Risk Ratio (M‐H, Fixed, 95% CI)	4.96 [1.26, 19.47]
36.2 Very high amino acid intake (> 3 g/kg/day)	1	96	Risk Ratio (M‐H, Fixed, 95% CI)	1.15 [0.54, 2.45]
37 Hypoglycaemia	1	123	Risk Ratio (M‐H, Fixed, 95% CI)	1.68 [0.83, 3.41]
37.1 High amino acid intake (> 2 to ≤ 3 g/kg/day)	1	123	Risk Ratio (M‐H, Fixed, 95% CI)	1.68 [0.83, 3.41]
38 Metabolic acidosis	1	15	Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
38.1 Low amino acid intake (> 1 to ≤ 2 g/kg/day)	1	15	Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]

Comparison 3. Higher versus lower amino acid intake at maximal intake of parenteral nutrition: subgrouped by maximal intake.

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Mortality before hospital discharge	2	292	Risk Ratio (M‐H, Fixed, 95% CI)	0.94 [0.57, 1.55]
1.1 High amino acid intake (> 3 to ≤ 4 g/kg/day)	2	292	Risk Ratio (M‐H, Fixed, 95% CI)	0.94 [0.57, 1.55]
2 Head circumference growth cm/week to 1 month	1	135	Mean Difference (IV, Fixed, 95% CI)	0.13 [0.05, 0.20]
2.1 High amino acid intake (> 3 to ≤ 4 g/kg/day)	1	135	Mean Difference (IV, Fixed, 95% CI)	0.13 [0.05, 0.20]
3 Head circumference change z‐score to 1 month	1	135	Mean Difference (IV, Fixed, 95% CI)	0.37 [0.15, 0.59]
3.1 High amino acid intake (> 3 to ≤ 4 g/kg/day)	1	135	Mean Difference (IV, Fixed, 95% CI)	0.37 [0.15, 0.59]
4 Days to regain birth weight	1	114	Mean Difference (IV, Fixed, 95% CI)	‐3.60 [‐5.88, ‐1.32]
4.1 High amino acid intake (> 3 to ≤ 4 g/kg/day)	1	114	Mean Difference (IV, Fixed, 95% CI)	‐3.60 [‐5.88, ‐1.32]
5 Days to full enteral feeds	1	114	Mean Difference (IV, Fixed, 95% CI)	4.0 [1.01, 6.99]
5.1 High amino acid intake (> 3 to ≤ 4 g/kg/day)	1	114	Mean Difference (IV, Fixed, 95% CI)	4.0 [1.01, 6.99]
6 Late‐onset sepsis	1	127	Risk Ratio (M‐H, Fixed, 95% CI)	0.94 [0.63, 1.41]
6.1 High amino acid intake (> 3 to ≤ 4 g/kg/day)	1	127	Risk Ratio (M‐H, Fixed, 95% CI)	0.94 [0.63, 1.41]
7 Necrotising enterocolitis	2	241	Risk Ratio (M‐H, Fixed, 95% CI)	0.76 [0.37, 1.59]
7.1 High amino acid intake (> 3 to ≤ 4 g/kg/day)	2	241	Risk Ratio (M‐H, Fixed, 95% CI)	0.76 [0.37, 1.59]
8 Chronic lung disease at ≥ 36 weeks' PMA	2	241	Risk Ratio (M‐H, Fixed, 95% CI)	1.10 [0.92, 1.31]
8.1 High amino acid intake (> 3 to ≤ 4 g/kg/day)	2	241	Risk Ratio (M‐H, Fixed, 95% CI)	1.10 [0.92, 1.31]
9 Patent ductus arteriosus	1	127	Risk Ratio (M‐H, Fixed, 95% CI)	1.02 [0.66, 1.56]
9.1 High amino acid intake (> 3 to ≤ 4 g/kg/day)	1	127	Risk Ratio (M‐H, Fixed, 95% CI)	1.02 [0.66, 1.56]
10 Severe intraventricular haemorrhage	2	241	Risk Ratio (M‐H, Fixed, 95% CI)	1.16 [0.51, 2.63]
10.1 High amino acid intake (> 3 to ≤ 4 g/kg/day)	2	241	Risk Ratio (M‐H, Fixed, 95% CI)	1.16 [0.51, 2.63]
11 Periventricular leukomalacia	1	127	Risk Ratio (M‐H, Fixed, 95% CI)	2.03 [0.39, 10.70]
11.1 High amino acid intake (> 3 to ≤ 4 g/kg/day)	1	127	Risk Ratio (M‐H, Fixed, 95% CI)	2.03 [0.39, 10.70]
12 Severe retinopathy of prematurity (> stage 2 or treated)	1	127	Risk Ratio (M‐H, Fixed, 95% CI)	2.71 [0.75, 9.75]
12.1 High amino acid intake (> 3 to ≤ 4 g/kg/day)	1	127	Risk Ratio (M‐H, Fixed, 95% CI)	2.71 [0.75, 9.75]
13 Hyperglycaemia treated with insulin	1	114	Risk Ratio (M‐H, Fixed, 95% CI)	1.69 [1.12, 2.53]
13.1 High amino acid intake (> 3 to ≤ 4 g/kg/day)	1	114	Risk Ratio (M‐H, Fixed, 95% CI)	1.69 [1.12, 2.53]
14 Cholestasis	2	241	Risk Ratio (M‐H, Fixed, 95% CI)	1.21 [0.76, 1.94]
14.1 High amino acid intake (> 3 to ≤ 4 g/kg/day)	2	241	Risk Ratio (M‐H, Fixed, 95% CI)	1.21 [0.76, 1.94]

Comparison 4. Higher versus lower amino acid intake at commencement and maximal intake of parenteral nutrition: subgrouped by commencement intake.

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Mortality to hospital discharge	5	567	Risk Ratio (M‐H, Fixed, 95% CI)	0.97 [0.66, 1.42]
1.1 Very low amino acid intake (≤ 1 g/kg/day)	1	85	Risk Ratio (M‐H, Fixed, 95% CI)	1.14 [0.72, 1.81]
1.2 Low amino acid intake (> 1 to ≤ 2 g/kg/day)	2	183	Risk Ratio (M‐H, Fixed, 95% CI)	1.61 [0.56, 4.57]
1.3 High amino acid intake (> 2 to ≤ 3 g/kg/day)	1	131	Risk Ratio (M‐H, Fixed, 95% CI)	0.84 [0.24, 2.98]
1.4 Very high amino acid intake (> 3 g/kg/day)	1	168	Risk Ratio (M‐H, Fixed, 95% CI)	0.45 [0.17, 1.25]
2 Days to regain birth weight	5	496	Mean Difference (IV, Fixed, 95% CI)	‐1.86 [‐2.79, ‐0.93]
2.1 Very low amino acid intake (≤ 1 g/kg/day)	1	85	Mean Difference (IV, Fixed, 95% CI)	‐1.0 [‐5.03, 3.03]
2.2 Low amino acid intake (> 1 to ≤ 2 g/kg/day)	1	115	Mean Difference (IV, Fixed, 95% CI)	‐1.33 [‐3.74, 1.08]
2.3 High amino acid intake (> 2 to ≤ 3 g/kg/day)	3	296	Mean Difference (IV, Fixed, 95% CI)	‐2.02 [‐3.06, ‐0.97]
3 Maximal weight loss (grams)	2	185	Mean Difference (IV, Fixed, 95% CI)	‐29.79 [‐41.58, ‐17.99]
3.1 High amino acid intake (> 2 to ≤ 3 g/kg/day)	2	185	Mean Difference (IV, Fixed, 95% CI)	‐29.79 [‐41.58, ‐17.99]
4 Maximal weight loss %	2	229	Mean Difference (IV, Fixed, 95% CI)	0.22 [‐1.20, 1.64]
4.1 Low amino acid intake (> 1 to ≤ 2 g/kg/day)	1	115	Mean Difference (IV, Fixed, 95% CI)	0.51 [‐1.66, 2.68]
4.2 High amino acid intake (> 2 to ≤ 3 g/kg/day)	1	114	Mean Difference (IV, Fixed, 95% CI)	0.0 [‐1.87, 1.87]
5 Weight gain g/kg/day up to 1 month age	2	154	Mean Difference (IV, Fixed, 95% CI)	1.48 [‐0.29, 3.25]
5.1 Low amino acid intake (> 1 to ≤ 2 g/kg/day)	2	154	Mean Difference (IV, Fixed, 95% CI)	1.48 [‐0.29, 3.25]
6 Weight gain g/kg/day to discharge	1	114	Mean Difference (IV, Fixed, 95% CI)	0.60 [‐0.34, 1.54]
6.1 High amino acid intake (> 2 to ≤ 3 g/kg/day)	1	114	Mean Difference (IV, Fixed, 95% CI)	0.60 [‐0.34, 1.54]
7 Linear growth cm/week up to 1 month age	1	122	Mean Difference (IV, Fixed, 95% CI)	0.0 [‐0.15, 0.15]
7.1 Low amino acid intake (> 1 to ≤ 2 g/kg/day)	1	122	Mean Difference (IV, Fixed, 95% CI)	0.0 [‐0.15, 0.15]
8 Head circumference growth cm/week up to 1 month age	1		Mean Difference (IV, Fixed, 95% CI)	Subtotals only
8.1 Low amino acid intake (> 1 to ≤ 2 g/kg/day)	1	122	Mean Difference (IV, Fixed, 95% CI)	0.0 [‐0.12, 0.12]
9 Head circumference growth cm/week to discharge	2	182	Mean Difference (IV, Fixed, 95% CI)	0.11 [0.07, 0.15]
9.1 High amino acid intake (> 2 to ≤ 3 g/kg/day)	2	182	Mean Difference (IV, Fixed, 95% CI)	0.11 [0.07, 0.15]
10 Days to full enteral feeds	5	431	Mean Difference (IV, Fixed, 95% CI)	‐1.08 [‐2.42, 0.25]
10.1 Low amino acid intake (> 1 to ≤ 2 g/kg/day)	2	147	Mean Difference (IV, Fixed, 95% CI)	2.47 [‐1.73, 6.68]
10.2 High amino acid intake (> 2 to ≤ 3 g/kg/day)	2	158	Mean Difference (IV, Fixed, 95% CI)	‐3.32 [‐5.39, ‐1.25]
10.3 Very high amino acid intake (> 3 g/kg/day)	1	126	Mean Difference (IV, Fixed, 95% CI)	0.09 [‐1.83, 2.01]
11 Late‐onset sepsis	8	772	Risk Ratio (M‐H, Fixed, 95% CI)	0.96 [0.72, 1.29]
11.1 Very low amino acid intake (≤ 1 g/kg/day)	2	106	Risk Ratio (M‐H, Fixed, 95% CI)	0.72 [0.27, 1.95]
11.2 Low amino acid intake (> 1 to ≤ 2 g/kg/day)	3	288	Risk Ratio (M‐H, Fixed, 95% CI)	1.10 [0.67, 1.80]
11.3 High amino acid intake (> 2 to ≤ 3 g/kg/day)	2	210	Risk Ratio (M‐H, Fixed, 95% CI)	1.23 [0.56, 2.69]
11.4 Very high amino acid intake (> 3 g/kg/day)	1	168	Risk Ratio (M‐H, Fixed, 95% CI)	0.82 [0.52, 1.30]
12 Necrotising enterocolitis	6	683	Risk Ratio (M‐H, Fixed, 95% CI)	1.14 [0.63, 2.07]
12.1 Low amino acid intake (> 1 to ≤ 2 g/kg/day)	3	288	Risk Ratio (M‐H, Fixed, 95% CI)	1.67 [0.72, 3.87]
12.2 High amino acid intake (> 2 to ≤ 3 g/kg/day)	2	227	Risk Ratio (M‐H, Fixed, 95% CI)	0.82 [0.19, 3.47]
12.3 Very high amino acid intake (> 3 g/kg/day)	1	168	Risk Ratio (M‐H, Fixed, 95% CI)	0.71 [0.24, 2.16]
13 Chronic lung disease at ≥ 36 weeks' PMA	4	376	Risk Ratio (M‐H, Fixed, 95% CI)	0.81 [0.55, 1.19]
13.1 Low amino acid intake (> 1 to ≤ 2 g/kg/day)	2	166	Risk Ratio (M‐H, Fixed, 95% CI)	1.05 [0.66, 1.69]
13.2 High amino acid intake (> 2 to ≤ 3 g/kg/day)	2	210	Risk Ratio (M‐H, Fixed, 95% CI)	0.56 [0.29, 1.08]
14 Patent ductus arteriosus	2	236	Risk Ratio (M‐H, Fixed, 95% CI)	0.81 [0.60, 1.10]
14.1 Low amino acid intake (> 1 to ≤ 2 g/kg/day)	1	122	Risk Ratio (M‐H, Fixed, 95% CI)	0.65 [0.40, 1.07]
14.2 High amino acid intake (> 2 to ≤ 3 g/kg/day)	1	114	Risk Ratio (M‐H, Fixed, 95% CI)	0.96 [0.65, 1.42]
15 Intraventricular haemorrhage	2	218	Risk Ratio (M‐H, Fixed, 95% CI)	1.09 [0.70, 1.70]
15.1 Low amino acid intake (> 1 to ≤ 2 g/kg/day)	1	122	Risk Ratio (M‐H, Fixed, 95% CI)	1.05 [0.64, 1.73]
15.2 High amino acid intake (> 2 to ≤ 3 g/kg/day)	1	96	Risk Ratio (M‐H, Fixed, 95% CI)	1.22 [0.47, 3.13]
16 Severe intraventricular haemorrhage	4	402	Risk Ratio (M‐H, Fixed, 95% CI)	0.96 [0.46, 2.02]
16.1 Low amino acid intake (> 1 to ≤ 2 g/kg/day)	3	288	Risk Ratio (M‐H, Fixed, 95% CI)	1.04 [0.47, 2.29]
16.2 High amino acid intake (> 2 to ≤ 3 g/kg/day)	1	114	Risk Ratio (M‐H, Fixed, 95% CI)	0.52 [0.05, 5.55]
17 Periventricular leukomalacia	4	447	Risk Ratio (M‐H, Fixed, 95% CI)	0.32 [0.10, 1.00]
17.1 Low amino acid intake (> 1 to ≤ 2 g/kg/day)	2	237	Risk Ratio (M‐H, Fixed, 95% CI)	0.14 [0.03, 0.79]
17.2 High amino acid intake (> 2 to ≤ 3 g/kg/day)	2	210	Risk Ratio (M‐H, Fixed, 95% CI)	1.37 [0.20, 9.33]
18 Severe retinopathy of prematurity (> stage 2 or treated)	3	280	Risk Ratio (M‐H, Fixed, 95% CI)	1.24 [0.49, 3.09]
18.1 Low amino acid intake (> 1 to ≤ 2 g/kg/day)	2	166	Risk Ratio (M‐H, Fixed, 95% CI)	1.24 [0.49, 3.09]
18.2 High amino acid intake (> 2 to ≤ 3 g/kg/day)	1	114	Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
19 Cerebral palsy	1	32	Risk Ratio (M‐H, Fixed, 95% CI)	3.0 [0.35, 25.87]
19.1 Low amino acid intake (> 1 to ≤ 2 g/kg/day)	1	32	Risk Ratio (M‐H, Fixed, 95% CI)	3.0 [0.35, 25.87]
20 Developmental delay at ≥ 18 months	1	100	Risk Ratio (M‐H, Fixed, 95% CI)	3.25 [0.35, 30.19]
20.1 High amino acid intake (> 2 to ≤ 3 g/kg/day)	1	100	Risk Ratio (M‐H, Fixed, 95% CI)	3.25 [0.35, 30.19]
21 Blindness	1	32	Risk Ratio (M‐H, Fixed, 95% CI)	2.0 [0.20, 19.91]
21.1 Low amino acid intake (> 1 to ≤ 2 g/kg/day)	1	32	Risk Ratio (M‐H, Fixed, 95% CI)	2.0 [0.20, 19.91]
22 Abnormal serum ammonia	1	61	Risk Ratio (M‐H, Fixed, 95% CI)	3.10 [0.13, 73.16]
22.1 Low amino acid intake (> 1 to ≤ 2 g/kg/day)	1	61	Risk Ratio (M‐H, Fixed, 95% CI)	3.10 [0.13, 73.16]
23 Abnormal blood urea nitrogen (various criteria)	5	550	Risk Ratio (M‐H, Fixed, 95% CI)	3.19 [2.24, 4.53]
23.1 Very low amino acid intake (≤ 1 g/kg/day)	1	85	Risk Ratio (M‐H, Fixed, 95% CI)	10.74 [1.45, 79.59]
23.2 Low amino acid intake (> 1 to ≤ 2 g/kg/day)	2	183	Risk Ratio (M‐H, Fixed, 95% CI)	12.29 [1.66, 90.79]
23.3 High amino acid intake (> 2 to ≤ 3 g/kg/day)	1	114	Risk Ratio (M‐H, Fixed, 95% CI)	2.44 [1.47, 4.05]
23.4 Very high amino acid intake (> 3 g/kg/day)	1	168	Risk Ratio (M‐H, Fixed, 95% CI)	2.73 [1.64, 4.54]
24 Hyperglycaemia, plasma glucose > 8.3 mmol/L	4	463	Risk Ratio (M‐H, Fixed, 95% CI)	0.54 [0.36, 0.82]
24.1 Very low amino acid intake (≤ 1 g/kg/day)	1	85	Risk Ratio (M‐H, Fixed, 95% CI)	1.95 [0.18, 20.74]
24.2 High amino acid intake (> 2 to ≤ 3 g/kg/day)	2	210	Risk Ratio (M‐H, Fixed, 95% CI)	0.51 [0.30, 0.87]
24.3 Very high amino acid intake (> 3 g/kg/day)	1	168	Risk Ratio (M‐H, Fixed, 95% CI)	0.53 [0.26, 1.06]
25 Hyperglycaemia treated with insulin	2	282	Risk Ratio (M‐H, Fixed, 95% CI)	0.62 [0.35, 1.08]
25.1 High amino acid intake (> 2 to ≤ 3 g/kg/day)	1	114	Risk Ratio (M‐H, Fixed, 95% CI)	0.35 [0.04, 3.22]
25.2 Very high amino acid intake (> 3 g/kg/day)	1	168	Risk Ratio (M‐H, Fixed, 95% CI)	0.65 [0.37, 1.16]
26 Hypoglycaemia	2	253	Risk Ratio (M‐H, Fixed, 95% CI)	1.03 [0.70, 1.50]
26.1 Very low amino acid intake (≤ 1 g/kg/day)	1	85	Risk Ratio (M‐H, Fixed, 95% CI)	1.22 [0.35, 4.24]
26.2 Very high amino acid intake (> 3 g/kg/day)	1	168	Risk Ratio (M‐H, Fixed, 95% CI)	1.0 [0.67, 1.49]
27 Metabolic acidosis	2	253	Risk Ratio (M‐H, Fixed, 95% CI)	2.05 [0.94, 4.47]
27.1 Very low amino acid intake (≤ 1 g/kg/day)	1	85	Risk Ratio (M‐H, Fixed, 95% CI)	8.80 [0.49, 158.47]
27.2 Very high amino acid intake (> 3 g/kg/day)	1	168	Risk Ratio (M‐H, Fixed, 95% CI)	1.63 [0.71, 3.72]
28 Cholestasis	3	375	Risk Ratio (M‐H, Fixed, 95% CI)	1.34 [0.71, 2.50]
28.1 Very low amino acid intake (≤ 1 g/kg/day)	1	85	Risk Ratio (M‐H, Fixed, 95% CI)	12.70 [0.74, 218.66]
28.2 Low amino acid intake (> 1 to ≤ 2 g/kg/day)	1	122	Risk Ratio (M‐H, Fixed, 95% CI)	1.45 [0.50, 4.18]
28.3 Very high amino acid intake (> 3 g/kg/day)	1	168	Risk Ratio (M‐H, Fixed, 95% CI)	0.7 [0.28, 1.75]

Comparison 5. Higher versus lower amino acid intake at commencement and maximal intake of parenteral nutrition: subgrouped by maximal intake.

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Mortality before hospital discharge	5	567	Risk Ratio (M‐H, Fixed, 95% CI)	0.97 [0.66, 1.42]
2 Days to regain birth weight	5	496	Mean Difference (IV, Fixed, 95% CI)	‐1.86 [‐2.79, ‐0.93]
2.1 Low amino acid intake (> 2 to ≤ 3 g/kg/day)	1	85	Mean Difference (IV, Fixed, 95% CI)	‐1.0 [‐5.03, 3.03]
2.2 High amino acid intake (> 3 to ≤ 4 g/kg/day)	4	411	Mean Difference (IV, Fixed, 95% CI)	‐1.91 [‐2.87, ‐0.95]
3 Maximal weight loss (grams)	2	185	Mean Difference (IV, Fixed, 95% CI)	‐29.79 [‐41.58, ‐17.99]
3.1 High amino acid intake (> 3 to ≤ 4 g/kg/day)	2	185	Mean Difference (IV, Fixed, 95% CI)	‐29.79 [‐41.58, ‐17.99]
4 Maximal weight loss %	2	229	Mean Difference (IV, Fixed, 95% CI)	0.22 [‐1.20, 1.64]
4.1 High amino acid intake (> 3 to ≤ 4 g/kg/day)	2	229	Mean Difference (IV, Fixed, 95% CI)	0.22 [‐1.20, 1.64]
5 Weight gain g/kg/day up to 1 month	2	154	Mean Difference (IV, Fixed, 95% CI)	1.48 [‐0.29, 3.25]
5.1 High amino acid intake (> 3 to ≤ 4 g/kg/day)	2	154	Mean Difference (IV, Fixed, 95% CI)	1.48 [‐0.29, 3.25]
6 Weight gain g/kg/day to discharge	1	114	Mean Difference (IV, Fixed, 95% CI)	0.60 [‐0.34, 1.54]
6.1 High amino acid intake (> 3 to ≤ 4 g/kg/day)	1	114	Mean Difference (IV, Fixed, 95% CI)	0.60 [‐0.34, 1.54]
7 Linear growth cm/week up to 1 month	1	122	Mean Difference (IV, Fixed, 95% CI)	0.0 [‐0.15, 0.15]
7.1 High amino acid intake (> 3 to ≤ 4 g/kg/day)	1	122	Mean Difference (IV, Fixed, 95% CI)	0.0 [‐0.15, 0.15]
8 Head circumference growth cm/week up to 1 month	1	122	Mean Difference (IV, Fixed, 95% CI)	0.0 [‐0.12, 0.12]
8.1 High amino acid intake (> 3 to ≤ 4 g/kg/day)	1	122	Mean Difference (IV, Fixed, 95% CI)	0.0 [‐0.12, 0.12]
9 Head circumference growth cm/week to discharge	2	182	Mean Difference (IV, Fixed, 95% CI)	0.11 [0.07, 0.15]
9.1 High amino acid intake (> 3 to ≤ 4 g/kg/day)	2	182	Mean Difference (IV, Fixed, 95% CI)	0.11 [0.07, 0.15]
10 Days to full enteral feeds	5	431	Mean Difference (IV, Fixed, 95% CI)	‐1.08 [‐2.42, 0.25]
10.1 High amino acid intake (> 3 to ≤ 4 g/kg/day)	5	431	Mean Difference (IV, Fixed, 95% CI)	‐1.08 [‐2.42, 0.25]
11 Late‐onset sepsis	8	772	Risk Ratio (M‐H, Fixed, 95% CI)	0.96 [0.72, 1.29]
11.1 Low amino acid intake (> 2 to ≤ 3 g/kg/day)	2	106	Risk Ratio (M‐H, Fixed, 95% CI)	0.72 [0.27, 1.95]
11.2 High amino acid intake (> 3 to ≤ 4 g/kg/day)	6	666	Risk Ratio (M‐H, Fixed, 95% CI)	0.99 [0.73, 1.35]
12 Necrotising enterocolitis	6	683	Risk Ratio (M‐H, Fixed, 95% CI)	1.14 [0.63, 2.07]
12.1 High amino acid intake (> 3 to ≤ 4 g/kg/day)	6	683	Risk Ratio (M‐H, Fixed, 95% CI)	1.14 [0.63, 2.07]
13 Chronic lung disease at ≥ 36 weeks' PMA	4	376	Risk Ratio (M‐H, Fixed, 95% CI)	0.81 [0.55, 1.19]
13.1 High amino acid intake (> 3 to ≤ 4 g/kg/day)	4	376	Risk Ratio (M‐H, Fixed, 95% CI)	0.81 [0.55, 1.19]
14 Patent ductus arteriosus	2	236	Risk Ratio (M‐H, Fixed, 95% CI)	0.81 [0.60, 1.10]
14.1 High amino acid intake (> 3 to ≤ 4 g/kg/day)	2	236	Risk Ratio (M‐H, Fixed, 95% CI)	0.81 [0.60, 1.10]
15 Intraventricular haemorrhage	2	218	Risk Ratio (M‐H, Fixed, 95% CI)	1.09 [0.70, 1.70]
15.1 High amino acid intake (> 3 to ≤ 4 g/kg/day)	2	218	Risk Ratio (M‐H, Fixed, 95% CI)	1.09 [0.70, 1.70]
16 Severe intraventricular haemorrhage	4	402	Risk Ratio (M‐H, Fixed, 95% CI)	0.96 [0.46, 2.02]
16.1 High amino acid intake (> 3 to ≤ 4 g/kg/day)	4	402	Risk Ratio (M‐H, Fixed, 95% CI)	0.96 [0.46, 2.02]
17 Periventricular leukomalacia	4	447	Risk Ratio (M‐H, Fixed, 95% CI)	0.32 [0.10, 1.00]
17.1 High amino acid intake (> 3 to ≤ 4 g/kg/day)	4	447	Risk Ratio (M‐H, Fixed, 95% CI)	0.32 [0.10, 1.00]
18 Severe retinopathy of prematurity (> stage 2 or treated)	3	280	Risk Ratio (M‐H, Fixed, 95% CI)	1.24 [0.49, 3.09]
18.1 High amino acid intake (> 3 to ≤ 4 g/kg/day)	3	280	Risk Ratio (M‐H, Fixed, 95% CI)	1.24 [0.49, 3.09]
19 Cerebral palsy	1	32	Risk Ratio (M‐H, Fixed, 95% CI)	3.0 [0.35, 25.87]
19.1 High amino acid intake (> 3 to ≤ 4 g/kg/day)	1	32	Risk Ratio (M‐H, Fixed, 95% CI)	3.0 [0.35, 25.87]
20 Developmental delay at ≥ 18 months	1	100	Risk Ratio (M‐H, Fixed, 95% CI)	3.25 [0.35, 30.19]
20.1 High amino acid intake (> 3 to ≤ 4 g/kg/day)	1	100	Risk Ratio (M‐H, Fixed, 95% CI)	3.25 [0.35, 30.19]
21 Blindness	1	32	Risk Ratio (M‐H, Fixed, 95% CI)	2.0 [0.20, 19.91]
21.1 High amino acid intake (> 3 to ≤ 4 g/kg/day)	1	32	Risk Ratio (M‐H, Fixed, 95% CI)	2.0 [0.20, 19.91]
22 Abnormal serum ammonia	1		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only
22.1 High amino acid intake (> 3 to ≤ 4 g/kg/day)	1	61	Risk Ratio (M‐H, Fixed, 95% CI)	3.10 [0.13, 73.16]
23 Abnormal blood urea nitrogen (various criteria)	5	550	Risk Ratio (M‐H, Fixed, 95% CI)	3.19 [2.24, 4.53]
23.1 Low amino acid intake (> 2 to ≤ 3 g/kg/day)	1	85	Risk Ratio (M‐H, Fixed, 95% CI)	10.74 [1.45, 79.59]
23.2 High amino acid intake (> 3 to ≤ 4 g/kg/day)	4	465	Risk Ratio (M‐H, Fixed, 95% CI)	2.93 [2.05, 4.18]
24 Hyperglycaemia, plasma glucose > 8.3 mmol/L	4	463	Risk Ratio (M‐H, Fixed, 95% CI)	0.54 [0.36, 0.82]
24.1 Low amino acid intake (> 2 to ≤ 3 g/kg/day)	1	85	Risk Ratio (M‐H, Fixed, 95% CI)	1.95 [0.18, 20.74]
24.2 High amino acid intake (> 3 to ≤ 4 g/kg/day)	3	378	Risk Ratio (M‐H, Fixed, 95% CI)	0.51 [0.34, 0.79]
25 Hyperglycaemia treated with insulin	2	282	Risk Ratio (M‐H, Fixed, 95% CI)	0.62 [0.35, 1.08]
25.1 High amino acid intake (> 3 to ≤ 4 g/kg/day)	2	282	Risk Ratio (M‐H, Fixed, 95% CI)	0.62 [0.35, 1.08]
26 Hypoglycaemia	2	253	Risk Ratio (M‐H, Fixed, 95% CI)	1.03 [0.70, 1.50]
26.1 Low amino acid intake (> 2 to ≤ 3 g/kg/day)	1	85	Risk Ratio (M‐H, Fixed, 95% CI)	1.22 [0.35, 4.24]
26.2 High amino acid intake (> 3 to ≤ 4 g/kg/day)	1	168	Risk Ratio (M‐H, Fixed, 95% CI)	1.0 [0.67, 1.49]
27 Metabolic acidosis	2	253	Risk Ratio (M‐H, Fixed, 95% CI)	2.05 [0.94, 4.47]
27.1 Low amino acid intake (> 2 to ≤ 3 g/kg/day)	1	85	Risk Ratio (M‐H, Fixed, 95% CI)	8.80 [0.49, 158.47]
27.2 High amino acid intake (> 3 to ≤ 4 g/kg/day)	1	168	Risk Ratio (M‐H, Fixed, 95% CI)	1.63 [0.71, 3.72]
28 Cholestasis	3	375	Risk Ratio (M‐H, Fixed, 95% CI)	1.34 [0.71, 2.50]
28.1 Low amino acid intake (> 2 to ≤ 3 g/kg/day)	1	85	Risk Ratio (M‐H, Fixed, 95% CI)	12.70 [0.74, 218.66]
28.2 High amino acid intake (> 3 to ≤ 4 g/kg/day)	2	290	Risk Ratio (M‐H, Fixed, 95% CI)	0.96 [0.48, 1.90]

Comparison 6. Higher versus lower amino acid intake in parenteral nutrition: subgrouped according to management of caloric balance.

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Mortality to hospital discharge	14	1407	Risk Ratio (M‐H, Fixed, 95% CI)	0.90 [0.69, 1.17]
1.1 Increase amino acids and provide isocaloric non‐protein intake	7	828	Risk Ratio (M‐H, Fixed, 95% CI)	0.78 [0.51, 1.20]
1.2 Increase amino acids and non‐protein caloric intake	7	579	Risk Ratio (M‐H, Fixed, 95% CI)	1.00 [0.71, 1.39]
2 Neurodevelopmental disability	2	201	Risk Ratio (M‐H, Fixed, 95% CI)	1.04 [0.48, 2.23]
2.1 Increase amino acids and provide isocaloric non‐protein intake	2	201	Risk Ratio (M‐H, Fixed, 95% CI)	1.04 [0.48, 2.23]
3 Postnatal growth failure at discharge	3	203	Risk Ratio (M‐H, Fixed, 95% CI)	0.74 [0.56, 0.97]
3.1 Increase amino acids and provide isocaloric non‐protein intake	1	111	Risk Ratio (M‐H, Fixed, 95% CI)	0.75 [0.44, 1.30]
3.2 Increase amino acids and non‐protein caloric intake	2	92	Risk Ratio (M‐H, Fixed, 95% CI)	0.73 [0.55, 0.98]
4 Days to regain birth weight	13	950	Mean Difference (IV, Fixed, 95% CI)	‐1.14 [‐1.73, ‐0.56]
4.1 Increase amino acids and provide isocaloric non‐protein intake	8	615	Mean Difference (IV, Fixed, 95% CI)	‐1.06 [‐1.77, ‐0.34]
4.2 Increase amino acids and non‐protein caloric intake	5	335	Mean Difference (IV, Fixed, 95% CI)	‐1.32 [‐2.33, ‐0.31]
5 Maximal weight loss (grams)	3	235	Mean Difference (IV, Fixed, 95% CI)	‐22.71 [‐33.68, ‐11.74]
5.1 Increase amino acids and provide isocaloric non‐protein intake	2	185	Mean Difference (IV, Fixed, 95% CI)	‐29.79 [‐41.58, ‐17.99]
5.2 Increase amino acids and non‐protein caloric intake	1	50	Mean Difference (IV, Fixed, 95% CI)	22.60 [‐7.25, 52.45]
6 Maximal weight loss %	4	288	Mean Difference (IV, Fixed, 95% CI)	‐0.33 [‐1.61, 0.96]
6.1 Increase amino acids and provide isocaloric non‐protein intake	3	246	Mean Difference (IV, Fixed, 95% CI)	0.25 [‐1.13, 1.64]
6.2 Increase amino acids and non‐protein caloric intake	1	42	Mean Difference (IV, Fixed, 95% CI)	‐3.80 [‐7.20, ‐0.40]
7 Weight gain g/kg/day up to 1 month	4	373	Mean Difference (IV, Fixed, 95% CI)	‐1.50 [‐2.56, ‐0.44]
7.1 Increase amino acids and provide isocaloric non‐protein intake	4	373	Mean Difference (IV, Fixed, 95% CI)	‐1.50 [‐2.56, ‐0.44]
8 Weight gain g/kg/day to discharge	4	291	Mean Difference (IV, Fixed, 95% CI)	0.76 [‐0.02, 1.54]
8.1 Increase amino acids and provide isocaloric non‐protein nutrition	3	249	Mean Difference (IV, Fixed, 95% CI)	0.81 [‐0.03, 1.66]
8.2 Increase amino acids and non‐protein caloric intake	1	42	Mean Difference (IV, Fixed, 95% CI)	0.40 [‐1.69, 2.49]
9 Linear growth cm/week up to 1 month	1	122	Mean Difference (IV, Fixed, 95% CI)	0.0 [‐0.15, 0.15]
9.1 Increase amino acids and provide isocaloric non‐protein intake	1	122	Mean Difference (IV, Fixed, 95% CI)	0.0 [‐0.15, 0.15]
10 Linear growth cm/week to discharge	1	123	Mean Difference (IV, Fixed, 95% CI)	‐0.27 [‐0.40, ‐0.14]
10.1 Increase amino acids and provide isocaloric non‐protein intake	1	123	Mean Difference (IV, Fixed, 95% CI)	‐0.27 [‐0.40, ‐0.14]
11 Head circumference growth cm/week up to 1 month	3	380	Mean Difference (IV, Fixed, 95% CI)	0.01 [‐0.05, 0.07]
11.1 Increase amino acids and provide isocaloric non‐protein intake	2	245	Mean Difference (IV, Fixed, 95% CI)	‐0.16 [‐0.25, ‐0.07]
11.2 Increase amino acids and non‐protein caloric intake	1	135	Mean Difference (IV, Fixed, 95% CI)	0.13 [0.05, 0.20]
12 Head circumference growth cm/week to discharge	4	315	Mean Difference (IV, Fixed, 95% CI)	0.09 [0.06, 0.13]
12.1 Increase amino acids and provide isocaloric non‐protein intake	4	315	Mean Difference (IV, Fixed, 95% CI)	0.09 [0.06, 0.13]
13 Weight change z‐score to discharge	2	207	Mean Difference (IV, Fixed, 95% CI)	0.01 [‐0.33, 0.36]
13.1 Increase amino acids and provide isocaloric non‐protein intake	2	207	Mean Difference (IV, Fixed, 95% CI)	0.01 [‐0.33, 0.36]
14 Head circumference change z‐score to 1 month	2	231	Mean Difference (IV, Fixed, 95% CI)	0.27 [0.08, 0.46]
14.1 Increase amino acids and provide isocaloric non‐protein intake	1	96	Mean Difference (IV, Fixed, 95% CI)	0.0 [‐0.36, 0.36]
14.2 Increase amino acids and non‐protein caloric intake	1	135	Mean Difference (IV, Fixed, 95% CI)	0.37 [0.15, 0.59]
15 Head circumference change z‐score to discharge	2	207	Mean Difference (IV, Fixed, 95% CI)	0.18 [‐0.15, 0.50]
15.1 Increase amino acids and provide isocaloric non‐protein intake	2	207	Mean Difference (IV, Fixed, 95% CI)	0.18 [‐0.15, 0.50]
16 Days to full enteral feeds	11	778	Mean Difference (IV, Fixed, 95% CI)	‐0.19 [‐1.07, 0.70]
16.1 Increase amino acids and provide isocaloric non‐protein intake	7	495	Mean Difference (IV, Fixed, 95% CI)	‐0.90 [‐2.14, 0.35]
16.2 Increase amino acids and non‐protein caloric intake	4	283	Mean Difference (IV, Fixed, 95% CI)	0.56 [‐0.71, 1.83]
17 Late‐onset sepsis	15	1255	Risk Ratio (M‐H, Fixed, 95% CI)	0.96 [0.79, 1.18]
17.1 Increase amino acids and provide isocaloric non‐protein intake	10	949	Risk Ratio (M‐H, Fixed, 95% CI)	0.99 [0.77, 1.27]
17.2 Increase amino acids and non‐protein caloric intake	5	306	Risk Ratio (M‐H, Fixed, 95% CI)	0.90 [0.64, 1.27]
18 Necrotising enterocolitis	14	1301	Risk Ratio (M‐H, Fixed, 95% CI)	1.00 [0.68, 1.47]
18.1 Increase amino acids and provide isocaloric non‐protein intake	10	966	Risk Ratio (M‐H, Fixed, 95% CI)	1.11 [0.69, 1.79]
18.2 Increase amino acids and non‐protein caloric intake	4	335	Risk Ratio (M‐H, Fixed, 95% CI)	0.80 [0.41, 1.56]
19 Chronic lung disease ≥ 36 weeks' PMA	10	819	Risk Ratio (M‐H, Fixed, 95% CI)	1.04 [0.89, 1.23]
19.1 Increase amino acids and provide isocaloric non‐protein intake	6	499	Risk Ratio (M‐H, Fixed, 95% CI)	0.96 [0.70, 1.31]
19.2 Increase amino acids and non‐protein caloric intake	4	320	Risk Ratio (M‐H, Fixed, 95% CI)	1.10 [0.93, 1.31]
20 Intraventricular haemorrhage	4	370	Risk Ratio (M‐H, Fixed, 95% CI)	1.08 [0.73, 1.59]
20.1 Increase amino acids and provide isocaloric non‐protein intake	3	341	Risk Ratio (M‐H, Fixed, 95% CI)	1.12 [0.74, 1.69]
20.2 Increase amino acids and non‐protein caloric intake	1	29	Risk Ratio (M‐H, Fixed, 95% CI)	0.86 [0.29, 2.56]
21 Severe intraventricular haemorrhage	11	904	Risk Ratio (M‐H, Fixed, 95% CI)	1.16 [0.74, 1.82]
21.1 Increase amino acids and provide isocaloric non‐protein intake	6	527	Risk Ratio (M‐H, Fixed, 95% CI)	1.00 [0.56, 1.78]
21.2 Increase amino acids and non‐protein caloric intake	5	377	Risk Ratio (M‐H, Fixed, 95% CI)	1.43 [0.70, 2.92]
22 Periventricular leukomalacia	7	720	Risk Ratio (M‐H, Fixed, 95% CI)	0.55 [0.24, 1.25]
22.1 Increase amino acids and provide isocaloric non‐protein intake	5	543	Risk Ratio (M‐H, Fixed, 95% CI)	0.32 [0.10, 1.00]
22.2 Increase amino acids and non‐protein caloric intake	2	177	Risk Ratio (M‐H, Fixed, 95% CI)	1.30 [0.33, 5.11]
23 Retinopathy of prematurity	4	269	Risk Ratio (M‐H, Fixed, 95% CI)	0.44 [0.21, 0.93]
23.1 Increase amino acids and provide isocaloric non‐protein intake	1	123	Risk Ratio (M‐H, Fixed, 95% CI)	1.58 [0.27, 9.10]
23.2 Increase amino acids and non‐protein caloric intake	3	146	Risk Ratio (M‐H, Fixed, 95% CI)	0.32 [0.13, 0.77]
24 Severe retinopathy of prematurity (> stage 2 or treated)	8	672	Risk Ratio (M‐H, Fixed, 95% CI)	0.96 [0.56, 1.63]
24.1 Increase amino acids and provide isocaloric non‐protein intake	4	378	Risk Ratio (M‐H, Fixed, 95% CI)	1.50 [0.63, 3.55]
24.2 Increase amino acids and non‐protein caloric intake	4	294	Risk Ratio (M‐H, Fixed, 95% CI)	0.73 [0.36, 1.46]
25 Cerebral palsy	2	122	Risk Ratio (M‐H, Fixed, 95% CI)	4.0 [0.89, 17.97]
25.1 Increase amino acids and provide isocaloric non‐protein intake	2	122	Risk Ratio (M‐H, Fixed, 95% CI)	4.0 [0.89, 17.97]
26 Developmental delay at ≥ 18 months	3	301	Risk Ratio (M‐H, Fixed, 95% CI)	1.35 [0.52, 3.53]
26.1 Increase amino acids and provide isocaloric non‐protein calorie nutrition	3	301	Risk Ratio (M‐H, Fixed, 95% CI)	1.35 [0.52, 3.53]
27 Blindness	2	122	Risk Ratio (M‐H, Fixed, 95% CI)	2.0 [0.20, 19.91]
27.1 Increase amino acids and provide isocaloric non‐protein intake	2	122	Risk Ratio (M‐H, Fixed, 95% CI)	2.0 [0.20, 19.91]
28 Deafness	1	90	Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
28.1 Increase amino acids and provide isocaloric non‐protein intake	1	90	Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
29 Abnormal serum ammonia	1	61	Risk Ratio (M‐H, Fixed, 95% CI)	3.10 [0.13, 73.16]
29.1 Increase amino acids and provide isocaloric non‐protein intake	1	61	Risk Ratio (M‐H, Fixed, 95% CI)	3.10 [0.13, 73.16]
30 Abnormal blood urea nitrogen (various criteria)	7	688	Risk Ratio (M‐H, Fixed, 95% CI)	2.77 [2.13, 3.61]
30.1 Increase amino acids and provide isocaloric non‐protein intake	5	561	Risk Ratio (M‐H, Fixed, 95% CI)	2.61 [2.00, 3.41]
30.2 Increase amino acids and non‐protein calorie nutrition	2	127	Risk Ratio (M‐H, Fixed, 95% CI)	6.45 [1.55, 26.84]
31 Hyperglycaemia, plasma glucose > 8.3 mmol/L	5	505	Risk Ratio (M‐H, Fixed, 95% CI)	0.69 [0.49, 0.96]
31.1 Increase amino acids and provide isocaloric non‐protein intake	3	378	Risk Ratio (M‐H, Fixed, 95% CI)	0.51 [0.34, 0.79]
31.2 Increase amino acids and non‐protein calorie nutrition	2	127	Risk Ratio (M‐H, Fixed, 95% CI)	1.51 [0.88, 2.62]
32 Hyperglycaemia treated with insulin	5	534	Risk Ratio (M‐H, Fixed, 95% CI)	1.24 [0.93, 1.66]
32.1 Increase amino acids and provide isocaloric non‐protein intake	3	378	Risk Ratio (M‐H, Fixed, 95% CI)	0.76 [0.49, 1.19]
32.2 Increase amino acids and non‐protein calorie nutrition	2	156	Risk Ratio (M‐H, Fixed, 95% CI)	2.00 [1.35, 2.98]
33 Hypoglycaemia	3	376	Risk Ratio (M‐H, Fixed, 95% CI)	1.17 [0.84, 1.63]
33.1 Increase amino acids and provide isocaloric non‐protein intake	2	291	Risk Ratio (M‐H, Fixed, 95% CI)	1.16 [0.82, 1.64]
33.2 Increase amino acids and non‐protein calorie nutrition	1	85	Risk Ratio (M‐H, Fixed, 95% CI)	1.22 [0.35, 4.24]
34 Metabolic acidosis	4	305	Risk Ratio (M‐H, Fixed, 95% CI)	2.05 [0.94, 4.47]
34.1 Increase amino acids and provide isocaloric non‐protein intake	3	220	Risk Ratio (M‐H, Fixed, 95% CI)	1.63 [0.71, 3.72]
34.2 Increase amino acids and non‐protein calorie nutrition	1	85	Risk Ratio (M‐H, Fixed, 95% CI)	8.80 [0.49, 158.47]
35 Cholestasis	5	616	Risk Ratio (M‐H, Fixed, 95% CI)	1.26 [0.86, 1.84]
35.1 Increase amino acids and provide isocaloric non‐protein intake	2	290	Risk Ratio (M‐H, Fixed, 95% CI)	0.96 [0.48, 1.90]
35.2 Increase amino acids and non‐protein calorie nutrition	3	326	Risk Ratio (M‐H, Fixed, 95% CI)	1.45 [0.92, 2.28]

Comparison 7. Higher versus lower amino acid intake in parenteral nutrition: very preterm or very low birth weight infants.

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Mortality before hospital discharge	14	1407	Risk Ratio (M‐H, Fixed, 95% CI)	0.90 [0.69, 1.17]
2 Neurodevelopmental disability	2	201	Risk Ratio (M‐H, Fixed, 95% CI)	1.04 [0.48, 2.23]
3 Postnatal growth failure	3		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only
3.1 At latest time measured to discharge	3	203	Risk Ratio (M‐H, Fixed, 95% CI)	0.74 [0.56, 0.97]
3.2 Post discharge	1	111	Risk Ratio (M‐H, Fixed, 95% CI)	0.66 [0.33, 1.32]
4 Days to regain birth weight	10	800	Mean Difference (IV, Fixed, 95% CI)	‐0.78 [‐1.46, ‐0.11]
5 Maximal weight loss (grams)	2	139	Mean Difference (IV, Fixed, 95% CI)	‐20.37 [‐32.68, ‐8.05]
6 Maximal weight loss %	3	271	Mean Difference (IV, Fixed, 95% CI)	‐0.38 [‐1.69, 0.93]
7 Weight gain g/kg/day	6		Mean Difference (IV, Fixed, 95% CI)	Subtotals only
7.1 Up to 1 month age	4	373	Mean Difference (IV, Fixed, 95% CI)	‐1.50 [‐2.56, ‐0.44]
7.2 At latest time measured to discharge	3	254	Mean Difference (IV, Fixed, 95% CI)	0.72 [‐0.09, 1.52]
8 Linear growth cm/week	2		Mean Difference (IV, Fixed, 95% CI)	Subtotals only
8.1 Up to 1 month age	2	245	Mean Difference (IV, Fixed, 95% CI)	‐0.16 [‐0.26, ‐0.06]
9 Head circumference growth cm/week	5	658	Mean Difference (IV, Fixed, 95% CI)	0.06 [0.03, 0.09]
9.1 Up to 1 month age	4	476	Mean Difference (IV, Fixed, 95% CI)	0.01 [‐0.04, 0.06]
9.2 At latest time measured to discharge	2	182	Mean Difference (IV, Fixed, 95% CI)	0.08 [0.05, 0.12]
10 Weight change z‐score	2		Mean Difference (IV, Fixed, 95% CI)	Subtotals only
10.1 Up to 1 month age	1	96	Mean Difference (IV, Fixed, 95% CI)	‐0.20 [‐0.62, 0.22]
10.2 At latest time measured to discharge	2	207	Mean Difference (IV, Fixed, 95% CI)	0.01 [‐0.33, 0.36]
10.3 Post discharge	2	201	Mean Difference (IV, Fixed, 95% CI)	0.13 [‐0.26, 0.52]
11 Head circumference change z‐score	3		Mean Difference (IV, Fixed, 95% CI)	Subtotals only
11.1 Up to 1 month age	2	231	Mean Difference (IV, Fixed, 95% CI)	0.27 [0.08, 0.46]
11.2 At latest time measured to discharge	2	207	Mean Difference (IV, Fixed, 95% CI)	0.18 [‐0.15, 0.50]
11.3 Post discharge	2	201	Mean Difference (IV, Fixed, 95% CI)	0.25 [‐0.14, 0.64]
12 Days to full enteral feeds	11	778	Mean Difference (IV, Fixed, 95% CI)	‐0.19 [‐1.07, 0.70]
13 Late‐onset sepsis	15	1255	Risk Ratio (M‐H, Fixed, 95% CI)	0.96 [0.79, 1.18]
14 Necrotising enterocolitis	14	1301	Risk Ratio (M‐H, Fixed, 95% CI)	1.00 [0.68, 1.47]
15 Chronic lung disease ≥ 36 weeks' PMA	10	819	Risk Ratio (M‐H, Fixed, 95% CI)	1.04 [0.89, 1.23]
16 Intraventricular haemorrhage	3	341	Risk Ratio (M‐H, Fixed, 95% CI)	1.12 [0.74, 1.69]
17 Severe intraventricular haemorrhage	11	904	Risk Ratio (M‐H, Fixed, 95% CI)	1.16 [0.74, 1.82]
18 Periventricular leukomalacia	6	624	Risk Ratio (M‐H, Fixed, 95% CI)	0.48 [0.20, 1.17]
19 Retinopathy of prematurity	4	269	Risk Ratio (M‐H, Fixed, 95% CI)	0.44 [0.21, 0.93]
20 Severe retinopathy of prematurity (> stage 2 or treated)	8	672	Risk Ratio (M‐H, Fixed, 95% CI)	0.96 [0.56, 1.63]
21 Cerebral palsy	2	122	Risk Ratio (M‐H, Fixed, 95% CI)	4.0 [0.89, 17.97]
22 Developmental delay at ≥ 18 months	3	301	Risk Ratio (M‐H, Fixed, 95% CI)	1.35 [0.52, 3.53]
22.1 MDI < 70	2	201	Risk Ratio (M‐H, Fixed, 95% CI)	1.04 [0.35, 3.11]
22.2 Severe mental retardation	1	100	Risk Ratio (M‐H, Fixed, 95% CI)	3.25 [0.35, 30.19]
23 Blindness	2	122	Risk Ratio (M‐H, Fixed, 95% CI)	2.0 [0.20, 19.91]
24 Deafness	1	90	Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
25 Abnormal serum ammonia > 122 μmol/L	1	61	Risk Ratio (M‐H, Fixed, 95% CI)	3.10 [0.13, 73.16]
26 Abnormal blood urea nitrogen > 21.4 mmol/L	7	688	Risk Ratio (M‐H, Fixed, 95% CI)	2.77 [2.13, 3.61]
27 Hyperglycaemia, plasma glucose > 8.3 mmol/L	4	409	Risk Ratio (M‐H, Fixed, 95% CI)	0.66 [0.45, 0.96]
28 Hyperglycaemia treated with insulin	5	534	Risk Ratio (M‐H, Fixed, 95% CI)	1.24 [0.93, 1.66]
29 Hypoglycaemia	3	376	Risk Ratio (M‐H, Fixed, 95% CI)	1.17 [0.84, 1.63]
30 Metabolic acidosis	2	253	Risk Ratio (M‐H, Fixed, 95% CI)	2.05 [0.94, 4.47]
31 Cholestasis	5	616	Risk Ratio (M‐H, Fixed, 95% CI)	1.26 [0.86, 1.84]

Comparison 8. Higher versus lower amino acid intake in parenteral nutrition: subgrouped according to age at commencement.

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Mortality before hospital discharge	14	1407	Risk Ratio (M‐H, Fixed, 95% CI)	0.90 [0.69, 1.17]
1.1 Commenced < 24 hours	12	1200	Risk Ratio (M‐H, Fixed, 95% CI)	0.82 [0.60, 1.13]
1.2 Commenced ≥ 24 to < 48 hours	1	122	Risk Ratio (M‐H, Fixed, 95% CI)	1.81 [0.17, 19.47]
1.3 Commenced ≥ 48 to < 72 hours	1	85	Risk Ratio (M‐H, Fixed, 95% CI)	1.14 [0.72, 1.81]
2 Neurodevelopmental disability	2	201	Risk Ratio (M‐H, Fixed, 95% CI)	1.04 [0.48, 2.23]
2.1 Commenced < 24 hours	2	201	Risk Ratio (M‐H, Fixed, 95% CI)	1.04 [0.48, 2.23]
3 Postnatal growth failure at discharge	3	203	Risk Ratio (M‐H, Fixed, 95% CI)	0.74 [0.56, 0.97]
3.1 Commenced < 24 hours	3	203	Risk Ratio (M‐H, Fixed, 95% CI)	0.74 [0.56, 0.97]
4 Days to regain birth weight	13	950	Mean Difference (IV, Fixed, 95% CI)	‐1.14 [‐1.73, ‐0.56]
4.1 Commenced < 24 hours	12	865	Mean Difference (IV, Fixed, 95% CI)	‐1.15 [‐1.74, ‐0.56]
4.2 Commenced ≥ 48 to < 72 hours	1	85	Mean Difference (IV, Fixed, 95% CI)	‐1.0 [‐5.03, 3.03]
5 Maximal weight loss (grams)	3	235	Mean Difference (IV, Fixed, 95% CI)	‐22.71 [‐33.68, ‐11.74]
5.1 Commenced < 24 hours	3	235	Mean Difference (IV, Fixed, 95% CI)	‐22.71 [‐33.68, ‐11.74]
6 Maximal weight loss %	4	288	Mean Difference (IV, Fixed, 95% CI)	‐0.33 [‐1.61, 0.96]
6.1 Commenced < 24 hours	4	288	Mean Difference (IV, Fixed, 95% CI)	‐0.33 [‐1.61, 0.96]
7 Weight gain g/kg/day up to 1 month	1	122	Mean Difference (IV, Fixed, 95% CI)	1.5 [‐0.27, 3.27]
7.1 Commenced ≥ 24 to < 48 hours	1	122	Mean Difference (IV, Fixed, 95% CI)	1.5 [‐0.27, 3.27]
8 Weight gain g/kg/day to discharge	6	446	Mean Difference (IV, Fixed, 95% CI)	‐0.16 [‐0.87, 0.54]
8.1 Commenced < 24 hours	5	348	Mean Difference (IV, Fixed, 95% CI)	‐0.35 [‐1.09, 0.39]
8.2 Commenced ≥ 24 to < 48 hours	1	98	Mean Difference (IV, Fixed, 95% CI)	2.0 [‐0.51, 4.51]
9 Linear growth cm/week up to 1 month	2	245	Mean Difference (IV, Fixed, 95% CI)	‐0.16 [‐0.26, ‐0.06]
9.1 Commenced < 24 hours	1	123	Mean Difference (IV, Fixed, 95% CI)	‐0.27 [‐0.40, ‐0.14]
9.2 Commenced ≥ 24 to < 48 hours	1	122	Mean Difference (IV, Fixed, 95% CI)	0.0 [‐0.15, 0.15]
10 Head circumference growth cm/week up to 1 month age	4	476	Mean Difference (IV, Fixed, 95% CI)	0.01 [‐0.04, 0.06]
10.1 Commenced < 24 hours	2	258	Mean Difference (IV, Fixed, 95% CI)	0.01 [‐0.06, 0.08]
10.2 Commenced ≥ 24 to < 48 hours	2	218	Mean Difference (IV, Fixed, 95% CI)	0.01 [‐0.07, 0.09]
11 Head circumference growth cm/week to discharge	4	315	Mean Difference (IV, Fixed, 95% CI)	0.09 [0.06, 0.13]
11.1 Commenced < 24 hours	3	219	Mean Difference (IV, Fixed, 95% CI)	0.12 [0.08, 0.17]
11.2 Commenced ≥ 24 to < 48 hours	1	96	Mean Difference (IV, Fixed, 95% CI)	0.03 [‐0.03, 0.09]
12 Weight change z‐score to discharge	2	207	Mean Difference (IV, Fixed, 95% CI)	0.01 [‐0.33, 0.36]
12.1 Commenced < 24 hours	1	111	Mean Difference (IV, Fixed, 95% CI)	‐0.22 [‐0.70, 0.26]
12.2 Commenced ≥ 24 to < 48 hours	1	96	Mean Difference (IV, Fixed, 95% CI)	0.27 [‐0.23, 0.77]
13 Head circumference change z‐score to 1 month age	2	231	Mean Difference (IV, Fixed, 95% CI)	0.27 [0.08, 0.46]
13.1 Commenced < 24 hours	1	135	Mean Difference (IV, Fixed, 95% CI)	0.37 [0.15, 0.59]
13.2 Commenced ≥ 24 to < 48 hours	1	96	Mean Difference (IV, Fixed, 95% CI)	0.0 [‐0.36, 0.36]
14 Head circumference change z‐score to discharge	2	207	Mean Difference (IV, Fixed, 95% CI)	0.18 [‐0.15, 0.50]
14.1 Commenced < 24 hours	1	111	Mean Difference (IV, Fixed, 95% CI)	‐0.15 [‐0.66, 0.36]
14.2 Commenced ≥ 24 to < 48 hours	1	96	Mean Difference (IV, Fixed, 95% CI)	0.4 [‐0.02, 0.82]
15 Days to full enteral feeds	11	778	Mean Difference (IV, Fixed, 95% CI)	‐0.19 [‐1.07, 0.70]
15.1 Commenced < 24 hours	11	778	Mean Difference (IV, Fixed, 95% CI)	‐0.19 [‐1.07, 0.70]
16 Late‐onset sepsis	15	1255	Risk Ratio (M‐H, Fixed, 95% CI)	0.96 [0.79, 1.18]
16.1 Commenced < 24 hours	12	952	Risk Ratio (M‐H, Fixed, 95% CI)	0.95 [0.75, 1.20]
16.2 Commenced ≥ 24 to < 48 hours	2	218	Risk Ratio (M‐H, Fixed, 95% CI)	1.09 [0.70, 1.67]
16.3 Commenced ≥ 48 to < 72 hours	1	85	Risk Ratio (M‐H, Fixed, 95% CI)	0.70 [0.24, 2.03]
17 Necrotising enterocolitis	14	1301	Risk Ratio (M‐H, Fixed, 95% CI)	1.00 [0.68, 1.47]
17.1 Commenced < 24 hours	12	1083	Risk Ratio (M‐H, Fixed, 95% CI)	0.98 [0.65, 1.49]
17.2 Commenced ≥ 24 to < 48 hours	2	218	Risk Ratio (M‐H, Fixed, 95% CI)	1.09 [0.40, 2.95]
18 Chronic lung disease ≥ 36 weeks' PMA	10	819	Risk Ratio (M‐H, Fixed, 95% CI)	1.04 [0.89, 1.23]
18.1 Commenced < 24 hours	9	723	Risk Ratio (M‐H, Fixed, 95% CI)	1.01 [0.85, 1.19]
18.2 Commenced ≥ 24 to < 48 hours	1	96	Risk Ratio (M‐H, Fixed, 95% CI)	1.52 [0.79, 2.92]
19 Intraventricular haemorrhage	3	341	Risk Ratio (M‐H, Fixed, 95% CI)	1.12 [0.74, 1.69]
19.1 Commenced < 24 hours	2	219	Risk Ratio (M‐H, Fixed, 95% CI)	1.23 [0.60, 2.55]
19.2 Commenced ≥ 24 to < 48 hours	1	122	Risk Ratio (M‐H, Fixed, 95% CI)	1.05 [0.64, 1.73]
20 Severe intraventricular haemorrhage	11	904	Risk Ratio (M‐H, Fixed, 95% CI)	1.16 [0.74, 1.82]
20.1 Commenced < 24 hours	9	686	Risk Ratio (M‐H, Fixed, 95% CI)	1.17 [0.68, 1.99]
20.2 Commenced ≥ 24 to < 48 hours	2	218	Risk Ratio (M‐H, Fixed, 95% CI)	1.15 [0.50, 2.63]
21 Periventricular leukomalacia	7	720	Risk Ratio (M‐H, Fixed, 95% CI)	0.55 [0.24, 1.25]
21.1 Commenced < 24 hours	5	502	Risk Ratio (M‐H, Fixed, 95% CI)	0.75 [0.30, 1.85]
21.2 Commenced ≥ 24 to < 48 hours	2	218	Risk Ratio (M‐H, Fixed, 95% CI)	0.10 [0.01, 1.83]
22 Retinopathy of prematurity	4	269	Risk Ratio (M‐H, Fixed, 95% CI)	0.44 [0.21, 0.93]
22.1 Commenced < 24 hours	4	269	Risk Ratio (M‐H, Fixed, 95% CI)	0.44 [0.21, 0.93]
23 Severe retinopathy of prematurity (> stage 2 or treated)	8	672	Risk Ratio (M‐H, Fixed, 95% CI)	0.96 [0.56, 1.63]
23.1 Commenced < 24 hours	7	574	Risk Ratio (M‐H, Fixed, 95% CI)	0.87 [0.50, 1.51]
23.2 Commenced ≥ 24 to < 48 hours	1	98	Risk Ratio (M‐H, Fixed, 95% CI)	5.0 [0.25, 101.53]
24 Cerebral palsy	2	122	Risk Ratio (M‐H, Fixed, 95% CI)	4.0 [0.89, 17.97]
24.1 Commenced < 24 hours	2	122	Risk Ratio (M‐H, Fixed, 95% CI)	4.0 [0.89, 17.97]
25 Developmental delay at ≥ 18 months	3	301	Risk Ratio (M‐H, Fixed, 95% CI)	1.35 [0.52, 3.53]
25.1 Commenced < 24 hours	3	301	Risk Ratio (M‐H, Fixed, 95% CI)	1.35 [0.52, 3.53]
26 Blindness	2	122	Risk Ratio (M‐H, Fixed, 95% CI)	2.0 [0.20, 19.91]
26.1 Commenced < 24 hours	2	122	Risk Ratio (M‐H, Fixed, 95% CI)	2.0 [0.20, 19.91]
27 Deafness	1	90	Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
27.1 Commenced ≥ 24 to < 48 hours	1	90	Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
28 Abnormal serum ammonia > 122 μmol/L	1	61	Risk Ratio (M‐H, Fixed, 95% CI)	3.10 [0.13, 73.16]
28.1 Commenced < 24 hours	1	61	Risk Ratio (M‐H, Fixed, 95% CI)	3.10 [0.13, 73.16]
29 Abnormal blood urea nitrogen (various criteria)	7	689	Risk Ratio (M‐H, Fixed, 95% CI)	2.77 [2.13, 3.60]
29.1 Commenced < 24 hours	4	386	Risk Ratio (M‐H, Fixed, 95% CI)	2.86 [2.01, 4.07]
29.2 Commenced ≥ 24 to < 48 hours	2	218	Risk Ratio (M‐H, Fixed, 95% CI)	2.20 [1.50, 3.23]
29.3 Commenced ≥ 48 to < 72 hours	1	85	Risk Ratio (M‐H, Fixed, 95% CI)	10.74 [1.45, 79.59]
30 Hyperglycaemia, plasma glucose > 8.3 mmol/L	5	505	Risk Ratio (M‐H, Fixed, 95% CI)	0.69 [0.49, 0.96]
30.1 Commenced < 24 hours	4	420	Risk Ratio (M‐H, Fixed, 95% CI)	0.67 [0.48, 0.94]
30.2 Commenced ≥ 48 to < 72 hours	1	85	Risk Ratio (M‐H, Fixed, 95% CI)	1.95 [0.18, 20.74]
31 Hyperglycaemia treated with insulin	5	534	Risk Ratio (M‐H, Fixed, 95% CI)	1.24 [0.93, 1.66]
31.1 Commenced < 24 hours	4	438	Risk Ratio (M‐H, Fixed, 95% CI)	1.26 [0.92, 1.72]
31.2 Commenced ≥ 24 to < 48 hours	1	96	Risk Ratio (M‐H, Fixed, 95% CI)	1.15 [0.54, 2.45]
32 Hypoglycaemia	3	376	Risk Ratio (M‐H, Fixed, 95% CI)	1.17 [0.84, 1.63]
32.1 Commenced < 24 hours	2	291	Risk Ratio (M‐H, Fixed, 95% CI)	1.16 [0.82, 1.64]
32.2 Commenced ≥ 48 to < 72 hours	1	85	Risk Ratio (M‐H, Fixed, 95% CI)	1.22 [0.35, 4.24]
33 Metabolic acidosis	4	305	Risk Ratio (M‐H, Fixed, 95% CI)	2.05 [0.94, 4.47]
33.1 Commenced < 24 hours	3	220	Risk Ratio (M‐H, Fixed, 95% CI)	1.63 [0.71, 3.72]
33.2 Commenced ≥ 48 to < 72 hours	1	85	Risk Ratio (M‐H, Fixed, 95% CI)	8.80 [0.49, 158.47]
34 Cholestasis	5	616	Risk Ratio (M‐H, Fixed, 95% CI)	1.26 [0.86, 1.84]
34.1 Commenced < 24 hours	3	409	Risk Ratio (M‐H, Fixed, 95% CI)	1.06 [0.70, 1.61]
34.2 Commenced ≥ 24 to < 48 hours	1	122	Risk Ratio (M‐H, Fixed, 95% CI)	1.45 [0.50, 4.18]
34.3 Commenced ≥ 48 to < 72 hours	1	85	Risk Ratio (M‐H, Fixed, 95% CI)	12.70 [0.74, 218.66]

Comparison 9. Higher versus lower amino acid intake in parenteral nutrition: subgrouped according to lipid intake.

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Mortality before hospital discharge	14	1407	Risk Ratio (M‐H, Fixed, 95% CI)	0.90 [0.69, 1.17]
1.1 Early lipid infusion	12	1161	Risk Ratio (M‐H, Fixed, 95% CI)	0.91 [0.70, 1.20]
1.2 Delayed lipid infusion ≥ 5 days	1	131	Risk Ratio (M‐H, Fixed, 95% CI)	0.84 [0.24, 2.98]
1.3 No lipid infusion	1	115	Risk Ratio (M‐H, Fixed, 95% CI)	0.31 [0.01, 7.36]
2 Neurodevelopmental disability	2	201	Risk Ratio (M‐H, Fixed, 95% CI)	1.04 [0.48, 2.23]
2.1 Early lipid infusion	2	201	Risk Ratio (M‐H, Fixed, 95% CI)	1.04 [0.48, 2.23]
3 Postnatal growth failure at discharge	3	203	Risk Ratio (M‐H, Fixed, 95% CI)	0.74 [0.56, 0.97]
3.1 Early lipid infusion	3	203	Risk Ratio (M‐H, Fixed, 95% CI)	0.74 [0.56, 0.97]
4 Days to regain birth weight	13	950	Mean Difference (IV, Fixed, 95% CI)	‐1.14 [‐1.73, ‐0.56]
4.1 Early lipid infusion	9	513	Mean Difference (IV, Fixed, 95% CI)	‐2.02 [‐2.73, ‐1.31]
4.2 Delayed lipid infusion ≥ 5 days	2	199	Mean Difference (IV, Fixed, 95% CI)	‐0.57 [‐2.04, 0.91]
4.3 No lipid infusion	2	238	Mean Difference (IV, Fixed, 95% CI)	2.04 [0.58, 3.50]
5 Maximal weight loss (grams)	3	235	Mean Difference (IV, Fixed, 95% CI)	‐22.71 [‐33.68, ‐11.74]
5.1 Early lipid infusion	3	235	Mean Difference (IV, Fixed, 95% CI)	‐22.71 [‐33.68, ‐11.74]
6 Maximal weight loss %	4	288	Mean Difference (IV, Fixed, 95% CI)	‐0.33 [‐1.61, 0.96]
6.1 Early lipid infusion	2	59	Mean Difference (IV, Fixed, 95% CI)	‐2.73 [‐5.71, 0.25]
6.2 Delayed lipid infusion ≥ 5 days	1	114	Mean Difference (IV, Fixed, 95% CI)	0.0 [‐1.87, 1.87]
6.3 No lipid infusion	1	115	Mean Difference (IV, Fixed, 95% CI)	0.51 [‐1.66, 2.68]
7 Weight gain g/kg/day to 1 month	4	373	Mean Difference (IV, Fixed, 95% CI)	‐1.50 [‐2.56, ‐0.44]
7.1 Early lipid infusion	3	250	Mean Difference (IV, Fixed, 95% CI)	0.42 [‐0.94, 1.78]
7.2 No lipid infusion	1	123	Mean Difference (IV, Fixed, 95% CI)	‐4.48 [‐6.17, ‐2.79]
8 Weight gain g/kg/day to discharge	4	291	Mean Difference (IV, Fixed, 95% CI)	0.76 [‐0.02, 1.54]
8.1 Early lipid infusion	3	177	Mean Difference (IV, Fixed, 95% CI)	1.11 [‐0.30, 2.52]
8.2 Delayed lipid infusion ≥ 5 days	1	114	Mean Difference (IV, Fixed, 95% CI)	0.60 [‐0.34, 1.54]
9 Linear growth cm/week up to 1 month age	2	245	Mean Difference (IV, Fixed, 95% CI)	‐0.16 [‐0.26, ‐0.06]
9.1 Early lipid infusion	1	122	Mean Difference (IV, Fixed, 95% CI)	0.0 [‐0.15, 0.15]
9.2 No lipid infusion	1	123	Mean Difference (IV, Fixed, 95% CI)	‐0.27 [‐0.40, ‐0.14]
10 Head circumference growth cm/week up to 1 month age	4	476	Mean Difference (IV, Fixed, 95% CI)	0.01 [‐0.04, 0.06]
10.1 Early lipid infusion	3	353	Mean Difference (IV, Fixed, 95% CI)	0.07 [0.02, 0.13]
10.2 No lipid infusion	1	123	Mean Difference (IV, Fixed, 95% CI)	‐0.38 [‐0.51, ‐0.24]
11 Head circumference growth cm/week to discharge	4	315	Mean Difference (IV, Fixed, 95% CI)	0.09 [0.06, 0.13]
11.1 Early lipid infusion	4	315	Mean Difference (IV, Fixed, 95% CI)	0.09 [0.06, 0.13]
12 Weight change z‐score to 1 month	1	96	Mean Difference (IV, Fixed, 95% CI)	‐0.20 [‐0.62, 0.22]
12.1 Early lipid infusion	1	96	Mean Difference (IV, Fixed, 95% CI)	‐0.20 [‐0.62, 0.22]
13 Weight change z‐score to discharge	2	207	Mean Difference (IV, Fixed, 95% CI)	0.01 [‐0.33, 0.36]
13.1 Early lipid infusion	2	207	Mean Difference (IV, Fixed, 95% CI)	0.01 [‐0.33, 0.36]
14 Weight change z‐score post discharge	2	201	Mean Difference (IV, Fixed, 95% CI)	0.13 [‐0.26, 0.52]
14.1 Early lipid infusion	2	201	Mean Difference (IV, Fixed, 95% CI)	0.13 [‐0.26, 0.52]
15 Head circumference change z‐score to 1 month	2	231	Mean Difference (IV, Fixed, 95% CI)	0.27 [0.08, 0.46]
15.1 Early lipid infusion	2	231	Mean Difference (IV, Fixed, 95% CI)	0.27 [0.08, 0.46]
16 Head circumference change z‐score to discharge	2	207	Mean Difference (IV, Fixed, 95% CI)	0.18 [‐0.15, 0.50]
16.1 Early lipid infusion	2	207	Mean Difference (IV, Fixed, 95% CI)	0.18 [‐0.15, 0.50]
17 Head circumference change z‐score post discharge	2	201	Mean Difference (IV, Fixed, 95% CI)	0.25 [‐0.14, 0.64]
17.1 Early lipid infusion	2	201	Mean Difference (IV, Fixed, 95% CI)	0.25 [‐0.14, 0.64]
18 Days to full enteral feeds	11	778	Mean Difference (IV, Fixed, 95% CI)	‐0.19 [‐1.07, 0.70]
18.1 Early lipid infusion	10	663	Mean Difference (IV, Fixed, 95% CI)	‐0.24 [‐1.14, 0.66]
18.2 No lipid infusion	1	115	Mean Difference (IV, Fixed, 95% CI)	2.04 [‐3.63, 7.71]
19 Late‐onset sepsis	15	1255	Risk Ratio (M‐H, Fixed, 95% CI)	0.96 [0.79, 1.18]
19.1 Early lipid infusion	12	933	Risk Ratio (M‐H, Fixed, 95% CI)	0.98 [0.79, 1.22]
19.2 Delayed lipid infusion ≥ 5 days	2	199	Risk Ratio (M‐H, Fixed, 95% CI)	0.89 [0.46, 1.71]
19.3 No lipid infusion	1	123	Risk Ratio (M‐H, Fixed, 95% CI)	0.82 [0.32, 2.05]
20 Necrotising enterocolitis	14	1301	Risk Ratio (M‐H, Fixed, 95% CI)	1.00 [0.68, 1.47]
20.1 Early lipid infusion	11	932	Risk Ratio (M‐H, Fixed, 95% CI)	0.91 [0.58, 1.43]
20.2 Delayed lipid infusion ≥5 days	1	131	Risk Ratio (M‐H, Fixed, 95% CI)	1.05 [0.15, 7.21]
20.3 No lipid infusion	2	238	Risk Ratio (M‐H, Fixed, 95% CI)	1.34 [0.59, 3.04]
21 Chronic lung disease ≥ 36 weeks' PMA	10	819	Risk Ratio (M‐H, Fixed, 95% CI)	1.04 [0.89, 1.23]
21.1 Early lipid infusion	8	590	Risk Ratio (M‐H, Fixed, 95% CI)	1.15 [0.98, 1.37]
21.2 Delayed lipid infusion ≥ 5 days	1	114	Risk Ratio (M‐H, Fixed, 95% CI)	0.56 [0.24, 1.29]
21.3 No lipid infusion	1	115	Risk Ratio (M‐H, Fixed, 95% CI)	0.61 [0.30, 1.24]
22 Patent ductus arteriosus	6	480	Risk Ratio (M‐H, Fixed, 95% CI)	0.78 [0.61, 0.99]
22.1 Early lipid infusion	4	243	Risk Ratio (M‐H, Fixed, 95% CI)	0.78 [0.56, 1.07]
22.2 Delayed lipid infusion ≥ 5 days	1	114	Risk Ratio (M‐H, Fixed, 95% CI)	0.96 [0.65, 1.42]
22.3 No lipid infusion	1	123	Risk Ratio (M‐H, Fixed, 95% CI)	0.46 [0.20, 1.04]
23 Intraventricular haemorrhage	3	341	Risk Ratio (M‐H, Fixed, 95% CI)	1.12 [0.74, 1.69]
23.1 Early lipid infusion	2	218	Risk Ratio (M‐H, Fixed, 95% CI)	1.09 [0.70, 1.70]
23.2 No lipid infusion	1	123	Risk Ratio (M‐H, Fixed, 95% CI)	1.26 [0.41, 3.91]
24 Severe intraventricular haemorrhage	11	904	Risk Ratio (M‐H, Fixed, 95% CI)	1.16 [0.74, 1.82]
24.1 Early lipid infusion	9	675	Risk Ratio (M‐H, Fixed, 95% CI)	1.25 [0.79, 2.00]
24.2 Delayed lipid infusion ≥ 5 days	1	114	Risk Ratio (M‐H, Fixed, 95% CI)	0.52 [0.05, 5.55]
24.3 No lipid infusion	1	115	Risk Ratio (M‐H, Fixed, 95% CI)	0.31 [0.01, 7.36]
25 Periventricular leukomalacia	7	720	Risk Ratio (M‐H, Fixed, 95% CI)	0.55 [0.24, 1.25]
25.1 Early lipid infusion	5	491	Risk Ratio (M‐H, Fixed, 95% CI)	0.71 [0.26, 1.91]
25.2 Delayed lipid infusion ≥ 5 days	1	114	Risk Ratio (M‐H, Fixed, 95% CI)	1.04 [0.07, 16.16]
25.3 No lipid infusion	1	115	Risk Ratio (M‐H, Fixed, 95% CI)	0.18 [0.02, 1.52]
26 Retinopathy of prematurity	4	269	Risk Ratio (M‐H, Fixed, 95% CI)	0.44 [0.21, 0.93]
26.1 Early lipid infusion	3	146	Risk Ratio (M‐H, Fixed, 95% CI)	0.32 [0.13, 0.77]
26.2 No lipid infusion	1	123	Risk Ratio (M‐H, Fixed, 95% CI)	1.58 [0.27, 9.10]
27 Severe retinopathy of prematurity > stage 2 or treated	8	672	Risk Ratio (M‐H, Fixed, 95% CI)	0.96 [0.56, 1.63]
27.1 Early lipid infusion	6	443	Risk Ratio (M‐H, Fixed, 95% CI)	0.92 [0.53, 1.59]
27.2 Delayed lipid infusion ≥ 5 days	1	114	Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
27.3 No lipid infusion	1	115	Risk Ratio (M‐H, Fixed, 95% CI)	1.83 [0.17, 19.66]
28 Cerebral palsy	2	122	Risk Ratio (M‐H, Fixed, 95% CI)	4.0 [0.89, 17.97]
28.1 Early lipid infusion	2	122	Risk Ratio (M‐H, Fixed, 95% CI)	4.0 [0.89, 17.97]
29 Developmental delay at ≥ 18 months	3	301	Risk Ratio (M‐H, Fixed, 95% CI)	1.35 [0.52, 3.53]
29.1 Early lipid infusion	2	201	Risk Ratio (M‐H, Fixed, 95% CI)	1.04 [0.35, 3.11]
29.2 Delayed lipid infusion ≥ 5 days	1	100	Risk Ratio (M‐H, Fixed, 95% CI)	3.25 [0.35, 30.19]
30 Blindness	2	122	Risk Ratio (M‐H, Fixed, 95% CI)	2.0 [0.20, 19.91]
30.1 Early lipid infusion	2	122	Risk Ratio (M‐H, Fixed, 95% CI)	2.0 [0.20, 19.91]
31 Deafness	1	90	Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
31.1 Early lipid infusion	1	90	Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
32 Abnormal serum ammonia	1	61	Risk Ratio (M‐H, Fixed, 95% CI)	3.10 [0.13, 73.16]
32.1 Early lipid infusion	1	61	Risk Ratio (M‐H, Fixed, 95% CI)	3.10 [0.13, 73.16]
33 Abnormal blood urea nitrogen	7	688	Risk Ratio (M‐H, Fixed, 95% CI)	2.77 [2.12, 3.60]
33.1 Early lipid infusion	5	489	Risk Ratio (M‐H, Fixed, 95% CI)	2.66 [1.95, 3.64]
33.2 Delayed lipid infusion ≥ 5 days	2	199	Risk Ratio (M‐H, Fixed, 95% CI)	3.01 [1.83, 4.95]
34 Hyperglycaemia, plasma glucose > 8.3 mmol/L	5	505	Risk Ratio (M‐H, Fixed, 95% CI)	0.69 [0.49, 0.96]
34.1 Early lipid infusion	3	306	Risk Ratio (M‐H, Fixed, 95% CI)	0.84 [0.57, 1.22]
34.2 Delayed lipid infusion ≥ 5 days	2	199	Risk Ratio (M‐H, Fixed, 95% CI)	0.39 [0.18, 0.83]
35 Hyperglycaemia treated with insulin	5	534	Risk Ratio (M‐H, Fixed, 95% CI)	1.24 [0.93, 1.66]
35.1 Early lipid infusion	4	420	Risk Ratio (M‐H, Fixed, 95% CI)	1.29 [0.96, 1.73]
35.2 Delayed lipid infusion ≥ 5 days	1	114	Risk Ratio (M‐H, Fixed, 95% CI)	0.35 [0.04, 3.22]
36 Hypoglycaemia	3	376	Risk Ratio (M‐H, Fixed, 95% CI)	1.17 [0.84, 1.63]
36.1 Early lipid infusion	1	168	Risk Ratio (M‐H, Fixed, 95% CI)	1.0 [0.67, 1.49]
36.2 Delayed lipid infusion ≥ 5 days	1	85	Risk Ratio (M‐H, Fixed, 95% CI)	1.22 [0.35, 4.24]
36.3 No lipid infusion	1	123	Risk Ratio (M‐H, Fixed, 95% CI)	1.68 [0.83, 3.41]
37 Metabolic acidosis	4	305	Risk Ratio (M‐H, Fixed, 95% CI)	2.05 [0.94, 4.47]
37.1 Early lipid infusion	2	205	Risk Ratio (M‐H, Fixed, 95% CI)	1.63 [0.71, 3.72]
37.2 Delayed lipid infusion ≥ 5 days	1	85	Risk Ratio (M‐H, Fixed, 95% CI)	8.80 [0.49, 158.47]
37.3 No lipid infusion	1	15	Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
38 Cholestasis	5	616	Risk Ratio (M‐H, Fixed, 95% CI)	1.26 [0.86, 1.84]
38.1 Early lipid infusion	4	531	Risk Ratio (M‐H, Fixed, 95% CI)	1.12 [0.76, 1.64]
38.2 Delayed lipid infusion ≥ 5 days	1	85	Risk Ratio (M‐H, Fixed, 95% CI)	12.70 [0.74, 218.66]

Comparison 10. Higher versus lower amino acid intake in parenteral nutrition: sensitivity analysis (allocation concealment, adequate randomisation, blinding of treatment, less than 10% loss to follow‐up).

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Mortality before hospital discharge	14	1407	Risk Ratio (M‐H, Fixed, 95% CI)	0.90 [0.69, 1.17]
1.1 Studies at low risk of bias	5	568	Risk Ratio (M‐H, Fixed, 95% CI)	0.74 [0.42, 1.29]
1.2 Methodological concern	9	839	Risk Ratio (M‐H, Fixed, 95% CI)	0.96 [0.71, 1.30]
2 Neurodevelopmental disability	2	201	Risk Ratio (M‐H, Fixed, 95% CI)	1.04 [0.48, 2.23]
2.1 Studies at low risk of bias	0	0	Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
2.2 Methodological concern	2	201	Risk Ratio (M‐H, Fixed, 95% CI)	1.04 [0.48, 2.23]
3 Postnatal growth failure at discharge	3	203	Risk Ratio (M‐H, Fixed, 95% CI)	0.74 [0.56, 0.97]
3.1 Studies at low risk of bias	1	50	Risk Ratio (M‐H, Fixed, 95% CI)	0.59 [0.39, 0.88]
3.2 Methodological concern	2	153	Risk Ratio (M‐H, Fixed, 95% CI)	0.84 [0.58, 1.20]
4 Postnatal growth failure post discharge	1	111	Risk Ratio (M‐H, Fixed, 95% CI)	0.66 [0.33, 1.32]
4.1 Studies at low risk of bias	0	0	Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
4.2 Methodological concern	1	111	Risk Ratio (M‐H, Fixed, 95% CI)	0.66 [0.33, 1.32]
5 Days to regain birth weight	13	950	Mean Difference (IV, Fixed, 95% CI)	‐1.14 [‐1.73, ‐0.56]
5.1 Studies at low risk of bias	2	94	Mean Difference (IV, Fixed, 95% CI)	‐0.49 [‐1.87, 0.89]
5.2 Methodological concern	11	856	Mean Difference (IV, Fixed, 95% CI)	‐1.29 [‐1.93, ‐0.64]
6 Maximal weight loss (grams)	3	235	Mean Difference (IV, Fixed, 95% CI)	‐22.71 [‐33.68, ‐11.74]
6.1 Studies at low risk of bias	1	50	Mean Difference (IV, Fixed, 95% CI)	22.60 [‐7.25, 52.45]
6.2 Methodological concern	2	185	Mean Difference (IV, Fixed, 95% CI)	‐29.79 [‐41.58, ‐17.99]
7 Maximal weight loss %	4	288	Mean Difference (IV, Fixed, 95% CI)	‐0.33 [‐1.61, 0.96]
7.1 Studies at low risk of bias	0	0	Mean Difference (IV, Fixed, 95% CI)	0.0 [0.0, 0.0]
7.2 Methodological concern	4	288	Mean Difference (IV, Fixed, 95% CI)	‐0.33 [‐1.61, 0.96]
8 Weight gain g/kg/day up to 1 month age	4	373	Mean Difference (IV, Fixed, 95% CI)	‐1.50 [‐2.56, ‐0.44]
8.1 Studies at low risk of bias	1	122	Mean Difference (IV, Fixed, 95% CI)	1.5 [‐0.27, 3.27]
8.2 Methodological concern	3	251	Mean Difference (IV, Fixed, 95% CI)	‐3.16 [‐4.48, ‐1.84]
9 Weight gain g/kg/day to discharge	4		Mean Difference (IV, Fixed, 95% CI)	Subtotals only
9.1 Studies at low risk of bias	0	0	Mean Difference (IV, Fixed, 95% CI)	0.0 [0.0, 0.0]
9.2 Methodological concern	4	291	Mean Difference (IV, Fixed, 95% CI)	0.76 [‐0.02, 1.54]
10 Linear growth cm/week up to 1 month age	2	245	Mean Difference (IV, Fixed, 95% CI)	‐0.16 [‐0.26, ‐0.06]
10.1 Studies at low risk of bias	1	122	Mean Difference (IV, Fixed, 95% CI)	0.0 [‐0.15, 0.15]
10.2 Methodological concern	1	123	Mean Difference (IV, Fixed, 95% CI)	‐0.27 [‐0.40, ‐0.14]
11 Head circumference growth cm/week up to 1 month age	5	562	Mean Difference (IV, Fixed, 95% CI)	0.07 [0.03, 0.11]
11.1 Studies at low risk of bias	2	257	Mean Difference (IV, Fixed, 95% CI)	0.09 [0.02, 0.15]
11.2 Methodological concern	3	305	Mean Difference (IV, Fixed, 95% CI)	0.06 [0.02, 0.10]
12 Head circumference growth cm/week to discharge	3	229	Mean Difference (IV, Fixed, 95% CI)	0.07 [0.02, 0.11]
12.1 Studies at low risk of bias	0	0	Mean Difference (IV, Fixed, 95% CI)	0.0 [0.0, 0.0]
12.2 Methodological concern	3	229	Mean Difference (IV, Fixed, 95% CI)	0.07 [0.02, 0.11]
13 Weight change z‐score up to 1 month age	1	96	Mean Difference (IV, Fixed, 95% CI)	‐0.20 [‐0.62, 0.22]
13.1 Studies at low risk of bias	0	0	Mean Difference (IV, Fixed, 95% CI)	0.0 [0.0, 0.0]
13.2 Methodological concern	1	96	Mean Difference (IV, Fixed, 95% CI)	‐0.20 [‐0.62, 0.22]
14 Weight change z‐score to discharge	2	207	Mean Difference (IV, Fixed, 95% CI)	0.01 [‐0.33, 0.36]
14.1 Studies at low risk of bias	0	0	Mean Difference (IV, Fixed, 95% CI)	0.0 [0.0, 0.0]
14.2 Methodological concern	2	207	Mean Difference (IV, Fixed, 95% CI)	0.01 [‐0.33, 0.36]
15 Weight change z‐score post discharge	2	201	Mean Difference (IV, Fixed, 95% CI)	0.13 [‐0.26, 0.52]
15.1 Studies at low risk of bias	0	0	Mean Difference (IV, Fixed, 95% CI)	0.0 [0.0, 0.0]
15.2 Methodological concern	2	201	Mean Difference (IV, Fixed, 95% CI)	0.13 [‐0.26, 0.52]
16 Head circumference change z‐score up to 1 month	2	231	Mean Difference (IV, Fixed, 95% CI)	0.27 [0.08, 0.46]
16.1 Studies at low risk of bias	1	135	Mean Difference (IV, Fixed, 95% CI)	0.37 [0.15, 0.59]
16.2 Methodological concern	1	96	Mean Difference (IV, Fixed, 95% CI)	0.0 [‐0.36, 0.36]
17 Head circumference change z‐score to discharge	2	207	Mean Difference (IV, Fixed, 95% CI)	0.18 [‐0.15, 0.50]
17.1 Studies at low risk of bias	0	0	Mean Difference (IV, Fixed, 95% CI)	0.0 [0.0, 0.0]
17.2 Methodological concern	2	207	Mean Difference (IV, Fixed, 95% CI)	0.18 [‐0.15, 0.50]
18 Head circumference change z‐score post discharge	1	111	Mean Difference (IV, Fixed, 95% CI)	0.03 [‐0.46, 0.52]
18.1 Studies at low risk of bias	0	0	Mean Difference (IV, Fixed, 95% CI)	0.0 [0.0, 0.0]
18.2 Methodological concern	1	111	Mean Difference (IV, Fixed, 95% CI)	0.03 [‐0.46, 0.52]
19 Days to full enteral feeds	11	778	Mean Difference (IV, Fixed, 95% CI)	‐0.19 [‐1.07, 0.70]
19.1 Studies at low risk of bias	3	169	Mean Difference (IV, Fixed, 95% CI)	‐0.20 [‐1.60, 1.20]
19.2 Methodological concern	8	609	Mean Difference (IV, Fixed, 95% CI)	‐0.17 [‐1.32, 0.97]
20 Late‐onset sepsis	15	1255	Risk Ratio (M‐H, Fixed, 95% CI)	0.96 [0.79, 1.18]
20.1 Studies at low risk of bias	4	461	Risk Ratio (M‐H, Fixed, 95% CI)	0.94 [0.71, 1.25]
20.2 Methodological concern	11	794	Risk Ratio (M‐H, Fixed, 95% CI)	0.98 [0.73, 1.31]
21 Necrotising enterocolitis	14	1428	Risk Ratio (M‐H, Fixed, 95% CI)	0.93 [0.65, 1.33]
21.1 Studies at low risk of bias	5	511	Risk Ratio (M‐H, Fixed, 95% CI)	0.89 [0.50, 1.60]
21.2 Methodological concern	10	917	Risk Ratio (M‐H, Fixed, 95% CI)	0.95 [0.60, 1.50]
22 Chronic lung disease at ≥ 36 weeks' PMA	10	819	Risk Ratio (M‐H, Fixed, 95% CI)	1.04 [0.89, 1.23]
22.1 Studies at low risk of bias	2	177	Risk Ratio (M‐H, Fixed, 95% CI)	1.02 [0.79, 1.31]
22.2 Methodological concern	8	642	Risk Ratio (M‐H, Fixed, 95% CI)	1.06 [0.86, 1.30]
23 Intraventricular haemorrhage	3	341	Risk Ratio (M‐H, Fixed, 95% CI)	1.12 [0.74, 1.69]
23.1 Studies at low risk of bias	1	122	Risk Ratio (M‐H, Fixed, 95% CI)	1.05 [0.64, 1.73]
23.2 Methodological concern	2	219	Risk Ratio (M‐H, Fixed, 95% CI)	1.23 [0.60, 2.55]
24 Severe intraventricular haemorrhage	11	904	Risk Ratio (M‐H, Fixed, 95% CI)	1.16 [0.74, 1.82]
24.1 Studies at low risk of bias	4	343	Risk Ratio (M‐H, Fixed, 95% CI)	1.42 [0.66, 3.03]
24.2 Methodological concern	7	561	Risk Ratio (M‐H, Fixed, 95% CI)	1.03 [0.59, 1.81]
25 Periventricular leukomalacia	7	720	Risk Ratio (M‐H, Fixed, 95% CI)	0.55 [0.24, 1.25]
25.1 Studies at low risk of bias	3	299	Risk Ratio (M‐H, Fixed, 95% CI)	0.61 [0.21, 1.81]
25.2 Methodological concern	4	421	Risk Ratio (M‐H, Fixed, 95% CI)	0.47 [0.13, 1.69]
26 Retinopathy of prematurity	4	269	Risk Ratio (M‐H, Fixed, 95% CI)	0.44 [0.21, 0.93]
26.1 Studies at low risk of bias	1	75	Risk Ratio (M‐H, Fixed, 95% CI)	0.16 [0.04, 0.67]
26.2 Methodological concern	3	194	Risk Ratio (M‐H, Fixed, 95% CI)	0.85 [0.33, 2.22]
27 Severe retinopathy of prematurity (> stage 2 or treated)	8	672	Risk Ratio (M‐H, Fixed, 95% CI)	0.96 [0.56, 1.63]
27.1 Studies at low risk of bias	3	252	Risk Ratio (M‐H, Fixed, 95% CI)	0.77 [0.36, 1.66]
27.2 Methodological concern	5	420	Risk Ratio (M‐H, Fixed, 95% CI)	1.20 [0.57, 2.55]
28 Cerebral palsy	2	122	Risk Ratio (M‐H, Fixed, 95% CI)	4.0 [0.89, 17.97]
28.1 Studies at low risk of bias	0	0	Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
28.2 Methodological concern	2	122	Risk Ratio (M‐H, Fixed, 95% CI)	4.0 [0.89, 17.97]
29 Developmental delay at ≥ 18 months	3	301	Risk Ratio (M‐H, Fixed, 95% CI)	1.35 [0.52, 3.53]
29.1 Studies at low risk of bias	0	0	Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
29.2 Methodological concern	3	301	Risk Ratio (M‐H, Fixed, 95% CI)	1.35 [0.52, 3.53]
30 Blindness	2	122	Risk Ratio (M‐H, Fixed, 95% CI)	2.0 [0.20, 19.91]
30.1 Studies at low risk of bias	0	0	Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
30.2 Methodological concern	2	122	Risk Ratio (M‐H, Fixed, 95% CI)	2.0 [0.20, 19.91]
31 Deafness	1	90	Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
31.1 Studies at low risk of bias	0	0	Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
31.2 Methodological concern	1	90	Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
32 Abnormal serum ammonia > 122 μmol/L	1	61	Risk Ratio (M‐H, Fixed, 95% CI)	3.10 [0.13, 73.16]
32.1 Studies at low risk of bias	1	61	Risk Ratio (M‐H, Fixed, 95% CI)	3.10 [0.13, 73.16]
32.2 Methodological concern	0	0	Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
33 Abnormal blood urea nitrogen	7	688	Risk Ratio (M‐H, Fixed, 95% CI)	2.77 [2.12, 3.60]
33.1 Studies at low risk of bias	2	183	Risk Ratio (M‐H, Fixed, 95% CI)	12.29 [1.66, 90.79]
33.2 Methodological concern	5	505	Risk Ratio (M‐H, Fixed, 95% CI)	2.57 [1.97, 3.34]
34 Hyperglycaemia, plasma glucose > 8.3 mmol/L	5	505	Risk Ratio (M‐H, Fixed, 95% CI)	0.69 [0.49, 0.96]
34.1 Studies at low risk of bias	0	0	Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
34.2 Methodological concern	5	505	Risk Ratio (M‐H, Fixed, 95% CI)	0.69 [0.49, 0.96]
35 Hyperglycaemia treated with insulin	5	534	Risk Ratio (M‐H, Fixed, 95% CI)	1.24 [0.93, 1.66]
35.1 Studies at low risk of bias	0	0	Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
35.2 Methodological concern	5	534	Risk Ratio (M‐H, Fixed, 95% CI)	1.24 [0.93, 1.66]
36 Hypoglycaemia	3	376	Risk Ratio (M‐H, Fixed, 95% CI)	1.17 [0.84, 1.63]
36.1 Studies at low risk of bias	0	0	Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
36.2 Methodological concern	3	376	Risk Ratio (M‐H, Fixed, 95% CI)	1.17 [0.84, 1.63]
37 Metabolic acidosis	4	305	Risk Ratio (M‐H, Fixed, 95% CI)	2.05 [0.94, 4.47]
37.1 Studies at low risk of bias	0	0	Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
37.2 Methodological concern	4	305	Risk Ratio (M‐H, Fixed, 95% CI)	2.05 [0.94, 4.47]
38 Cholestasis	5	616	Risk Ratio (M‐H, Fixed, 95% CI)	1.26 [0.86, 1.84]
38.1 Studies at low risk of bias	2	249	Risk Ratio (M‐H, Fixed, 95% CI)	1.21 [0.67, 2.17]
38.2 Methodological concern	3	367	Risk Ratio (M‐H, Fixed, 95% CI)	1.30 [0.79, 2.13]

Characteristics of studies

Characteristics of included studies [ordered by study ID]

Anderson 1979.

Methods	Single‐centre randomised controlled trial in USA before 1979
Participants	Inclusion criteria: Appropriate‐for‐gestational‐age preterm infants whose clinical condition seemed to preclude oral feedings for a period of at least 5 days were enrolled in the study (total n = unclear). Exclusion criteria: none reported
Interventions	Higher group (n = 7): glucose plus AA 2.5 g/kg/d (Aminosyn) 60 calories/kg/d Lower group (n = 7): isocaloric at 60 calories/kg/d glucose alone All infants: nil by mouth for 5 days
Outcomes	Primary outcomes: not reported Other outcomes: plasma electrolytes, BUN, and acid‐base status; plasma amino acid concentrations and fatty acid patterns of total serum lipids at 0 and at 5 days; fatty acid composition Nitrogen balances were determined on the third and fourth days. Nitrogen balances were calculated as intake minus all measured output, corrected for measured change in BUN, with the volume distribution of urea assumed to be 75% of body weight.
Notes	Trial of higher early parenteral amino acid vs isocaloric glucose intake. No early parenteral lipid intake. Nil by mouth 5 days Nutritional intakes: Higher group: day 1 to 5: protein 2.5 g/kg/d; NPE 50 kcal/kg; NPE/g protein 20.0 kcal/g Lower group: day 1 to 5: protein 0 g/kg/d; NPE 60 kcal/kg; NPE/g protein * kcal/g Note: No data could be used in the review. Reported mean weight loss over 5 days (higher AA ‐2.0 g/kg/d vs lower AA ‐12.2 g/kg/d; P = NS); mean nitrogen balance (+ 178 mg/kg/d vs ‐132 mg/kg/d; P < 0.001); and mean BUN values (17 +/‐ 4.5 mg/dL vs 13 +/‐ 12 mg/dL; P = NS)
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Not reported
Allocation concealment (selection bias)	Unclear risk	"the infants were randomly assigned". Method not reported
Blinding of participants and personnel (performance bias) All outcomes	Unclear risk	Not reported
Blinding of outcome assessment (detection bias) All outcomes	Unclear risk	Not reported
Incomplete outcome data (attrition bias) All outcomes	High risk	One infant receiving the glucose regimen and 2 receiving the glucose plus amino acid regimen were excluded from the study when their clinical condition improved and oral feedings were begun before the end of the 5‐day study period; 1 infant in each group was excluded owing to glucose intolerance (5/14 (35%) excluded).
Selective reporting (reporting bias)	Unclear risk	Primary outcome not stated. Trial protocol not available
Other bias	Low risk	Similar at baseline

Balasubramanian 2013.

Methods	Single‐centre randomised controlled trial in India from 2008 to 2010
Participants	Inclusion criteria: inborn babies with birth weight 900 to 1250 grams from a level 3 NICU Exclusion criteria: babies at > first 24 hours of life, having obvious congenital anomalies affecting growth and requiring surgical intervention Mean gestational age (weeks (SD)): higher: 31.65 (1.97); lower: 32.12 (2.3)
Interventions	Higher group (n = 75): 3 g/kg/d of parenteral amino acids on day 1; dose increased to 4 g/kg/d on next day. No lipid Lower group (n = 75): 1 g/kg/d of parenteral amino acids on day 1; dose increased by 1 g/kg every day to maximum of 4 g/kg/d. No lipid All infants: PN was administered through peripheral intravenous line. Consisted of dextrose, amino acids, sodium, and potassium. Lipids, multi‐vitamins, and trace elements were not routinely provided (16/150 received parenteral lipid). All babies started on trophic feeds (10 mL/kg/d) on day 1; feeds were not advanced for the first 4 days (until dose advancement of parenteral amino acid supplements was complete). Subsequent feeds were advanced at a rate of 10 to 15 mL/kg/d if babies tolerated feeds.
Outcomes	Primary outcome: postnatal growth at 28 days (g/kg/d) Other outcomes: weight (g), length (cm), and head circumference (cm) at 28 days; gain in length and head circumference by 28 days (cm/week); days on PN; days required to regain birth weight; duration of hospital stay; and incidence of: patent ductus arteriosus, sepsis (early and late onset), intraventricular haemorrhage, necrotising enterocolitis, chronic lung disease, retinopathy of prematurity, hypoglycaemia (BGL < 40 mg/dL), and anaemia
Notes	Trial high early parenteral amino acid. No early parenteral lipid intake. Enteral feeds commenced day 1 Nutritional intakes: Higher group: day 1: protein 3.0 g/kg/d; NPE 44 kcal/kg; NPE/g protein 14.7 kcal/g. Day 4: protein 4.0 g/kg/d; NPE 56 to 70 kcal/kg; NPE/g protein 14 to 17.5 kcal/g Lower group: day 1: protein 1.0 g/kg/d; NPE 36 kcal/kg; NPE/g protein 36 kcal/g. Day 4: protein 4.0 g/kg/d; NPE 56 to 70 kcal/kg. NPE/g protein 14 to 17.5 kcal/g Death within 28 days not reported separately from discharge against medical advice
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Random number sequence was generated in a variable block size of 2 or 4 each, via a “Random Allocation Software” computer programme.
Allocation concealment (selection bias)	Low risk	Random codes were kept in serially numbered, opaque, sealed, and identical envelopes.
Blinding of participants and personnel (performance bias) All outcomes	Low risk	Blinding of clinicians involved in care of the infant
Blinding of outcome assessment (detection bias) All outcomes	Low risk	Blinding of outcome assessors
Incomplete outcome data (attrition bias) All outcomes	High risk	27/150 (18%) not reported at 28 days owing to death or discharge (15/75 in higher group and 12/75 in lower group)
Selective reporting (reporting bias)	Unclear risk	Primary outcome stated as postnatal growth at 28 days (g/kg/d). Trial protocol not available
Other bias	Low risk	No imbalances after randomisation

Black 1981.

Methods	Single‐centre randomised controlled trial in USA before 1981
Participants	Infants admitted for respiratory distress (n = 21); average age at entry 3.4 to 4 days. Gestation not reported
Interventions	Higher group (n = 11): gradually increasing AA solution (Travasol) to 2.5 g/kg/d in addition to glucose and electrolyte solution. Infants in the experimental group also received intravenous lipid (Intralipid) if total serum bilirubin concentration did not exceed 6 mg/dL. Lower group (n = 10): glucose and electrolyte solution until enteral feedings were initiated All infants: Enteral feedings were initiated when the individual infant's respiratory status permitted.
Outcomes	Primary outcome: effects of PN on hepatic function (GGT, bile salts, conjugated bilirubin) reported at 0 and 7 days Other outcomes: sepsis
Notes	Trial of higher parenteral amino acid and lipid intake. Similar enteral feeds Nutritional intakes: Higher group: maximal intake: protein 2.5 g/kg/d; NPE maximal intake kcal/kg; NPE/g protein * kcal/g Lower group: maximal intake: protein 0 g/kg/d; NPE maximal intake kcal/kg; NPE/g protein * kcal/g Note: cholestasis not included in review as reported at 7 days only
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Table of random numbers used
Allocation concealment (selection bias)	Unclear risk	Method not reported
Blinding of participants and personnel (performance bias) All outcomes	Unclear risk	Not reported
Blinding of outcome assessment (detection bias) All outcomes	Unclear risk	Not reported
Incomplete outcome data (attrition bias) All outcomes	Unclear risk	2/21 excluded as developed cholestasis related to causes other than TPN therapy (1 in each group)
Selective reporting (reporting bias)	Unclear risk	Trial protocol not available
Other bias	Unclear risk	Baseline data inadequate to determine similarity of groups

Blanco 2008.

Methods	Single‐centre randomised controlled trial in USA from 2002 to 2005
Participants	Inclusion criteria: birth weight < 1000 grams and age < 12 hours of life. Gestational age > 24 weeks added by data safety monitoring board after enrolment of 20 infants because of high mortality rate of infants at < 24 weeks' gestation Exclusion criteria: major congenital anomalies and imminent death
Interventions	Higher group (n = 30): 2.0 g/kg/d of AA soon after enrolment with increases of 1 g/kg/d every 24 hours up to maximum of 4 g/kg/d, and continued at that level until day 7. Lipid commenced day 1 at 0.5 g/kg/d and increased to 2.7 g/kg/d on day 6 Lower group (n = 31): 0.5 g/kg/d AA (Aminosyn PF; with 40 mg/kg/d cysteine hydrochloride) in total parenteral nutrition solution starting in first 24 to 36 hours, with increases of 0.5 g/kg/d every 24 hours to maximum of 3.0 g/kg/d, and continued until day 7. Lipid commenced day 1 at 0.6 g/kg/d and increased to 2.8 g/kg/d on day 6 All infants: After study period, all infants were maintained on PN with AA 3.5 g/kg/d until sufficient enteral feedings were accomplished, then were weaned as PN volume decreased (approximately 2 g/kg/d on half of total fluid intake and 1 g/kg/d on less than one‐third of total fluid intake). All infants were prescribed lipids, glucose, minerals, trace elements, and vitamins. Initiation and advancement of oral feedings were determined by attending neonatologist (details not reported).
Outcomes	Primary outcome: mean serum K during first 3 days Other outcomes: Evaluated at 0, 3, 6, 12, and 18 months' corrected gestational age and at 24 months' chronological age by examination, Bayley SCID II. Abnormal urea > 60 mg/dL (21.4 mmol/L). Ammonia obtained if urea > 60 mg/dL. In survivors, reported grade 3 to 4 IVH; threshold ROP; necrotising enterocolitis; sepsis; BPD (oxygen at 36 weeks). In survivors followed up, reported weight gain at 28 days; days to full feeds; and neurodevelopment
Notes	Trial of higher early and maximal parenteral amino acid intake. Parenteral lipid started day 1. Unclear timing of enteral feeds. Higher group AA solution not documented Nutritional intakes: Higher group: day 1: protein 1.4 g/kg/d; NPE 22 kcal/kg; NPE/g protein 15.7 kcal/g. Day 7: protein 3.7 g/kg/d; NPE 55.9 kcal/kg; NPE/g protein 15.1 kcal/g Lower group: day 1: protein 0.0 g/kg/d; NPE 22 kcal/kg; NPE/g protein * kcal/g. Day 7: protein 2.9 g/kg/d; NPE 52.6 kcal/kg; NPE/g protein 18.1 kcal/g
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Method not reported
Allocation concealment (selection bias)	Low risk	infants were randomised by the clinical pharmacist with cards in sealed sequential opaque envelopes.
Blinding of participants and personnel (performance bias) All outcomes	Low risk	AA solution was added via pharmacy per study protocol, and clinical care team was unaware of group allocation.
Blinding of outcome assessment (detection bias) All outcomes	Low risk	Not reported for short‐term outcomes; 2‐year follow up: "All of the members of the clinic staff were masked to treatment group allocation of each infant"
Incomplete outcome data (attrition bias) All outcomes	High risk	Variable losses reported for neonatal outcomes. 1/62 (2%) lost for biochemical and mortality outcomes. Losses to other neonatal growth and late follow‐up: 11/27 survivors lower AA group and 8/24 survivors AA group (29/61 = 47%)
Selective reporting (reporting bias)	Low risk	Primary outcome hyperkalaemia. ClinicalTrials.gov. Registration number: NCT00290160
Other bias	High risk	Greater number of infants at ≤ 24 weeks' gestation allocated to higher AA group

Bulbul 2012.

Methods	Single‐centre randomised controlled trial in Turkey before 2012
Participants	Inclusion criteria: preterm infants appropriately sized for gestational age < 32 weeks Exclusion criteria: transfer to another hospital within 48 hours after birth, congenital (cardiac, pulmonary, or gastrointestinal) anomalies or metabolic abnormalities known to affect energy or nutrient metabolism, severe asphyxia characterised by seizures or severe metabolic acidosis on first day of life, evidence of infection, and infants of diabetic mothers
Interventions	Higher group (n = 22): parenteral nutrition starting with 3.0 g/kg/d amino acids and 3.0 g/kg/d lipids on day 1 Lower group (n = 22): parenteral nutrition starting with 1.0 g/kg/d amino acids (Primene 10%) and 1.0 g/kg/d lipid (Intralipid 20%) increased by 1.0 g/kg/d with an aimed intake of 3.0 g/kg/d amino acids and 3 g/kg/d lipid on day 3 All infants: glucose started at 6 to 8 mg/kg/min the first day increased gradually to 12 mg/kg/min to maintain blood glucose 80 to 100 mg/dL. Target non‐protein calorie intakes (glucose plus lipid) were 35 to 40 kcal/kg/d on first day and 70 to 80 kcal/kg on third day of life. Enteral feeds commenced first 24 to 48 hours. Maximum parenteral amino acid dosage was reduced by percentage of total nutrition volume, represented by patient’s enteral feeding volume. Parenteral amino acid dosage was reduced when enteral feedings supplied 0.5 g/kg/d protein and was stopped when enteral feedings supplied 75% of total nutrition volume.
Outcomes	Primary outcome: plasma amino acid concentrations during 2 postnatal weeks Other outcomes: blood ammonia, blood urea nitrogen, triglyceride concentrations, and postnatal growth. Reported sepsis; IVH grade 3 or 4; NEC stage 2
Notes	Trial of high early parenteral amino acid and lipid intake. Early enteral feeds Nutritional intakes: Higher group: day 1: protein 3.0 g/kg/d; NPE ˜59 kcal/kg; NPE/g protein 19.7 ± 6.6 kcal/g. Day 7: protein 3.0 g/kg/d; NPE ˜90 kcal/kg; NPE/g protein 31.1 ± 6.7 kcal/g Lower group:day 1: protein 1.0 g/kg/d; NPE 37.9 kcal/kg; NPE/g protein 37.9 ± 6.1 kcal/g. Day 7: protein 3.0 g/kg/d; NPE ˜90 kcal/kg; NPE/g protein 29.7 ± 6.7 kcal/g
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Independent researcher used a computer‐generated randomisation table based on blocks of 4 to assign to group 1 or 2, which corresponded to batch numbers on parenteral nutrition products.
Allocation concealment (selection bias)	Low risk	Investigators, parents, and nursing staff were unaware of treatment allocation. The code of batch numbers was broken after data analysis had been performed.
Blinding of participants and personnel (performance bias) All outcomes	Low risk	Investigators, parents, and nursing stuff were unaware of treatment allocation. The code of batch numbers was broken after data analysis had been performed.
Blinding of outcome assessment (detection bias) All outcomes	Low risk	"Investigators, parents, and nursing staff were unaware of treatment allocation. The code of the batch numbers was broken after data analysis had been performed".
Incomplete outcome data (attrition bias) All outcomes	Low risk	None reported
Selective reporting (reporting bias)	Unclear risk	Protocol not available
Other bias	Low risk	Groups similar at baseline

Burattini 2013.

Methods	Single‐centre randomised controlled trial in Italy from 2006 to 2009
Participants	Inclusion criteria: infants with birth weight 500 to 1249 grams Exclusion criteria: out born admitted beyond 24 hours' age, patients with birth asphyxia, life expectancy shorter than 7 days, major congenital abnormalities, and congenital metabolic disorders
Interventions	Higher group (n = 64): AA 2.5 g/kg/d on day 1 and reaching maximum of 4 g/kg/d on day 4. Lipid commenced day 5 Lower group (n = 67): AA 1.5 g/kg/d on day 1 followed by increments of 0.5 g/kg/d to maximum of 2.5 g/kg/d on third day. Lipid commenced day 5 All infants: Non‐protein energy (NPE), minerals, and micronutrient intakes were identical for the 2 groups; AA solution was TrophAmine 6%. Glucose was increased from 6 to 12 g/kg/d from first to sixth day of life and lipids from 0.5 to 2.5 g/kg/d from first to fifth day of life. Minimal enteral feeds given from birth to day 7
Outcomes	Primary outcome: body weight and incidence of small‐for‐gestational‐age infants at 36 weeks' postmenstrual age Other outcomes: maximum weight loss, age regained birth weight, age at 1800 grams, growth velocity birth to 1800 grams, growth velocity regained BW to 1800 grams and from regained birth weight to 36 weeks' PMA, weight, total body length, and head circumference at 36 weeks' PMA Metabolic tolerance assessed by blood urea/BUN, triglycerides, and glucose concentrations, pH, and standard base excess. Did not report SD or ranges for urea Reported high BUN > 32.6 mg/dL (11.6 mmol/L) as percentages Reported mortality; NEC (no definition); ROP > grade 1; IVH grade 3 or 4; PVL (no definition); BPD (oxygen at 36 weeks) 2‐Year follow‐up included body weight, total body length, head circumference, and neurodevelopment assessed with Bayley SCID III.
Notes	Trial of high early and maximal parenteral amino acid intake. Parenteral lipid from day 5. Minimal enteral feeds for first 7 days Nutritional intakes: Higher group: day 1: protein 2.5 g/kg/d; NPE kcal/kg; NPE/g protein kcal/g. Day 4: protein 4.0 g/kg/d; NPE kcal/kg; NPE/g protein kcal/g Lower group:day 1: protein 1.5 g/kg/d; NPE kcal/kg; NPE/g protein kcal/g. Day 4: protein 2.5 g/kg/d; NPE kcal/kg; NPE/g protein kcal/g NPE intakes not reported Note: higher mean BUN 14.49 mmol/L on day 6 in higher AA group vs 10.9 mmol/L on day 5 for lower AA group (P < 0.001).
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Random permuted blocks within strata protocol. Stratification groups 500 to 749 grams, 750 to 999 grams, and 1000 to 1249 grams
Allocation concealment (selection bias)	Low risk	Sealed envelopes
Blinding of participants and personnel (performance bias) All outcomes	High risk	Caregivers were aware of PN group assignment.
Blinding of outcome assessment (detection bias) All outcomes	Low risk	Growth and neurodevelopment were assessed by personnel blinded to treatment assignment.
Incomplete outcome data (attrition bias) All outcomes	High risk	17/131 (13%) withdrawn post randomisation ‐ death (n = 9), necrotising enterocolitis (n = 4), and gastrointestinal surgery (n = 4). 18 further losses at 2 years of age (total 27%)
Selective reporting (reporting bias)	Unclear risk	Trial protocol not available
Other bias	Low risk	Similar at baseline

Can 2012.

Methods	Single‐centre randomised controlled trial in Turkey from February 2009 to May 2010
Participants	Inclusion criteria: preterm infants born at 27 to 33 weeks' gestation appropriate for gestational age Exclusion criteria: transfer to another hospital after birth, major congenital anomalies (cardiac, pulmonary, or gastrointestinal), metabolic abnormalities (severe asphyxia characterised by seizures or severe metabolic acidosis on first day of life, evidence of infection and maternal diabetes). Neonates on formula owing to inadequate breast milk
Interventions	Higher group (n = 26): 3.0 g/kg/d amino acids (Primene 10%) and 2.0 g/kg/d lipids (Intralipid 20%) with increment of 1.0 g/kg/d for target intake of 4.0 g/kg/d amino acids and 3.0 g/kg/d lipids on day 2 Lower group (n = 27): 1.5 g/kg/d amino acids and 1.0 g/kg/d lipids on first day of life with increment of 1.0 g/kg/d for target intake of 4.0 g/kg/d amino acids and 3.0 g/kg/d lipids on day 3 All infants: Intake of fluid, glucose, and electrolytes was ordered by attending neonatologist. Glucose infusion was started at 6 to 8 mg/kg/min during first day to maintain blood glucose 80 to 100 mg/dL. Parenteral amino acid dosage was reduced when enteral feeding supplied 0.5 g/kg/d protein and was terminated when enteral feeding supplied 75% of total nutrition volume. Infants initially fed unfortified expressed breast milk. Trophic enteral feeding started within first 24 hours and advanced 10 to 20 mL/kg/d after feeding volumes were tolerated. If amount of breast milk reached 100 mL/kg/d, human milk fortifier was added.
Outcomes	Primary outcomes: postnatal growth factors ‐ daily weight, total daily fluid intake, PN fluid volume and composition, enteral feeding volume, time of initiation of PN and enteral feeding, duration of PN and full enteral feeding time. Postnatal growth retardation defined as body weight < 10th percentile of national standards for infants at 40 weeks' gestation Other outcomes: BPD (oxygen at 36 weeks' postmenstrual age), NEC (Bell’s stage 2 or higher), PDA (diagnosed on echocardiography, considered clinically significant when it required medical treatment), IVH grade II or higher, cystic periventricular leukomalacia, ROP
Notes	Trial of higher early parenteral amino acid and lipid intake. Early minimal enteral nutrition Nutritional intakes: Higher group: day 1: protein g/kg/d. Day 2: protein 4 g/kg/d. Week 1: average protein intake: 3.87 (SD 0.7) g/kg/d; average energy intake: 74.3 (SD 19.1) kcal/kg/d. Average NPE/g protein ˜15.2 kcal/g Lower group: day 1: protein 1.5 g/kg/d. Day 3: protein 4 g/kg/d. Week 1: average protein intake 3.07 (SD 0.4); average energy intake: 64.6 (SD 18.7) kcal/kg/d. Average NPE/g protein ˜17.0 kcal/g Weight, length, and head circumference reported at 3 weeks of age Note: Trial authors provided clarification that publications Can 2012 and Can 2013 are separate studies without duplicate reporting of infants.
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Computer‐generated randomisation table based on blocks of 4 were used to allocate participants to group 1 or 2.
Allocation concealment (selection bias)	Low risk	Batch numbers on PN products corresponded to the individual's randomisation code.
Blinding of participants and personnel (performance bias) All outcomes	Low risk	PN was prepared by the hospital pharmacy. Investigators, parents, and nursing staff were unaware of treatment allocation.
Blinding of outcome assessment (detection bias) All outcomes	Low risk	The code of batch numbers was broken after data analysis had been performed.
Incomplete outcome data (attrition bias) All outcomes	Low risk	53 infants were enrolled, 3 (6%) died from NEC complications, and 50 infants reported growth outcomes.
Selective reporting (reporting bias)	Unclear risk	Trial protocol not available
Other bias	Low risk	Similar at baseline

Can 2013.

Methods	Single‐centre randomised controlled trial in Turkey from April 2009 to December 2010
Participants	Inclusion criteria: preterm infants appropriately sized at gestational age < 32 weeks Exclusion criteria: transfer to another hospital within 48 hours, intrauterine growth retardation, small‐for‐gestational‐age and large‐for‐gestational‐age birth weights, congenital (cardiac, pulmonary, or gastrointestinal) anomalies or metabolic diseases known to affect energy or nutrient metabolism, severe asphyxia, and evidence of infection
Interventions	Higher group (n = 40): 3.0 g/kg/d amino acids (Primene 10%) and 2.0 g/kg/d lipids (Intralipid 20%) day 1 increased by 1.0 g/kg/d with aimed intake of 4.0 g/kg/d amino acids and 3.0 g/kg/d lipids on day 2 Lower group (n = 35): 1.5 g/kg/d amino acids and 1.0 g/kg/d lipids day 1 increased by 1.0 g/kg/d with aimed intake of 4.0 g/kg/d amino acids and 3.0 g/kg/d lipids on day 3 All infants: intake of fluid, glucose, and electrolytes ordered by attending neonatologist. Glucose infusion started at 6 to 8 mg/kg/min during first day of life increased to 12 mg/kg/min to maintain blood glucose concentration between 80 and 100 mg/dL. Parenteral amino acid and lipid dosage was reduced when enteral feedings supplied 0.5 g/kg/d protein and 1 g/kg/d lipids. They were terminated when enteral feedings supplied 100 to 140 mL/kg/d of total nutrition volume. Infants were initially fed unfortified expressed breast milk when clinically stable within first day. Trophic enteral feeding was initiated and advanced 10 to 20 mL/kg/d after feeding volumes were tolerated. If breast milk reached 100 mL/kg/d, human milk fortifier was added.
Outcomes	Primary outcome: levels of IGF‐1 and IGFBP3 Other outcomes: ROP; laser ablation. Did not specify timing of report of weight gain
Notes	Trial of higher early parenteral amino acid and lipid intake. Early minimal enteral nutrition Nutritional intakes: Higher group: day 1: protein 3 g/kg/d. Day 2: protein 4 g/kg/d. Average protein intake: 3.52 (SD 0.7) g/kg/d; average energy intake: 121.5 (SD 35.5) kcal/kg/d. Average NPE:g protein: 30.5 kcal/g Lower group: day 1: protein 1.5 g/kg/d. Day 3: protein 4 g/kg/d. Average protein intake: 3.2 (SD 0.5) g/kg/d; average energy intake: 115.5 (28.5) kcal/kg/d. Average NPE:g protein: 32.1 kcal/g Note: Trial authors provided clarification that publications Can 2012 and Can 2013 are separate studies without duplicate reporting of infants.
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Computer‐generated randomisation table based on blocks of 4 were used to allocate participants to group 1 or 2.
Allocation concealment (selection bias)	Low risk	Batch numbers on PN products corresponded to the individual's randomisation code.
Blinding of participants and personnel (performance bias) All outcomes	Low risk	Parenteral nutrition was prepared by the hospital pharmacy. Investigators, parents, and nursing staff were blinded to treatment allocation.
Blinding of outcome assessment (detection bias) All outcomes	Low risk	The code of batch numbers was broken after data analysis had been performed.
Incomplete outcome data (attrition bias) All outcomes	Low risk	None reported
Selective reporting (reporting bias)	Unclear risk	Timing of clinical and growth measurements not reported. Protocol not available
Other bias	Low risk	Similar at baseline

Clark 2007.

Methods	Multi‐centre randomised controlled trial in USA from 2005 to 2006
Participants	Inclusion criteria: infants born at 23 weeks 0 days to 29 weeks 6 days gestation, inborn and parental consent Exclusion criteria: infants 48 hours of age or with a major congenital anomaly
Interventions	Higher group: amino acid supplementation started at 1.5 g/kg/d of amino acids advanced 1 g/kg/d to maximum of 3.5 g/kg/d on day 3 of treatment. Lipid 0.5 g/kg/d advanced 0.5 g/kg/d to maximum of 3.5 g/kg/d Lower group: amino acid supplementation started at 1.0 g/kg/d advanced 0.5 g/kg/d to maximum of 2.5 g/kg/d on day 4 of treatment. Lipid 0.5 g/kg/d advanced 0.5 g/kg/d to maximum of 3.5 g/kg/d All infants: As feedings were advanced, intravenous fluids were decreased accordingly. When parenteral nutrition was administered at 70 mL/kg/d, the quantity of amino acids that could be added to the parenteral nutrition decreased (limited by the solubility of elements in the parenteral nutrition). For both groups, amino acid supplementation was stopped when feedings reached 100 to 130 mL/kg/d.
Outcomes	Primary outcomes: growth, assessed as changes in weight, length, and head circumference over first 28 days. Data were reported as medians (interquartile range) and so could not be included in meta‐analysis. Other outcomes: blood amino acid profiles and incidence of mortality and major morbidities reported to 28 days. Cholestasis: direct serum bilirubin > 5 mg/dL. Abnormal blood urea nitrogen > 50 mg/dL (17.85 mmol/L)
Notes	Trial of higher early and maximal parenteral amino acid intake. Parenteral lipid commenced early. Early minimal enteral nutrition Nutritional intakes: Higher group: day 1: protein 1.5 g/kg/d. Day 3: protein 3.5 g/kg/d. NPE and NPE/g protein not reported. Average parenteral NPE to day 7: 65.9 kcal/kg/d; average NPE/g protein: 18.8 kcal/g Lower group: day 1: protein 1.0 g/kg/d. Day 4: protein 2.5 g/kg/d. NPE and NPE/g protein not reported. Average parenteral NPE to day 7: 66.4 kcal/kg/d; average NPE/g protein: 26.6 kcal/g
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Used an electronic system to assign a randomised code. Random assignment was stratified according to site.
Allocation concealment (selection bias)	Low risk	PN solution was mixed according to the random assignment code for each treatment assignment.
Blinding of participants and personnel (performance bias) All outcomes	Low risk	Parenteral nutrition solution was labelled “study AA,” and the concentrations of amino acids was not indicated on the bag. A pharmacy log tracked quantities of amino acids in the solution for each patient.
Blinding of outcome assessment (detection bias) All outcomes	Unclear risk	None reported
Incomplete outcome data (attrition bias) All outcomes	Low risk	Intention‐to‐treat analysis ‐ reported clinical outcomes of all infants. 11/122 (9%) did not complete the study and therefore did not have follow‐up laboratory information.
Selective reporting (reporting bias)	Low risk	Predefined outcomes. Clinicaltrials.gov identifier NCT00120926
Other bias	Low risk	Similar at baseline

Hata 2002.

Methods	Single‐centre randomised controlled trial in Japan from 1990 to 1992
Participants	Inclusion criteria: neonatal surgical patients who received TPN. All patients were fasted and were given fat‐free parenteral nutrition for at least 10 days.
Interventions	Higher group 1 (n = 12): AA 3.45 +/‐ 0.07 g/kg/d. No lipid Higher group 2 (n = 8): AA 2.59 +/‐ 0.07 g/kg/d. No lipid Lower group (n = 10): AA 1.72 +/‐ 0.06 g/kg/d (data not reported in the review) All infants: dextrose average 21.5 g/kg/d and no lipid. All participants were fasted and were given fat‐free parenteral nutrition for at least 10 days. Received the same quantities of vitamins and electrolytes
Outcomes	Primary outcome: cholestasis Other outcomes: not documented
Notes	Trial of higher early and maximal parenteral amino acid intake. No parenteral lipid. Surgical infants nil by mouth Nutritional intakes: Higher group 1: protein 3.45 g/kg/d; NPE 86.0 kcal/kg; NPE/g protein 24.9 kcal/g Higher group 2: protein 2.59 g/kg/d; NPE 85.6 kcal/kg; NPE/g protein 33.1 kcal/g Lower group: protein 1.72 g/kg/d; NPE 86.0 kcal/kg; NPE/g protein 50.0 kcal/g
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Method not reported
Allocation concealment (selection bias)	Unclear risk	Method not reported
Blinding of participants and personnel (performance bias) All outcomes	Unclear risk	None reported
Blinding of outcome assessment (detection bias) All outcomes	Unclear risk	None reported
Incomplete outcome data (attrition bias) All outcomes	Unclear risk	None reported
Selective reporting (reporting bias)	Unclear risk	Protocol not available
Other bias	High risk	Small sample size with variable gender ratios and surgical diagnoses

Heimler 2010.

Methods	Single‐centre randomised controlled trial in USA before 2010
Participants	Inclusion criteria: appropriate‐for‐gestational‐age preterm infants at < 34 weeks' gestation requiring respiratory support and intravenous nutrition in first week Exclusion criteria: major congenital anomalies or sepsis
Interventions	Higher group (n = 10): 1.5 g/kg amino acids at mean age of 15 hours (range 8 to 24 hours) (Trophamine) with 40 mg cysteine hydrochloride per 1 gram amino acids advanced by 0.5 g/kg/d to maximum 2.5 g/kg day 3. No lipid to day 4 Lower group (n = 10): glucose solution with vitamins and calcium gluconate. Received amino acids 1 g/kg/d starting at a mean age of 78 hours (range 72 to 88 hours), advanced by 0.5 g/kg/d to maximum 2.5 g/kg day 7. No lipid to day 4 All infants: Infants did not receive any oral intake during first 3 days. Received intravenous glucose solution with 200 mg/kg/d of calcium gluconate and vitamins. Lipid introduced day 4
Outcomes	Primary outcomes: weight change and redistribution of fluid compartments (deuterium oxide dilution) during first week; infant’s ability to tolerate parenteral amino acid solution Other outcomes: not documented. Nitrogen balance estimated for intake minus estimated urinary nitrogen loss
Notes	Trial of higher early parenteral amino acid intake. Parenteral lipid commenced day 4. No enteral intake to day 4 Nutritional intakes: Higher group: day 1 to 3: protein 1.7 g/kg/d; NPE 34 kcal/kg; NPE/g protein 20 kcal/g. Day 1 to 7: protein 2.3 g/kg/d; NPE 51 kcal/kg; NPE/g protein 22.2 kcal/g Lower group:day 1 to 3: protein 0.0 g/kg/d; NPE 32 kcal/kg; NPE/g protein * kcal/g. Day 1 to 7: protein 1.0 g/kg/d; NPE 53 kcal/kg; NPE/g protein 53 kcal/g
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	"Randomisation". Method not reported
Allocation concealment (selection bias)	Unclear risk	Envelope. Method not reported
Blinding of participants and personnel (performance bias) All outcomes	Unclear risk	None reported
Blinding of outcome assessment (detection bias) All outcomes	Unclear risk	None reported
Incomplete outcome data (attrition bias) All outcomes	High risk	3/20 (15%) infants did not complete study.
Selective reporting (reporting bias)	Unclear risk	Designed to study effects on body weight, fluid compartments, and metabolic parameters. Protocol not available
Other bias	Low risk	Similar at baseline

Ibrahim 2004.

Methods	Single‐centre randomised controlled trial in USA from 2001 to 2002
Participants	Inclusion criteria: preterm infants at birth weight 501 to 1250 grams and gestational age 24 to 32 weeks who required mechanical ventilation for respiratory distress syndrome, at 1 hour of age, whose clinical conditions seemed to preclude oral feedings for at least 5 to 7 days Exclusion criteria: major congenital anomalies, twin‐to‐twin transfusion (haemoglobin concentrations differ by more than 5 g/dL), maternal diabetes treated with insulin, placenta previa, placenta abruptio, maternal history of drug abuse
Interventions	Higher group (n = 16): 3.5 g/kg/d AA (10% Trophamine) and 3 g/kg/d 20% Intralipid started within 2 hours. The non‐protein calorie‐to‐nitrogen ratio was 100:1. Lower group (n = 16): 5% to 10% glucose first 48 hours of life, then 2 g/kg/d AA and 0.5 g/kg/d 20% Intralipid after 48 hours. Amino acid and 20% Intralipid each increased by 0.5 g/kg/d to maximum 3.5 g/kg/d and 3 g/kg/d, respectively All infants: nil by mouth first 7 days
Outcomes	Primary outcomes: nitrogen balance and caloric intake during 7‐day study period. Nitrogen balance estimated for intake minus estimated urinary nitrogen loss Other outcomes: Apgar scores at 5 minutes, bilirubin, clinically significant PDA diagnosed by echocardiogram at the discretion of the attending physician, grade III or IV IVH, ROP, sepsis (positive blood culture), respiratory impairment, BPD (supplemental oxygen at 36 weeks' corrected age)
Notes	Trial of higher early parenteral amino acid and lipid intake. No enteral nutrition first 7 days Nutritional intakes (estimated): Higher group: day 1: protein 3.5 g/kg/d; NPE 51 kcal/kg; NPE/g protein 14.6 kcal/g. Day 7: protein g/kg/d; NPE 91.5 kcal/kg; NPE/g protein 26.1 kcal/g Lower group: day 1: protein 0 g/kg/d; NPE 32.2 kcal/kg; NPE/g protein * kcal/g. Day 7: protein 3.5 g/kg/d; 85 NPE kcal/kg; NPE/g protein 24.3 kcal/g Note: Data for nitrogen balance were reported numerically in each group for different time periods.
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	"Randomised". Method not reported
Allocation concealment (selection bias)	Low risk	Numbered, sealed envelopes
Blinding of participants and personnel (performance bias) All outcomes	High risk	None reported. Different management reported between groups
Blinding of outcome assessment (detection bias) All outcomes	Unclear risk	None reported
Incomplete outcome data (attrition bias) All outcomes	Low risk	Outcome data available for 15/16 infants in the higher AA group and 14/16 infants in the lower AA group with adequate urinary volumes to allow testing
Selective reporting (reporting bias)	Unclear risk	Protocol not available
Other bias	Unclear risk	Similar at baseline Secondary outcomes reported for surviving infants. Demoninators for each group appear to have been transposed in Table 3.

Kashyap 2007.

Methods	Single‐centre randomised controlled trial in USA
Participants	Inclusion criteria: appropriate‐for‐gestational‐age VLBW infants (less than 1250 g) Exclusion criteria: not documented
Interventions	Higher group (n = 53): early parenteral nutrition providing 18% of energy as protein with target of achieving 4.0 g/kg/d of protein intake. Unclear starting AA and rate of grading Lower group (n = 48): early parenteral nutrition providing 12.5% of energy as protein with target of 3.0 g/kg/d of protein intake. Unclear starting AA and rate of grading All infants: Once targeted protein intakes were achieved, they were maintained and energy intake was increased to provide 100 to 105 kcal/kg/d. Parenteral nutrition was discontinued when 120 mL/kg/d of enteral feeding was tolerated. Feeds were then advanced to provide protein intake of 4.0 g/kg/d and energy intake of 132 kcal/kg/d for both groups.
Outcomes	Primary outcome: not documented Other outcomes: not documented
Notes	Trial of higher early and maximal parenteral amino acid intake. Unclear commencement of parenteral lipid. Early minimal enteral nutrition Note: not published in peer‐reviewed journal Nutritional intakes: unclear from reports to date
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Method not reported
Allocation concealment (selection bias)	Unclear risk	Method not reported
Blinding of participants and personnel (performance bias) All outcomes	Unclear risk	None reported
Blinding of outcome assessment (detection bias) All outcomes	Unclear risk	None reported
Incomplete outcome data (attrition bias) All outcomes	Unclear risk	None reported
Selective reporting (reporting bias)	Unclear risk	Protocol not available
Other bias	Unclear risk	Not reported

Liu 2015.

Methods	Randomised controlled trial in China March 2013 and June 2014
Participants	Inclusion criteria: preterm infants at birth weight 1000 to 2000 grams and admitted to hospital within 24 hours of birth Exclusion criteria: infants with congenital malformations, liver and kidney dysfunction
Interventions	Higher group (n = 29): 3.0 g/kg/d day 1 with increase of 0.5 to 1.0 g/kg/d and maximum 4.0 g/kg/d. Lipid 0.5 g/kg/d increased by 0.5 g/kg/d and maximum 3.0 g/kg/d Lower group 1 (n = 28): 2.0 g/kg/d day 1 with increase of 1.0 g/kg/d and maximum 3.7 g/kg/d. Lipid 0.5 g/kg/d increased by 0.5 g/kg/d and maximum 3.0 g/kg/d Lower group 2 (n = 29): 1.0 g/kg/d day 1 with increase of 1.0 g/kg/d and maximum 3.5 g/kg/d. Lipid 0.5 g/kg/d increased by 0.5 g/kg/d and maximum 3.0 g/kg/d All infants: Other routine parenteral nutrition and enteral nutrition support were also applied. Lipid commenced at 48 hours. Enteral feeds commenced within 72 hours.
Outcomes	Primary outcomes: short‐term response and tolerance Other outcomes: anthropometry and days to full enteral feeds, hospital stay, costs, and biochemical tolerance
Notes	Trial of higher early and maximal parenteral amino acid. Similar early lipid from day 2 and enteral feeds by day 3 Nutritional intakes: average reported in article: Higher group 1: protein 3.57 g/kg/d; NPE 56 +/‐ 9 kcal/kg; NPE/g protein 15.7 kcal/g Lower group: protein 2.53 g/kg/d; NPE 57 +/‐ 8 kcal/kg; NPE/g protein 22.5 kcal/g Lower group: protein 1.58 g/kg/d; NPE 58 +/‐ 8 kcal/kg; NPE/g protein 36.7 kcal/g Note: Two lower amino acid groups combined for analyses. Days to reach 100 kcal/kg of enteral nutrition used as days to full enteral feeds in review. Biochemical data could not be used in review.
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Method not reported
Allocation concealment (selection bias)	Unclear risk	Method not reported
Blinding of participants and personnel (performance bias) All outcomes	High risk	None reported. Different management reported between groups
Blinding of outcome assessment (detection bias) All outcomes	Unclear risk	None reported
Incomplete outcome data (attrition bias) All outcomes	Low risk	Outcome data available for all participants
Selective reporting (reporting bias)	Unclear risk	Protocol not available
Other bias	High risk	Differences in proportions of males and females between groups

Makay 2007.

Methods	Single‐centre randomised controlled trial in Turkey (n = 72) from 2003 to 2006
Participants	Inclusion criteria: singleton newborns with gestational age ≥ 35 weeks whose clinical condition precluded oral feeding for 3 days Exclusion criteria: major congenital anomalies and/or perinatal factors associated with increased risk of hyperbilirubinaemia, including maternal diabetes mellitus, polycythaemia, perinatal asphyxia, hypothermia, cephalohematoma, intracranial haemorrhage, or perinatal infection
Interventions	Higher group: Early parenteral nutrition group received 1.0 g/kg/d amino acids (TrophAmine 6%) started within first 8 hours and 1.0 g/kg/d lipid (intralipid 20%) day 2. Lower group: fluid regimen started with glucose 10% first day followed by glucose and electrolyte solution and added amino acids (0.5 g/kg/d) and lipid (0.5 g/kg/d) on days 3 and 4, respectively All infants: Amino acids and lipid were increased by 0.5 g/kg/d to maximum of 3.0 g/kg/d in both groups. Peripheral vein catheterisation was used for parenteral nutrition. Lipids were administered from a separate catheter over 24 hours. Planned intakes of the 2 regimens were isovolumetric.
Outcomes	Primary outcome: bilirubin levels Other outcomes: energy intake; changes in body weight; time of first stool production; quantity of daily stool output; relative changes in serum bilirubin levels at 24, 48, and 72 hours; need for phototherapy; duration of phototherapy
Notes	Trial of higher early parenteral amino acid and lipid intake. No enteral feeds Nutritional intakes: Higher group: day 1: protein 1.0 g/kg/d; NPE 23.7 kcal/kg; NPE/g protein 23.7 kcal/g. Day 3: protein 2.0 g/kg/d; NPE 47.8 kcal/kg; NPE/g protein 23.9 kcal/g Lower group: day 1: protein 0.0 g/kg/d; NPE 22.4 kcal/kg; NPE/g protein kcal/g. Day 3: protein 0.5 g/kg/d; NPE 37.4 kcal/kg; NPE/g protein 74.8 kcal/g Note: No data could be used in review.
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Method not reported
Allocation concealment (selection bias)	Unclear risk	Method of sequence generation not reported. Consecutively enrolled after informed consent and eligibility confirmed
Blinding of participants and personnel (performance bias) All outcomes	High risk	None reported. Different management reported between groups
Blinding of outcome assessment (detection bias) All outcomes	Unclear risk	None reported
Incomplete outcome data (attrition bias) All outcomes	High risk	18/72 (25%) withdrawn ‐ positive direct Coombs test findings (n = 7), intracranial haemorrhage (n = 1), and introduction of enteral feeding first 48 hours of life (n = 10)
Selective reporting (reporting bias)	Unclear risk	Protocol not available
Other bias	High risk	Baseline differences between groups including birth weight

Morgan 2014.

Methods	Single‐centre randomised controlled trial in UK October 2009 and July 2012
Participants	Inclusion criteria: infants at < 29 weeks’ gestation and weighing < 1200 grams. Randomisation occurred before 72 hours of age but always within 120 hours. Exclusion criteria: infants thought unlikely to survive, infants with major congenital or chromosomal abnormalities, infants known to have a parenchymal brain lesion on cranial ultrasound scan before 48 hours age, infants without parental consent
Interventions	All infants commenced on PN with AA 1.8 g/kg/d; lipid 1.0 g/kg/d; and 10% glucose day 1 to 2, then: Higher group (n = 74): AA 2.9 g/kg/d day 3 to 4 increased to 3.9 g/kg/d day 5; lipid increased to 1.9 g/kg/d day 3 to 4; 2.8 g/kg/d day 5 to 6; 3.8 g/kg/d from day 7; glucose increased 12% from day 3 Lower group (n = 76): AA 2.4 g/kg/d day 3 to 4 increased to 2.8 g/kg/d day 5; lipid increased to 1.9 g/kg/d day 3 to 4; 2.8 g/kg/d from day 5; glucose 10% All infants: preferential use of expressed or donor breast milk, which remained unfortified until 150 mL/kg/d enteral feeds. PN administration will continue until child is on 75% enteral feeds.
Outcomes	Primary outcome: change in head circumference day 28 and 36 weeks' PMA Other outcomes: growth measures expected to be concordant with primary outcomes; efficiency of nutrient delivery; metabolic tolerance to each regimen; issues related to delivery of nutritional regimens; major neonatal morbidity in survivors; neurodevelopmental outcome at 2 years; ROP (requiring laser treatment); conjugated hyperbilirubinaemia > 50 mmol/L
Notes	Trial of higher parenteral amino acid, lipid, and glucose intake during grading and maximal. Similar enteral feeds Nutritional intakes: Higher group: week 1: protein 2.8 g/kg/d; NPE 62.8 kcal/kg; NPE/g protein 22.4 kcal/g. Day 1 to 28: protein 3.19 g/kg/d; NPE 89.1 kcal/kg; NPE/g protein 27.92 kcal/g Lower group: week 1: protein 2.4 g/kg/d; NPE 58.4 kcal/kg; NPE/g protein 24.3 kcal/g. Day 1 to 28: protein 2.88 g/kg/d; NPE 83.6 kcal/kg; NPE/g protein 29.0 kcal/g Trial authors have indicated that they have no relevant financial relationships to disclose.
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Stata 10 used to generate block randomisation codes within strata defined by gestation at birth: 24 to 26 and 27 to 28 completed weeks
Allocation concealment (selection bias)	Low risk	Once generated, randomisation codes were sealed in opaque serially numbered envelopes and were given to the pharmacy to store in a secure place. After written parental consent, the pharmacy opened the next sequential envelope in the correct stratum.
Blinding of participants and personnel (performance bias) All outcomes	Low risk	Blinding of caregivers and parents
Blinding of outcome assessment (detection bias) All outcomes	Low risk	Blinding of outcome assessors
Incomplete outcome data (attrition bias) All outcomes	Low risk	None reported
Selective reporting (reporting bias)	Low risk	Prespecified outcomes and timing. ISRCTN Register identifier ISRCTN76597892
Other bias	Low risk	No clinically important differences between groups

Murdock 1995.

Methods	Single‐centre randomised controlled trial in England (n = 44) before 1995
Participants	Inclusion criteria: infants weighing less than 2000 grams at birth who for clinical reasons could not receive enteral feeds immediately after birth Exclusion criteria: infants requiring surgical treatment
Interventions	Higher group 1: amino acids (Vamin 9) 1 g/kg day 1 and 1.4 g/kg day 2; parenteral glucose 10% 7 g/kg day 1 and 10 g/kg day 2; lipid 1 g/kg days 1 and 2 Higher group 2: amino acids (Vamin 9) 1 g/kg day 1 and 1.4 g/kg day 2; parenteral glucose 10% 7 g/kg day 1 and 10 g/kg day 2. No lipid Lower group: glucose 10% 7 g/kg day 1 and 10 g/kg day 2. No amino acids or lipid All infants: Infants fed more than 1 mL/h of expressed breast milk or formula were withdrawn from the study.
Outcomes	Primary outcome: biochemical tolerance during first 48 hours Other outcomes: not documented
Notes	Trial of higher early parenteral amino acid with no lipid vs higher early parenteral amino acid and lipid intake vs no early parenteral amino acid or lipid intake. No enteral feeds Nutritional intakes: Higher group 1: day 1: protein 1 g/kg/d; NPE 37 kcal/kg; NPE/g protein 37.0 kcal/g. Day 2: protein 1.4 g/kg/d; NPE 49 kcal/kg; NPE/g protein 35.0 kcal/g Higher group 2: day 1: protein 1 g/kg/d; NPE 28 kcal/kg; NPE/g protein 28.0 kcal/g. Day 2: protein 1.4 g/kg/d; NPE 40 kcal/kg; NPE/g protein 28.6 kcal/g Lower group: day 1: protein 0 g/kg/d; NPE 28 kcal/kg; NPE/g * protein kcal/g. Day 2: protein 0 g/kg/d; NPE 40 kcal/kg; NPE/g protein * kcal/g Note: No data could be used in the review.
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	"Randomly allocated" method not reported
Allocation concealment (selection bias)	Unclear risk	"Recruited to the study after informed parental consent had been obtained. They were randomly allocated..." (method not reported)
Blinding of participants and personnel (performance bias) All outcomes	High risk	None reported. Different management reported between groups
Blinding of outcome assessment (detection bias) All outcomes	Unclear risk	None reported
Incomplete outcome data (attrition bias) All outcomes	High risk	15/44 (34%) infants were withdrawn owing to enteral feeding initiation.
Selective reporting (reporting bias)	Unclear risk	Protocol not available
Other bias	High risk	Imbalances in birth weight at baseline

Pappoe 2009.

Methods	Single‐centre randomised controlled trial in USA from 2005 to 2006
Participants	Inclusion criteria: birth weight 600 to 1200 grams Exclusion criteria: no life‐threatening or significant congenital malformations. Infants who died within 24 hours of admission were excluded.
Interventions	Higher group (n = 24): started on 49 kcal/kg/d non‐protein energy and 2 g/kg/d AA (Trophamine 10%) day 1; increased to 75 to 80 kcal/kg/d NPE and 3.5 g/kg/d AA by day 3. Lipid started 2 g/kg/d 20% intralipid day 1 increased to 3 g/kg day 2 and 3.5 g/kg day 3 Lower group (n = 19): started on 25 kcal/kg/d non‐protein energy and 1 g/kg/d AA day 1; increased to 75 to 80 kcal/kg/d NPE and 3.5 g/kg/d AA by day 6. Lipid started 1 g/kg/d 20% intralipid day 1 increased to 0.5 g/kg day 2 to maximum 3.5 g/kg/d All infants: glucose commenced 5 mg/kg/min increased to 12 mg/kg/min day 5. Enteral nutrition commenced at discretion of clinician
Outcomes	Primary outcome: growth (% weight loss and days to regain birth weight) Other outcomes: PDA, IVH, ROP, and mortality. Azotemia urea > 40 mg/dL (14.3 mmol/L); hyperglycaemia glucose > 200 mg/dL (11.1 mmol/L)
Notes	Trial of higher early parenteral amino acid and lipid intake. Early enteral nutrition Nutritional intakes: Higher group: day 1: protein 2 g/kg/d; NPE 49 kcal/kg; NPE/g protein 24.5 kcal/g. Day 3: protein 3.5 g/kg/d; NPE 75 to 80 kcal/kg; NPE/g protein 21.4 to 22.9 kcal/g Lower group: day 1: protein 1 g/kg/d; NPE 25 kcal/kg; NPE/g protein 25 kcal/g. Day 6: protein 3.5 g/kg/d; NPE 75 to 80 kcal/kg; NPE/g protein 21.4 to 22.9 kcal/g
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	"Randomized". Method not reported
Allocation concealment (selection bias)	Low risk	Opaque envelopes used
Blinding of participants and personnel (performance bias) All outcomes	Unclear risk	None reported
Blinding of outcome assessment (detection bias) All outcomes	Unclear risk	None reported
Incomplete outcome data (attrition bias) All outcomes	Low risk	1/43 excluded (trisomy 21)
Selective reporting (reporting bias)	Unclear risk	Protocol not available
Other bias	Low risk	Similar at baseline

Pildes 1973.

Methods	Single‐centre randomised controlled trial in USA before 1972
Participants	Inclusion criteria: preterm infants < 1500 grams at 24 to 48 hours of age (n = 51 infants) Exclusion criteria: none reported
Interventions	Higher group (n = not reported): used solution containing AA 3.4 g/100 mL; and glucose 10.5 g/100 mL with lactate, saline, and potassium added Lower group (n = not reported): 5% glucose saline and potassium added All infants: enteral feeds with formula containing 2.8 g protein per 100 mL. Total fluid intake increased by 15 mL/kg/d until maximum 150 mL/kg/d
Outcomes	Primary outcome: not reported Other outcomes: mortality; biochemical data; days to regain birth weight; weight gain to 21 days; time to reach discharge weight
Notes	Trial of higher early parenteral amino acid. No lipid intake. Similar enteral nutrition ‐ timing unclear Nutritional intakes: unclear from data given Notes: abnormal amniograms reported indicative of likely inappropriate amino acid balance of preparation Numbers in groups not reported, so data could not be used in the review
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Method not reported
Allocation concealment (selection bias)	Unclear risk	Method not reported
Blinding of participants and personnel (performance bias) All outcomes	Unclear risk	None reported
Blinding of outcome assessment (detection bias) All outcomes	Unclear risk	None reported
Incomplete outcome data (attrition bias) All outcomes	Low risk	None reported
Selective reporting (reporting bias)	Unclear risk	Primary outcome not stated
Other bias	Unclear risk	Baseline characteristics of groups not reported

Rivera 1993.

Methods	Single‐centre randomised controlled trial in USA before 1991
Participants	Inclusion criteria: preterm infants with respiratory distress who were less than 24 hours old and required mechanically assisted ventilation and indwelling arterial catheters Exclusion criteria: None reported.
Interventions	Higher group (n = 11): AA 1.5 g/kg/d (Aminosyn PF) with glucose Lower group (n = 12): glucose infusion All infants: No infant received lipid emulsion or enteral feeding.
Outcomes	Primary outcome: safety and efficacy Other outcomes: nitrogen balance and biochemical tolerance
Notes	Trial of higher early parenteral amino acid intake. Isocaloric NPE. No lipid intake or enteral feeds Nutritional intakes: Higher group: day 1 to 3: protein 1.5 g/kg/d; NPE not reported; NPE/protein not calculable Lower group: day 1 to 3: protein 0 g/kg/d; NPE not reported; NPE/protein * kcal/g Note: did not report clinical outcomes
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	"Randomisation". Method not reported
Allocation concealment (selection bias)	Unclear risk	Envelope randomisation. Detailed method not reported
Blinding of participants and personnel (performance bias) All outcomes	High risk	None reported. Different management reported between groups
Blinding of outcome assessment (detection bias) All outcomes	Unclear risk	None reported
Incomplete outcome data (attrition bias) All outcomes	Unclear risk	None reported
Selective reporting (reporting bias)	Unclear risk	Did not report clinical outcomes. Protocol not available
Other bias	High risk	Baseline differences between groups

Scattolin 2013.

Methods	Single‐centre randomised controlled trial in Italy (n = 136) from 2009 to 2010
Participants	Inclusion criteria: birth weight < 1250 grams and central venous line Exclusion criteria: > 72 hours of age, congenital infection, major congenital anomaly or metabolic disorders
Interventions	Before enrolment, all patients received an intravenous infusion of glucose and 1 to 1.5 g/kg/d of AA provided as TrophAmine 6% from birth. Higher group (n = 69): started at 2 g/kg/d and advanced from 1 g/kg/d to maximum of 4 g/kg/d on day 4 Lower group (n = 68): AA supplementation was started at 1.5 g/kg/d and advanced from 0.5 g/kg/d to maximum 3 g/kg/d on day 4. All infants: no parenteral lipid reported. Parenteral nutrition regimen with same non‐protein energy intake. As feeding advanced, intravenous fluids were decreased to keep total fluids below 150 mL/kg/d first month. Minimal enteral feeding (10 to 20 mL/kg/d) started on second day. After day 7, feedings were advanced at a rate of 10 to 20 mL/kg/d. When intake of 100 mL/kg/d was reached, human milk was fortified.
Outcomes	Primary outcome: growth and bone status without signs of AA intolerance Other outcomes: death, hospitalisation period, parenteral nutrition period, days at full enteral feeding, postnatal steroids, proven NEC (Bell's stage 2 or 3), severe intracranial haemorrhage (grade III or IV by Papile classification), periventricular leukomalacia and BPD (supplemental oxygen required at 36 weeks after conception), severe ROP (grade III or greater), proven sepsis (positive blood culture)
Notes	Trial of higher early and maximal parenteral amino acid intake. Isocaloric NPE. Lipid intake not reported. Early enteral intake Nutritional intakes: Higher group: day 1: protein 2 g/kg/d. Day 4: protein 4 g/kg/d Mean protein first week: 3.12 (SD 0.46) g/kg/d; mean NPE first week: 51.41 (SD 9.75) kcal kg//d; NPE/g protein 16.5 kcal/g Lower group: day 1: protein 1.5 g/kg/d. Day 4: protein 3 g/kg/d Mean protein first week: 2.10 (SD 0.46) g/kg/d; mean NPE first week: 48.69 (SD 10.41) kcal kg//d; NPE/g protein 23.2 kcal/g Note: denominator for outcome PVL unclear
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Method not reported
Allocation concealment (selection bias)	Unclear risk	Method not reported
Blinding of participants and personnel (performance bias) All outcomes	Low risk	All decisions to adjust clinical support of infants were made by their primary physicians, who were blinded to AA intake.
Blinding of outcome assessment (detection bias) All outcomes	Low risk	All physicians performing quantitative ultrasound and collecting anthropometric measures were blind to groups of examined infants.
Incomplete outcome data (attrition bias) All outcomes	High risk	21/136 (15%) were excluded as they were considered too unstable.
Selective reporting (reporting bias)	Unclear risk	Protocol not available
Other bias	Low risk	Similar at baseline

Tan 2008.

Methods	Single‐centre randomised controlled trial in England from 2004 to 2007
Participants	Inclusion criteria: infants born before 29 weeks’ gestation within 7 days of age Exclusion criteria: triplets and of higher multiplicity, those admitted after 7 days, infants with major congenital abnormalities
Interventions	Higher group (n = 68): PN increased stepwise from 1 g/kg/d protein and lipid, to 4 g/kg/d protein and lipid over 7 days. Target energy and protein intakes based on estimated composition of EBM were 133 to 150 kcal/kg/d and 4 g/kg/d. Lower group (n = 74): PN increased stepwise from 1 g/kg/d protein and lipid, to 3 g/kg/d protein and lipid over 5 days. Target energy and protein intakes were 133 kcal/kg/d and 3.3 g/kg/d for the control group. All infants: Carbohydrate intake was dependent upon total fluid allowance of each infant, which was increased from 60 and 90 mL/kg/d to 150 and 165 mL/kg/d in first 5 days. Micronutrients within the 2 PN were the same. Infants started milk within 48 hours or when clinically stable.
Outcomes	Primary outcome: head growth at 36 weeks' PMA Other outcomes: haemodynamically significant PDA; sepsis by positive blood, urine, or CSF culture, or raised C‐reactive protein with clinical signs of infection; NEC as all cases surgically confirmed or with strong clinical suspicion leading to medical treatment; cholestasis (conjugated bilirubin > 30 ųmol/L) and raised liver transaminases; severe IVH grade III and above; mechanical ventilation; CLD (oxygen requirement at 36 weeks’ PMA)
Notes	Trial of higher maximal parenteral and enteral amino acid and lipid intake. Early enteral nutrition Nutritional intakes: Higher group: day 1: protein 1 g/kg/d; NPE 25 kcal/kg; NPE/g protein 25 kcal/g. Day 7: protein 4 g/kg/d; NPE 89 kcal/kg; NPE/g protein 22.25 kcal/g Lower group: day 1: protein 1 g/kg/d; NPE 25 kcal/kg; NPE/g protein 25 kcal/g. Day 7: protein 3 g/kg/d; NPE 81 kcal/kg; NPE/g protein 27 kcal/g Note: reported outcomes at 36 weeks' PMA in survivors
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Variable‐length block randomisation was used.
Allocation concealment (selection bias)	Low risk	Randomisation codes were kept in sequentially numbered, opaque, sealed envelopes.
Blinding of participants and personnel (performance bias) All outcomes	High risk	None reported. Different management reported between groups
Blinding of outcome assessment (detection bias) All outcomes	High risk	Only measurement of OFC (primary outcome) blind to allocation
Incomplete outcome data (attrition bias) All outcomes	Unclear risk	Stated in text: "One hundred and forty‐two infants were randomised, 91 to the intervention group and 81 to the control group". Figure reports 142 randomised. All survivors reported
Selective reporting (reporting bias)	Unclear risk	Protocol not available
Other bias	Low risk	Similar at baseline

Tang 2009.

Methods	Single‐centre randomised controlled trial in China 2006; method of sequence generation not reported
Participants	Inclusion criteria: preterm infants at birth weight 1000 to 2000 grams Exclusion criteria: congenital malformations, severe lung and kidney dysfunction
Interventions	Higher group (n = 34): 2.4 g/kg/d of amino acid IV within 24 hours after birth increased by increments of 1.2 g/kg/d to maximum 3.6 g/kg/d Lower group 1 (n = 32): 1.0 g/kg/d of amino acid IV within 24 hours after birth, increased by increments of 0.5 g/kg/d until maximum of 3.0 g/kg/d Lower group 2 (n = 30): 0.5 g/kg/d of amino acid on day 3, increased by increments of 0.5 g/kg/d until maximum of 3.0 g/kg/d All infants: IV glucose 4 to 6 mg/kg/d (average 7.2 g/kg/d) day 1. From day 3 of life, commenced lipids 0.5 g/kg/d increased daily by 0.5 g/kg/d to maximum 3.0 g/kg/d
Outcomes	Primary outcome: efficacy and safety Other outcomes: postnatal weight loss, length of stay in NICU, days to reach 2000 grams, days to tolerate enteral nutrition, cost of hospitalisation, various biochemical markers
Notes	Trial of higher early and maximal parenteral amino acid intake Nutritional intakes: Higher group: day 1: protein 2.4 g/kg/d; NPE 28.8 kcal/kg; NPE/g protein 12.0 kcal/g. Day 3 to 7: protein 3.6 g/kg/d; NPE 54.8 kcal/kg; NPE/g protein ˜15.2 kcal/g Lower group 1: day 1: protein 1.0 g/kg/d; NPE 28.8 kcal/kg; NPE/g protein kcal/g. Day 5 to 7: protein 3.0 g/kg/d; NPE 57.7 kcal/kg; NPE/g protein 19.2 kcal/g Lower group 2: day 1: protein 0.5 g/kg/d; NPE 28.8 kcal/kg; NPE/g protein kcal/g. Day 6 to 7: protein 3.0 g/kg/d; NPE 53.6 kcal/kg; NPE/g protein 17.9 kcal/g Note: lower groups combined for comparison
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Method not reported
Allocation concealment (selection bias)	Unclear risk	Method not reported
Blinding of participants and personnel (performance bias) All outcomes	High risk	None reported. Different management reported between groups
Blinding of outcome assessment (detection bias) All outcomes	Unclear risk	None reported
Incomplete outcome data (attrition bias) All outcomes	Low risk	8/104 (8%) withdrawn
Selective reporting (reporting bias)	Unclear risk	Protocol not available
Other bias	Low risk	Groups similar at baseline

te Braake 2005.

Methods	Single‐centre randomised controlled trial in the Netherlands from 2003 to 2004
Participants	Inclusion criteria: preterm born infants with birth weights ≤ 1500 grams Exclusion criteria: congenital abnormalities; chromosome defects; metabolic diseases; endocrine, renal, or hepatic disorders
Interventions	Higher group (n = 66): AA 2.4 g/kg day 1 to 4 (Primene 10%) Lower group (n = 69): AA 0 g/kg day 1 increased to 1.2 g/kg day 3, 2.4 g/kg days 3 and 4 All infants: glucose 5.5 g/kg day 1, 5.6 g/kg day 2, 5.7 g/kg day 3, and 7.1 g/kg day 4. Lipid 0 g/kg day 1, 1.4 g/kg day 2, 2.8 g/kg day 3, and 2.8 g/kg day 4 (Intralipid 20%) Minimal enteral nutrition (6 to 12 feedings of 1.0 mL) was possible when started on postnatal day 2 to 3 and advanced to full enteral nutrition in subsequent days if tolerated. Fluid intakes were higher in the intervention group on postnatal days 1 and 2 owing to administration of AA. On all other days, fluid intakes were similar.
Outcomes	Primary outcome: safety and efficacy Other outcomes: blood gas, urea, glucose, amino acids. Nitrogen balance reported in subgroups of infants. Growth parameters (weight and head circumference and z‐score change) at 6 weeks and 2 years. Neurological and Bayley SCID II at 2 years. Postnatal growth failure reported at 6 weeks and 2 years of age (< 10th centile). Bayley MDI reported only in infants without disability
Notes	Trial of higher early parenteral amino acid intake. Lipid commenced early. Enteral feeds commenced early Nutritional intakes: Higher group: day 1: protein 2.4 g/kg/d; NPE 22 kcal/kg; NPE/g protein 9.2 kcal/g. Day 4: protein 2.4 g/kg/d; NPE 53.6 kcal/kg; NPE/g protein 22.3 kcal/g Lower group: day 1: protein 0 g/kg/d; NPE kcal/kg; NPE/g protein kcal/g. Day 4: protein 2.4 g/kg/d; NPE 53.6 kcal/kg; NPE/g protein 22.3 kcal/g Note: data for nitrogen balance presented in figures
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	"Randomized". Method not reported
Allocation concealment (selection bias)	Unclear risk	Method not reported
Blinding of participants and personnel (performance bias) All outcomes	High risk	Different management reported between groups. Blinding not reported
Blinding of outcome assessment (detection bias) All outcomes	Low risk	Follow‐up team blinded to allocation only
Incomplete outcome data (attrition bias) All outcomes	Low risk	6/135 (4%) excluded or lost to 2‐year follow‐up
Selective reporting (reporting bias)	Unclear risk	Protocol not available
Other bias	High risk	Infants in the intervention group were more frequently exposed to prenatal corticosteroids.

Thureen 2003.

Methods	Single‐centre randomised controlled trial in USA before 2003
Participants	Inclusion criteria: mechanically ventilated, ≤ 1300 grams in weight, anticipated to receive exclusive PN for first 48 hours of life, medically stable Exclusion criteria: sepsis and congenital or metabolic abnormalities known to affect energy or nutrient metabolism
Interventions	Higher group (n = 15): 3.0 g/kg/d amino acids (TrophAmine) day 1 to 2 Lower group (n = 13): 1.0 g/kg/d amino acids (TrophAmine) day 1 to 2 All infants: 1 g/kg/d lipid (Intralipid 20%). Glucose was administered at intakes to maintain serum glucose concentrations at 80 to 100 mg/dL. Target energy intakes (glucose plus lipid) were 35 to 40 kcal/kg/d. Minerals, trace elements, and vitamins were provided according to nursery protocol. Mean age at start of study amino acid infusion was 22.6 and 26.0 hours in low‐ vs high‐intake groups, respectively.
Outcomes	Primary outcome: protein balance by stable isotope method Other outcomes: safety and efficacy
Notes	Trial of higher early parenteral amino acid intake. Lipid commenced early. No enteral feeding Nutritional intakes: Higher group: day 2 to 3: protein 2.65 g/kg/d; NPE 49.2 kcal/kg; NPE/g protein 18.6 kcal/g Lower group: day 2 to 3: protein 0.85 g/kg/d; NPE 41.9 kcal/kg; NPE/g protein 49.3 kcal/g Note: Data for nitrogen balance differ from data reported in te Braake 2007 review.
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	"Randomised". Method not reported
Allocation concealment (selection bias)	Unclear risk	Method not reported
Blinding of participants and personnel (performance bias) All outcomes	High risk	None reported. Different management reported between groups
Blinding of outcome assessment (detection bias) All outcomes	Unclear risk	None reported
Incomplete outcome data (attrition bias) All outcomes	High risk	6/28 (21%) did not have leucine isotope studies, so protein balance was not determined.
Selective reporting (reporting bias)	Unclear risk	Protocol not available
Other bias	Low risk	Similar at baseline

Uthaya 2016.

Methods	2 X 2 factorial design randomised controlled trial in England starting July 2010 and ending July 2013 with final follow‐up in October 2013
Participants	Inclusion criteria: preterm infants born at < 31 weeks' gestation Exclusion criteria: infants with life‐threatening abnormalities, infants for whom we were unable to administer trial PN within 24 hours of birth
Interventions	Lower group 1 (n = 42): Inc‐AA/SO* = infants received 1.7 g/kg/d amino acids on day 1, 2.1 g/kg/d on day 2, and maximum 2.7 g/kg/d from day 3 Lower group 2 (n = 42): Inc‐AA/SMOF* = infants received 1.7 g/kg/d amino acids on day 1, 2.1 g/kg/d on day 2, and maximum 2.7 g/kg/d from day 3 Higher group 1 (n = 41): Imm‐RDI/SO* = Imm‐RDI infants received 3.6 g/kg/d from day 1. PN was provided in an aqueous volume of 90 mL/kg/d on days 1 and 2 and 120 mL/kg/d from day 3. Higher group 2 (n = 43): Imm‐RDI/SMOF* = Imm‐RDI infants received 3.6 g/kg/d from day 1. PN was provided in an aqueous volume of 90 mL/kg/d on days 1 and 2 and 120 mL/kg/d from day 3. *SMOF, soybean oil, medium‐chain triglycerides, olive oil, and fish oil; SO, soybean‐based lipid emulsion. All infants: Carbohydrate intake was 8.6 g/kg from day 1. An intravenous lipid was provided at 2 g/kg/d on day 1 increased to 3 g/kg/d from day 2. Weaning of trial PN was commenced once an infant received milk volumes > 60 mL/kg/d. Trial PN ceased when an infant had received and tolerated 150 mL milk/kg/d for ≥ 24 hours.
Outcomes	Primary outcomes: non‐adipose mass for amino acid intervention; intra‐hepatocellular lipid content for lipid intervention Secondary outcomes: total adiposity, adipose tissue depots, insulin sensitivity (quantitative insulin sensitivity check index), total and regional brain volumes, weight, head circumference, length Safety measures (serum lipids, cholesterol, creatinine, urea, bilirubin, liver function tests, blood glucose, and base deficit) from routine clinical tests Serious adverse events, including sepsis and death
Notes	Group 1 and group 2 (different lipid groups) combined within amino acid intake strata for meta‐analysis Trial of higher early and late parenteral amino acid intake. Lipid commenced early. Early enteral feeding Nutritional intakes: Higher group: day 1: protein 2.4 to 2.5 g/kg/d; NPE kcal/kg; NPE/g protein kcal/ g; day 3: protein 3.1 g/kg/d; NPE kcal/kg; NPE/g protein kcal/g Lower group: day 1: protein 1.2 g/kg/d; NPE 32.8 to 33.6 kcal/kg; NPE/g protein 28 kcal/g; day 3: protein 2.5 g/kg/d; NPE kcal/kg; NPE/g protein kcal/g
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Reported: randomly assigned eligible infants with use of an interactive voice recognition telephone system to 1 of 4 groups
Allocation concealment (selection bias)	Low risk	Reported: "trial was discussed with parents antenatally, and written informed consent was sought within 24 hours of birth"
Blinding of participants and personnel (performance bias) All outcomes	Low risk	Reported: "hospital pharmacy staff dispensed trial PN between 0900 and 1700; attending clinicians were blinded to trial allocation"
Blinding of outcome assessment (detection bias) All outcomes	Low risk	Missing info
Incomplete outcome data (attrition bias) All outcomes	High risk	Lost to follow‐up (excluding deaths): Inc‐AA/SO 4/42, Inc‐AA/SMOF (7/42), Imm‐RDI/SO (5/41), and Imm‐RDI/SMOF (3/43). Total lost: 19/168 (11%) Reported: "Used a modified intention‐to‐treat analysis because we anticipated we would be unable to obtain primary outcome measures in all infants" Intention‐to‐treat analysis reported for mortality, sepsis, and NEC (low risk) Other outcomes: some risk
Selective reporting (reporting bias)	Low risk	Prespecified outcomes. Trial was registered at www.isrctn.com as ISRCTN29665319, and at eudract.ema.europa.eu as EudraCT 2009‐016731‐34.
Other bias	Low risk	Groups similar at baseline

Vaidya 1995.

Methods	Single‐centre randomised controlled trial in India before 1994
Participants	Inclusion criteria: VLBW babies with birth weight < 1250 grams who survived first 48 hours Exclusion criteria: none reported
Interventions	Higher group (n = 43): amino acid solution (Vamin) started third day at 0.5 g/kg/d increased daily to maximum 3 g/kg/d. Lipid (Intralipid) started on fifth day at 0.5 g/kg/d increased to maximum 3 g/kg/d Lower group (n = 42): intravenous 10% dextrose at 60 mL/kg on day 1 increased to 120 to 150 mL/kg by end of first week All infants: enteral feeds started early and advanced as per tolerance up to maximum 200 mL/kg/d
Outcomes	Primary outcomes: mortality; morbidity (not prespecified) Other outcomes: reported local infection and infective complications separately. Criteria for azotaemia and cholestasis not reported
Notes	Trial of higher early and maximal parenteral amino acid and lipid intake vs intravenous glucose only. Early enteral intake Nutritional intakes (parenteral only): Higher group: day 3: protein 0.5 g/kg/d; NPE estimated kcal/kg; NPE/g protein 72 kcal/g. Day 7: protein 3 g/kg/d; NPE 87 kcal/kg; NPE/g protein 29 kcal/g Lower group: day 3: protein 0 g/kg/d; NPE estimated 36 kcal/kg; NPE/g protein * kcal/g. Day 7: protein 0 g/kg/d; NPE kcal/kg; NPE/g protein * kcal/g
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Method not reported
Allocation concealment (selection bias)	Unclear risk	Method not reported
Blinding of participants and personnel (performance bias) All outcomes	High risk	None reported. Different management reported between groups
Blinding of outcome assessment (detection bias) All outcomes	Unclear risk	None reported
Incomplete outcome data (attrition bias) All outcomes	Unclear risk	None reported
Selective reporting (reporting bias)	Unclear risk	Protocol not available
Other bias	Low risk	Similar at baseline

van Goudoever 1995.

Methods	Single‐centre randomised controlled trial in the Netherlands before 1994
Participants	Inclusion criteria: birth weight < 2000 grams, mechanical ventilation, indwelling arterial and venous catheters Exclusion criteria: congenital abnormality
Interventions	Higher group: glucose 10% 6.5 g/kg/d; AA 1.15 g/kg/d (Primène 10%) and energy 28.5 (SD 6.2) kcal/kg/d from birth onward Lower group: exclusively glucose 6.0 g/kg/d; energy 26.1 (SD 5.5) kcal/kg/d All infants: no enteral intake; no lipid
Outcomes	Primary outcomes: leucine kinetics, nitrogen balances, amino acid profiles Other outcomes: Glucose levels, blood urea nitrogen levels.
Notes	Trial of higher early amino acid intake. No parenteral lipid intake. No enteral intake Nutritional intakes: Higher group: day 1: protein 1.15 g/kg/d; NPE 28.5 kcal/kg; NPE/g protein 24.7 kcal/g Lower group: day 1: protein 0 g/kg/d; NPE 26.1 kcal/kg; NPE/g protein * kcal/g
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Method not reported
Allocation concealment (selection bias)	Unclear risk	Method not reported
Blinding of participants and personnel (performance bias) All outcomes	Unclear risk	None reported
Blinding of outcome assessment (detection bias) All outcomes	Unclear risk	None reported
Incomplete outcome data (attrition bias) All outcomes	High risk	3/18 (17%) did not have leucine isotope studies.
Selective reporting (reporting bias)	Unclear risk	Protocol not available
Other bias	Low risk	Similar at baseline

van Lingen 1992.

Methods	Single‐centre randomised controlled trial in the Netherlands before 1991
Participants	Inclusion criteria: preterm appropriate‐for‐gestational‐age infants; clinically stable; mean gestational age higher group 30.7 weeks and lower group 31.0 weeks Exclusion criteria: none reported
Interventions	Higher group (n = 9): glucose day 1, then glucose average 4.6 g/kg/d, lipid (intralipid 10%) average 1.9 g/kg/d, and amino acid (Aminovenos 10%) average 2.3 g/kg/d from day 2 Lower group (n = 9): glucose day 1, then glucose average 7.0 g/kg/d, lipid (intralipid 10%) average 1.9 g/kg/d. Isocaloric by increasing glucose intake All infants: exclusively parenterally fed
Outcomes	Primary outcome: nitrogen balance via stable isotope method Other outcomes: none reported
Notes	Trial of higher early parenteral amino acid intake. Parenteral lipid intake. No enteral intake. Isocaloric by increasing glucose intake Nutritional intakes: Higher group: day 2 to 4: protein 2.3 (SD 0.2) g/kg/d; NPE 47.8 kcal/kg; NPE/g protein 20.8 kcal/g Lower group: day 2 to 4: protein 0.02 g/kg/d; NPE 47.1 kcal/kg; NPE/g protein * kcal/g
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	"Randomly divided". Method not reported
Allocation concealment (selection bias)	Unclear risk	Method not reported
Blinding of participants and personnel (performance bias) All outcomes	High risk	None reported. Different management reported between groups
Blinding of outcome assessment (detection bias) All outcomes	Unclear risk	None reported
Incomplete outcome data (attrition bias) All outcomes	Low risk	Complete outcome data provided for both infant groups
Selective reporting (reporting bias)	Unclear risk	Protocol not available
Other bias	Low risk	Similar at baseline

Vlaardingerbroek 2013.

Methods	Single‐centre randomised controlled trial in Netherlands 2008 to 2012
Participants	Inclusion criteria: VLBW infants at birth weight < 1500 grams with central venous catheter Exclusion criteria: congenital anomalies, including chromosome defects and known metabolic diseases, or endocrine, renal, or hepatic disorders
Interventions	Higher group 1 (n = 47): glucose and AA 3.6 g/kg/d (Primene 10%) from birth onwards, with lipids started first day at 2.0 g/kg/d increased day 2 to 3.0 g/kg/d Lower group 1 (n = 49): glucose and AA 2.4 g/kg/d from birth, with lipids started first day at 2.0 g/kg/d increased day 2 to 3.0 g/kg/d Lower group 2 (n = 48): glucose and AA 2.4 g/kg/d from birth, with lipids started day 2 at 1.4 g/kg/d increased day 3 to 2.8 g/kg/d All infants: minimal enteral feeding initiated on the day of birth. After third day of life, the nutritional regimen, including enteral feeding, was provided at the discretion of the attending physician. Protocol to temporarily lower parenteral intake of AA when plasma urea concentrations were between 10 and 14 mmol/L and to temporarily cease AA administration when plasma urea concentrations exceeded 14 mmol/L. Lipid intake was temporarily lowered when triacylglycerol concentrations were between 3 and 5 mmol/L and was temporarily stopped when TG concentrations exceeded 5 mmol/L.
Outcomes	Primary outcomes: safe and well tolerated and would result in improved nitrogen balance; nitrogen balance Other outcomes: time to regain birth weight, growth rate during first 28 days, gain in lower leg length (knemometry) during first month, growth until discharge home (or until 40 weeks' corrected gestational age, whichever occurred first), hyperuraemia > 10 mmol/L, hypertriglyceridaemia > 3 mmol/L 2‐Year follow‐up: primary outcome composite outcome of “death or major disability” at 2 years' corrected age. Secondary outcomes were death, major disabilities, neurodevelopmental scores (Bayley SCID III), and anthropometry. Repeated failure on OAE hearing test reported at discharge. Incidence of severe hearing problems reported at 2 years of age used to indicate deafness in the review
Notes	Trial of higher early parenteral amino acid intake. Parenteral lipid intake. Early enteral intake Nutritional intakes (enteral and parenteral): Higher group 1: day 2: protein 3.2 g/kg/d; NPE 48.9 (SD 11.0) kcal/kg; NPE/g protein 15.3 kcal/g. Day 6: protein 3.0 g/kg/d; NPE 73.6 (16.8) kcal/kg; NPE/g protein 24.5 kcal/g Lower group 1: day 2: protein 2.6 g/kg/d; NPE 62.4 (15.1) kcal/kg; NPE/g protein 24.0 kcal/g. Day 6: protein 2.5 g/kg/d; NPE 75.8 (22.1) kcal/kg; NPE/g protein 30.3 kcal/g Lower group 2: day 2: protein 2.1 g/kg/d; NPE 62.7 (11.8) kcal/kg; NPE/g protein 29.9 kcal/g. Day 6: protein 2.6 g/kg/d; NPE 78.4 (19.0) kcal/kg; NPE/g protein 30.2 kcal/g Notes: Higher group 1 and lower group 1 data were used in the review, as they had the same lipid intake. Maximum urea reported as day 2 urea in the review. Hyperuraemia was defined as urea concentration > 10 mmol/L. Hyperglycaemia treated with insulin was calculated from percentages in text. Change in z‐scores at 2 years were calculated as 24 times change standard deviations per month (reported variable for weight and HC). Supplementary files not available from follow‐up publication
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Computer‐generated block randomisation list with variable block sizes provided by statistician
Allocation concealment (selection bias)	Low risk	Sealed, opaque randomisation envelope stratified for weight (< 1000 grams or 1000 to 1499 grams) and sex
Blinding of participants and personnel (performance bias) All outcomes	High risk	None reported. Study group randomisation was open after inclusion.
Blinding of outcome assessment (detection bias) All outcomes	Low risk	All technicians were blinded for study group randomisation throughout study and analyses.
Incomplete outcome data (attrition bias) All outcomes	Low risk	2/146 (1%) were withdrawn. In follow‐up of 144 infants, 2 infants were excluded because of congenital disorders, 8 (6%) were lost to follow‐up mainly owing to emigration, BSID III was administered to 103 infants (93% of surviving infants), and PDI was given to 90 (87%).
Selective reporting (reporting bias)	Low risk	Trial Register.nl: NTR1445. Prespecified outcomes
Other bias	Low risk	Similar at baseline

Weiler 2006.

Methods	Two‐centre randomised controlled trial in Canada from November 2001 to November 2003
Participants	Inclusion criteria: preterm infants born at or between 24 and 32 weeks' gestation at appropriate weight for gestational age (> third percentile) Exclusion criteria: congenital abnormalities, required any surgery, were not likely to remain in the province for the hospital stay. Also infants born of a mother who used alcohol or illicit drugs during pregnancy, had diabetes or other endocrine diseases known to affect bone metabolism, or took medications known to affect bone metabolism
Interventions	Higher group (n = 7 + 6): AA 1 g/kg within 24 hours in 10% glucose with and without early minimal enteral nutrition 12 mL/kg/d within first 72 hours. Advanced to maximal AA 3.0 g/kg/d and lipid 3.0 g/kg/d Lower group (n = 7 + 7): no amino acids day 1 with and without early minimal enteral nutrition 12 mL/kg/d within first 72 hours. From day 2, started AA 1.0 g/kg/d advanced to maximal AA 3.0 g/kg/d and lipid 3.0 g/kg/d All infants: All infants received 60 to 80 mL fluid/kg day 1, increased to 150 to 160 mL/kg within first week. From day 2, carbohydrate initiated at 4.5 to 5.5 mg/kg/min to maximum 10 to 12 mg/kg/min. AA began at 1 g/kg/d increased to 3 g/kg/d by 1‐gram increments, and lipid was started at 1 g/kg day 3 increased by 1 g/kg/d to 3 g/kg/d.
Outcomes	Primary outcomes: growth and bone mass (dual‐energy X‐ray absorptiometry) achieved by estimated term age Other outcomes: sepsis, BPD (oxygen beyond 36 weeks' PMA)
Notes	Trial of higher early parenteral amino acid intake (day 1). Parenteral lipid intake from day 3. Early enteral intake Nutritional intakes: Higher group 1: day 1: protein 1 g/kg/d; NPE 24 kcal; NPE:protein 24 kcal/g; Day 7: maximal protein 3 g/kg/d: NPE 96 kcal; NPE:protein 32 kcal/g Lower group 1: day 1: protein 0 g/kg/d; NPE 24 kcal; NPE:protein * kcal/g; Day 7: maximal protein 3 g/kg/d: NPE 96 kcal; NPE:protein 32 kcal/g Note: factorial design. Data from enteral feeding groups were combined in the review. "Days parenteral nutrition" used as "days to full enteral feeds" in the review
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Method not reported
Allocation concealment (selection bias)	Low risk	Precoded envelopes stratified by gestational age with 2‐week intervals beginning at 24 weeks' gestation
Blinding of participants and personnel (performance bias) All outcomes	High risk	"The interventions were not blinded..."
Blinding of outcome assessment (detection bias) All outcomes	Unclear risk	None reported
Incomplete outcome data (attrition bias) All outcomes	High risk	7/34 (21%) infants died and did not receive intervention.
Selective reporting (reporting bias)	Unclear risk	Protocol not available
Other bias	Low risk	Groups similar at baseline

Xie 2014.

Methods	Single‐centre randomised controlled trial in China from 2011 to 2013
Participants	Inclusion criteria: preterm infants at < 34 weeks' gestation admitted to NICU within 24 hours after birth at birth weight 1000 to 1800 grams Exclusion criteria: congenital anomalies; metabolic conditions; kidney or liver dysfunction
Interventions	Higher group (n = 18): amino acid 1.5 g/kg/d, increased by 1 g/kg/d to maximum 3.5 g/kg/d. Dosage of lipids, glucose, and electrolytes in parenteral nutrition provided routinely Lower group (n = 19): amino acid 1.5 g/kg/d, increased by 0.5 g/kg/d to maximum 3.5 g/kg/d All infants: Dosage of lipids, glucose, and electrolytes in parenteral nutrition provided routinely
Outcomes	Primary outcomes: nitrogen balance and growth Other outcomes: hospital stay and costs; biochemical tolerance; NEC and sepsis
Notes	Trial of faster grading parenteral amino acid intake. Early parenteral lipid intake Nutritional intakes: Higher group: day 1: protein 1.5 g/kg/d; NPE 31.8* kcal/kg; NPE/g protein 21.2 kcal/g. Day 5: protein 3.5 g/kg/d; NPE 58.5* kcal/kg; NPE/g protein 16.7 kcal/g Lower group: day 1: protein 1.5 g/kg/d; NPE 35.0* kcal/kg; NPE/g protein 23.3 kcal/g. Day 5: protein 3.5 g/kg/d; NPE 65.3* kcal/kg; NPE/g protein 18.7 kcal/g * = estimated from data in article
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Randomised number table
Allocation concealment (selection bias)	Unclear risk	Method not reported
Blinding of participants and personnel (performance bias) All outcomes	Low risk	"Double blind"
Blinding of outcome assessment (detection bias) All outcomes	Low risk	"Double blind"
Incomplete outcome data (attrition bias) All outcomes	Low risk	1/38 (3%)
Selective reporting (reporting bias)	Unclear risk	Protocol not available
Other bias	High risk	Differences between groups at baseline

AA: amino acid.

Bayley SCID II: Bayley Structured Clinical Interview for DSM DIsorders II.

Bayley SCID III: Bayley Structured Clinical Interview for DSM DIsorders III.

BGL: Blood glucose level.

BPD: bronchopulmonary dysplasia.

BUN: blood urea nitrogen.

BW: body weight.

CLD: chronic lung disease.

CSF: cerebrospinal fluid.

EBM: essential body medicine.

GGT: gamma glutamyltransferase.

HC: head circumference.

IVH: intraventricular haemorrhage.

MDI: Mental Developmental Index.

NEC: necrotising enterocolitis.

NICU: neonatal intensive care unit.

NPE: non‐protein energy.

NS: not significant.

OAE: otoacoustic emissions.

PDA: patent ductus arteriosus.

PDI: Psychomotor Developmental Index.

PMA: postmenstrual age.

PN: parenteral nutrition.

PVL: periventricular leukomalacia.

ROP: retinopathy of prematurity.

SD: standard deviation.

VLBW: very low birth weight.

Characteristics of excluded studies [ordered by study ID]

Study	Reason for exclusion
Abitbol 1975	Infants allocated to groups by alternation. Used a casein hydrolysate and preparation containing alcohol. Excluded as unclear if an AA solution
Adamkin 1991	Randomised trial of 2 different AA formulations
Adamkin 1995	Randomised trial of 2 different AA formulations
Alo 2010	Not randomised ‐ assigned to groups "according to wish of parents"
Bellagamba 2016	Randomised preterm infants with birth weight 500 to 1249 grams to high AA/protein intake (parenteral nutrition = 3.5 AA, enteral nutrition = 4.6 protein g/kg/d) or to standard of care group (parenteral nutrition = 2.5 AA, enteral nutrition = 3.6 protein g/kg/d). Excluded as differential enteral feeding regimens
Brown 1989	Trial of parenteral vs enteral protein nutrition. Differential enteral feeding regimen ‐ infants in no AA group received bovine whey protein enteral feeds
Bryan 1973	Randomised trial of fibrin hydrolysate and glucose vs glucose. Excluded as not reported to be an AA solution
Burger 1980	Randomised infants to 2 different AA formulations
Chessex 1985	Randomised trial of 2 different AA formulations
Iacobelli 2010	Trial of individualised vs standardised parenteral nutrition
Kadrofske 2006	Cross‐over biochemical tolerance study of infants commencing AA 1.5 3.0 g/kg/d increased to 3.0 g/kg/d for 24 hours; or commencing AA 3.0 g/kg/d decreased to 1.5 g/kg/d for 48 hours
Loughead 1996	Randomised infants to 2 different AA solutions
McIntosh 1990	Randomised infants to 2 different AA solutions with same nitrogen and energy density
Moltu 2014	Randomised trial of higher parenteral AA and lipid, as well as enteral AA and LCPUFA to discharge and postdischarge protein supplementation. Excluded as differential enteral feeding regimens
Ogata 1983	Randomised infants to 2 different AA solutions with same nitrogen content and energy density
Parimi 2005	Cross‐over biochemical tolerance study of infants commencing AA 1.5 3.0 g/kg/d increased to 3.0 g/kg/d for 25 hours; or commencing AA 3.0 g/kg/d decreased to 1.5 g/kg/d for 25 hours; or commencing AA 1.5 3.0 g/kg/d increased to 3.0 g/kg/d for 40 hours
Rosenthal 1987	Randomised infants to 2 different AA solutions with same nitrogen content and energy density
Rosenthal 1988	Randomised infants to 2 different AA solutions with same nitrogen content and energy density
Salle 1987	Randomised to 2 different AA solutions with similar nitrogen content
Savich 1988	Randomised trial of short‐term infusion (100 minutes) of lipid, lipid and AA, or AA
van Goudoever 1994	Randomised to 3 different AA solutions with similar nitrogen content
Wilson 1997	Randomised trial of higher early and maximal parenteral and enteral AA and lipid intake. Excluded as differential enteral feeding regimens
Yeung 2003	Retrospective study of individualised vs standardised parenteral nutrition

AA: amino acid.

LCPUFA: long‐chain polyunsaturated fatty acids.

Characteristics of ongoing studies [ordered by study ID]

Bloomfield 2015.

Trial name or title	ProVIDe study: the impact of protein intravenous nutrition on development in extremely low birth weight babies
Methods	Multi‐centre, 2‐arm, double‐blind, parallel, randomised, controlled trial
Participants	Babies with birth weight less than 1000 grams who have an umbilical arterial line in situ Exclusion criteria: admission to neonatal intensive care more than 24 hours after birth; multiple births of more than 2 babies; known chromosomal or genetic abnormality, or congenital disorder affecting growth; inborn error of metabolism; in danger of imminent death
Interventions	Randomised in 1:1 ratio to receive an amino acid solution (TrophAmine) or placebo (saline) administered through umbilical arterial catheter for first 5 days
Outcomes	Primary outcomes: survival free from neurodevelopmental disability at 2 years’ corrected age, where neurodevelopmental disability is defined as cerebral palsy, blindness, deafness, developmental delay (standardised score more than 1 standard deviation below the mean on cognitive, language, or motor subscales of the Bayley Scales of Infant Development Edition 3); Gross Motor Function Classification System score ≥ 1 Secondary outcomes: growth, from birth to 36 weeks’ corrected gestational age, at neonatal intensive care discharge, and at 2 years’ corrected age; body composition at 36 to 42 weeks’ corrected postmenstrual age and at 2 years’ corrected age; neonatal morbidity, including length of stay; nutritional intake
Starting date	2016
Contact information	Frank Bloomfield: email: f.bloomfield@auckland.ac.nz Liggins Institute, The University of Auckland, Auckland, New Zealand
Notes

Differences between protocol and review

The review includes an additional subgroup analysis based on parenteral lipid intake.

Subgroup analyses for extremely preterm or low birth weight infants were not possible.

The initial combined comparison includes some growth (size and size z‐scores), developmental (development scores and autism), clinical (patent ductus arteriosus), and biochemical outcomes (blood urea nitrogen levels; ammonia level > 69 μmol/L; and protein balance) that were not prespecified in view of variable reporting and completeness. We did not include these in other comparisons or subgroup analyses.

Contributions of authors

All authors contributed to protocol writing. DO contributed to all stages of protocol and review preparation, performed the literature search, assessed studies for eligibility, entered characteristics of studies, performed risk of bias assessments, extracted data, and wrote the review. SB contributed to the protocol, assessed studies for eligibility, cross‐checked characteristics of studies, and performed risk of bias assessments. LJ extracted data, updated and cross‐checked all sections of the text and tables of the review, cross‐checked the final data,,and contributed to the discussion, abstract, and conclusions. TS extracted data, cross‐checked the text, and contributed to the discussion, abstract, and conclusions.

Sources of support

Internal sources

• No sources of support supplied

External sources

• Australasian Satellite of the Cochrane Neonatal Review Group, Australia.

  Supported by NH&MRC grant project # 2013‐01632.

• National Institute for Health Research, UK.

  Editorial support for Cochrane Neonatal has been funded by a UK National Institute of Health Research Grant (NIHR) Cochrane Programme Grant (13/89/12). The views expressed in this publication are those of the review authors and not necessarily those of the NHS, the NIHR, or the UK Department of Health.

Declarations of interest

None.

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