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Seminars in Fetal & Neonatal Medicine 18 (2013) 160e165

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Seminars in Fetal & Neonatal Medicine

journal homepage: www.elsevier .com/locate/s iny

Early amino acid administration in very preterm infants: Too little, toolate or too much, too soon?

Colin Morgan*

Neonatal Intensive Care Unit, Liverpool Women’s Hospital, Crown Street, Liverpool L8 7SS, UK

Keywords:Amino acidsParenteral nutritionPostnatal growth failurePreterm infants

* Tel.: þ44 0151 7024029.E-mail address: colin.morgan@lwh.nhs.uk.

1744-165X/$ e see front matter � 2013 Published byhttp://dx.doi.org/10.1016/j.siny.2013.02.002

s u m m a r y

Early postnatal growth failure is well described in very preterm infants. It reflects the nutritional deficitsin protein and energy intake that accumulate in the first few weeks after birth. This coincides with theperiod of maximum parenteral nutrition (PN) dependency, so that protein intake is largely determinedby intravenous amino acid (AA) administration. The contribution of PN manufacture, supply, formulation,prescribing and administration to the early postnatal nutritional deficit is discussed, focusing on total AAintake. The implications of postnatal deficits in AA and energy intake for growth are reviewed, withparticular emphasis on early head/brain growth and long-term neurodevelopmental outcome. Therationale for maximising AA acid intake as soon as possible after birth is explained. This includes thebenefits for very early postnatal nutritional intake and metabolic adaptation after birth. These benefitsrelate to total AA intake and so have to be interpreted with some caution, given the very limited evidencebase surrounding the balance of individual AAs in neonatal PN formulations. This work mostly predatescurrent nutritional recommendations and therefore may not provide a true reflection of individual AAutilisation in current clinical practice.

� 2013 Published by Elsevier Ltd.

1. Introduction

Early postnatal growth failure or extrauterine growth restrictioncoincides with the severe nutritional deficit that develops in verypreterm infants (VPIs) in the first few weeks of life.1e3 The deficitrefers to the gap between the energy and protein actually providedandthat required tomimic fetal growthrates.4 Basedonthe latter, therecommended calorie intake is 110e135 kcal/kg/day (110e120 kcal/kg/day parenteral) and protein intake is 3e4.5 g/kg/day (2.5e4 g/kg/day parenteral).5,6 These estimates do not take into account co-morbidities that may increase individual infant requirements (suchas chronic respiratory disease) and therefore increase the risk ofpostnatal growth failure.7 Indeed, postnatal malnutrition may beinevitable based on current recommendations.8

This postnatal growth failure was described in detail byEhrenkranz et al.9 who produced growth curves based on gestationand birth weight for infants <30 weeks of gestation. These showedthat the majority of appropriate for gestational age (AGA) very lowbirth weight (VLBW) infant weights are below the 10th centile by36 weeks of corrected gestational age (CGA). Much of the growthfailure occurs in the first few weeks after birth, with infants born<1000 g taking a mean of 14.4e17.2 days to regain birth weight.

Elsevier Ltd.

VLBW infants born small for gestational age (SGA) are even morevulnerable to postnatal nutritional deficits because of the antenatalgrowth failure. The interpretation of early weight loss is compli-cated by physiological fluid loss in the first few days of life.10

Nevertheless, early nutritional interventions have been shown toimprove weight gain in VPIs in both observational studies11e15 andrandomised controlled trials.16,17 This suggests that there is areversible nutritional deficit.

2. Why is there an early nutritional deficit?

Very preterm infants have a gut that is too immature to digestmilk in sufficient quantity to meet nutritional requirements.Virtually all preterm infants <29 weeks of gestation and <1200 grequire parenteral nutrition (PN) for a period that depends ongestational birth weight and other morbidities. The mean durationof PN (>75% all nutrition) in these infants (survivors) is 15.6days.9,17 The data indicate that early protein intake in these infantsis mainly derived from intravenous amino acids (AAs) in PN andthat effective PN delivery is essential to avoid major early nutri-tional deficits in these infants.

There is now considerable evidence that one of the major bar-riers to achieving target early nutritional intakes is local nutritionalpolicy. This contributes to intersite differences in nutrient intakeand growth that have been described.11 Changing early nutritional

C. Morgan / Seminars in Fetal & Neonatal Medicine 18 (2013) 160e165 161

policy can improve growth in large preterm cohorts18 includingdischarge HC.12 It is well recognised that PN policy holds the key toreversing the early nutritional deficits in very preterm infants.1,2

Despite international guidance, PN policies show enormous varia-tion between units. These variations in practice have persisted inUK national neonatal PN surveys over the last decade.19e22

Anxiety surrounding PN use reflects understandable concernsabout metabolic ‘intolerance’ and the potential for toxicity. How-ever, outdated studies23 continue to influence nutritional policies.24

More recent evidence evaluating neonatal AA PN formulationssuggests that AAs can be rapidly introduced without metaboliccomplications25e29 even in sick infants30 and without causingacidosis.31 This is essential if fetal protein accretion rates are to bematched and the large protein deficits that are routinely encoun-tered in the first week of life are to be avoided.6Whereas AA intakes(determined by UK PN policies) have generally increased over thelast decade,19,20 several tertiary neonatal services still routinely fallbelow 3 g/kg/day as their target intake with all units falling below3 g/kg/day in the first week.22 This week 1 protein deficit resultsfrom slow introduction of AAs (comprising delayed start and in-cremental increases over several days).

Optimum utilisation of protein for growth depends on a supplyof adequate non-protein energy. A minimum of 20e25 kcal/gprotein is required,24,32 indicating that non-protein energyintake for preterm infants should be 100e120 kcal/kg/day toachieve maximum protein accretion33 in the PN-dependent infant.The rates of glucose and lipid infusion needed to achieve this maynot be tolerated, especially in the first week, leading to hyper-glycaemia and hyperlipidaemia. Reducing glucose or lipid intake inthese circumstances risks inadequate energy intake. Increasingprotein intake without providing an adequate non-protein calorieintake may result in growth failure and increased blood levels ofurea and AAs.34 The majority of neonatal services in the UK22 andUSA35 use insulin to control hyperglycaemia to help maintainenergy intake. However, there is enormous variation in UK clinicalpractice.22 Recent guidance in the USA cautions against using in-sulin routinely36 but this is not primarily based on evidenceinvestigating insulin-treated hyperglycaemia in clinical practice.The approach to hyperlipidaemia is also inconsistent betweenneonatal services.22

3. Early AA administration: practical difficulties

The limitations of PN policy/guidelines (i.e. factors that affect allPN-dependent infants) have to be distinguished from those factorsthat affect actual nutrient delivery. These factors involve PN pre-scription, formulation and administration and vary between in-fants. Conventional neonatal PN strategy has been based onindividualised prescription and formulation to address the rapidlychanging and variable fluid and electrolyte needs characteristic ofthe VPI. Unfortunately this process subverts early nutritionalstrategy unless individualised neonatal PN (iNPN) prescribersrecognise the problem. Their limited knowledge base19,20 oftenaggravates nutritional deficits. Computer-aided prescribing37 canimprove actual protein and energy intake.38,39 However, althoughiNPN prescription is flexible, the manufactured PN bag does notallow rapid responses to changes in fluid and electrolyte re-quirements. Thus Tan et al.17 only improved energy and proteinintake (days 1e14) by 11% and 16%, respectively, in a study designedto achieve a 30% difference. PN delivery was impaired by co-administration of other drug infusions, fluid restriction andchanging electrolyte requirements. Thus, increasing PN macronu-trient content does not necessarily translate into equivalent in-creases in actual nutritional intake. Not only does this waste PN butraises issues about patient safety.

The potential benefits and disadvantages of standardisingneonatal PN rather than using an iNPN regimen have beenreviewed40 but do not influence neonatal PN guidance.6,41

Although some studies favour iNPN,35,39,42 increasing evidencesuggests that, with careful attention to local workload and PNprescribing practice, most VPIs can be managed on a standard PNformulation43e49 and indeed improve macronutrient intake whencompared with iNPN regimens.46e49 Standardisation can evenimprove electrolyte balance.50 Increasing the concentration ofneonatal PN (i.e. reducing the volume) has the potential tomaintainnutritional intake in the face of fluid restriction and multiple druginfusions49,51 but few neonatal services use this approachroutinely.22

Using the standardisation and concentration concepts, optimumnutritional delivery can be achieved using a ‘two-compartment’ PNmodel.49 The nutrition compartment is ‘protected’. This systemallows maximum flexibility of fluid, electrolyte and drug infusionmanagement with minimum impact on nutrient delivery. Thisstandardised concentrated neonatal PN (scNPN) is more effective atdelivering AAs, with >90% VPIs receiving >90% prescribed AAs.49 A20% increase in the first 14-day protein intake was demonstratedwhen compared with a nutritionally identical iNPN regimen.49

Significant cost reductions can be achieved (38%) similar to thosereported for other standardised regimens.46 Subsequent modifica-tions to the scNPN regimen have demonstrated efficient introduc-tion of AA immediately after birth, resulting in a 25% increase inprotein intake (day 1e7).52 The regimen is currently the subject of arandomised controlled trial: the SCAMP nutrition study53 and theprimary outcome has just been reported in abstract form.54 It isclear that every aspect of the neonatal PN needs to be optimised forall VPIs in order to achieve actual parenteral AA and energy intakesthat avoid early nutritional deficits. This is especially important inthe first week of life.15,19e22,51,53 Only by doing this can the potentialbenefits for growth, development and metabolic adaptation berealised.

4. Nutrition, head growth and neurodevelopmental outcome

In humans, the fastest brain growth takes place during the lasttrimester and the first 3 months of postnatal life with high growthrates persisting until the end of the second year. There is growingevidence that malnutrition during this critical period of centralnervous system development results in irreversible long-termneurological deficits.55 VPIs have to navigate this period of criticalbrain growth entirely ex utero, exposed to all the risks of neonatalintensive care including compromised nutritional intake and earlygrowth failure. Head growth is an especially important measure ofgrowth failure because it correlates with brain growth.56 The cor-relation between head circumference and brain volume has alsobeen shown using neuroimaging at term.57,58 Ehrenkranz et al.9

also produced growth curves for length and head circumference.Whereas head circumference did not reduce in early life, the rate ofgrowth was insufficient to match the fetal reference curves. Thismanifests as a growth curve falling away from the original centileand a falling standard deviation score (SDS) in the early postnatalperiod. The nadir inweight and head growth (based on lowest SDS)appears to be about 4 weeks of postnatal age54,59,60 for VPIs(Table 1). It is closer to 6 weeks for length. Although there is usuallya period of later catch-up growth, this is often insufficient to makegood the deficit by 36 weeks of CGA. Clark et al.61 reported that 30%infants born <28 weeks of gestation with AGA head circumferenceat birth were below the 10th centile for head circumference at 36weeks CGA.

There is increasing evidence for a link between postnatal headgrowth, nutrition and long-term neurodevelopmental outcomes.

Table 1Change in head circumferencewith postnatal age in infants<29weeks of gestation.a

Postnatal age Mean (SDS) headcircumference(n ¼ 51)

No. (%) infantswith SDS <e2(n ¼ 51)

Birth �0.41 (0.89) 3 (6%)3 weeks �1.37 (1.10) 16 (31%)6 weeks �1.30 (1.18) 12 (23%)Discharge �0.46 (1.35) 7 (13%)

SDS, standard deviation score.a Previously unpublished data from 2002e2004 cohort (printed with permission

of R.W. Cooke).

C. Morgan / Seminars in Fetal & Neonatal Medicine 18 (2013) 160e165162

Georgieff et al.62 demonstrated that early caloric deprivation(<85 kcal/kg/day) was directly related to slow head growth andlower developmental scores at 1 year of corrected age in a cohort ofAGA and SGS infants. The effect of early energy intake in preterminfants on long-term head growth and adult developmental out-comes has also been described.63 Hack et al.64,65 showed thatsubnormal head size at 8 months was predictive of poorer verbaland performance IQ scores at 3 and 8 years. Brain growth by 28days after birth and the expected date of delivery are key predictorsof long-term brain growth.66,67 Motor impairment may be moredependent on early postnatal head growth than IQ which is moreclosely related to intrauterine growth restriction and later child-hood growth.67 More recent preterm cohorts have reproducedsimilar findings correlating head growth from birth to dischargewith improved neurodevelopmental outcomes at 2 years58,68 and 5years.69,70 Claas et al.71 studied infants born <750 g and reportedbetter cognitive and motor development at 5.5 years for AGA in-fants who remained abovee2 SDS, with SGA infants demonstratingcatch-up growth forming the next best group.

5. Early postnatal protein, head growth andneurodevelopmental outcome

Given that nadir in weight and head circumference occurs atabout 4 weeks of postnatal age, it is logical to focus on early post-natal nutrition in order to prevent the increased deficit occurring inthe first place, thus reducing the need for catch-up growth.Changing early nutritional policy can improve growth in largepreterm cohorts18 including discharge head circumference.12 Usingmultivariate analysis, Berry et al.7 showed that energy intakecorrelated positively with weight gain in the first 56 days, andprotein with growth in the first 14 days.

There are very few randomised controlled trials (RCTs) of earlynutritional intervention on growth. Wilson et al.16 demonstratedimproved weight and length over the first 42 days of life with a PNand enteral feeding regimen that provided about 30% more energyand protein intake. However, the mean maximum AA intake was3.0 g/kg/day versus 2.0 g/kg/day, suggesting that actual mean dailyprotein intake by the intervention group over the first 28 dayswould have been significantly less than 3 g/kg/day. There were nodifferences in mean head circumference at 36 weeks of CGAalthough fewer infants in the intervention group had an headcircumference <10th centile at discharge. Tan et al.17 performed asimilar study 10 years later in VPIs with a higher protein intaketarget (4 versus 3 g/kg/day) but only achieved mean actual intakesof 2.6 versus 2.3 g/kg/day in the first 28 days (only 1.8 versus 1.7 g/kg/day in the first week). The intervention failure meant no dif-ferences in growth outcomes at 36 weeks were identified althoughcorrelations between head circumference at 36 weeks of CGA andboth 28-day energy and protein deficits were described. Neuro-developmental outcome at 9 months showed no difference be-tween groups.72 It is important to note that the intervention groups

in both these studies still developed early protein and energydeficits, particularly in the first week of life. Preliminary reporting54

from the SCAMP nutrition study53 indicates that early head growthfailure can be prevented by nutritional intervention.

There are no published RCTs evaluating the effect of early pro-tein on head growth or neurodevelopmental outcome although theSCAMP nutrition study53 is about to report at the time of writing.Poindexter et al.73 performed a secondary analysis of a large RCT,restratifying groups to ‘early’ and ‘late’ protein. The early group hadbetter growth at 36 weeks of CGA including head circumference.Differences in head circumference but not neurodevelopment weredetectable at 18 months. Stephens et al.74 recently reported anassociation between first-week protein and energy intake and 18-month developmental outcomes in infants born <1000 g. Theyestablished that for every 1 g/kg/day increase in first-week proteinincrease there was an 8.2-point increase in the Mental Develop-mental Index. A more recent smaller observational study in infantsborn <1500 g failed to demonstrate an association between first-week protein and neurodevelopmental outcome at 18 months.52

Thus, definitive evidence linking early protein intake, head/braingrowth and long-term neurodevelopmental outcome is stilllacking.

6. Early protein and the regulation of early postnatal growth

Protein plays an important part in modulating the endocrinecontrols on growth as well as providing the substrate for proteinsynthesis. Growth is a complex process governed by the in-teractions between several hormone axes and adequate nutrition.75

Insulin-like growth factor-1 (IGF-1), IGF-2 and their binding pro-teins and receptors play an essential role in fetal growth togetherwith insulin.76 In postnatal life, nutrition, insulin and IGF-1 stilldominate growth regulation.77 Whereas growth hormone levelsare high in the fetus and newborn, its effects on growth are notprominent until the second year of life. Despite high growth hor-mone levels, IGF-1 levels fall sharply after birth and remain low forseveral weeks in VPIs.78 A similar pattern is seen in children withprotein/calorie malnutrition and inadequate protein intake. It hasbeen suggested that inadequate postnatal nutritionmay perpetuatelow IGF-1 production and bioavailability leading to growth failurein VPIs.75

The low postnatal IGF-1 levels seen in VPIs parallel their post-natal head growth deficit and also retinopathy of prematurity.79

Moreover, these infants demonstrate a correlation between IGF-1concentrations and total brain volume.80 However, early proteinand energy intake were not correlated with IGF-1 levels or brainvolumes. This has led to a hypothesis that postnatal growth has twophases, an early phase characterised by low IGF-1 levels andpostnatal growth failure resistant to nutritional intervention aloneand a later catch-up phase characterised by rising IGF-1 levels andcatch-up growth responsive to nutritional intake.59 The nutritionaldata (non-RCT) supporting this hypothesis are presented accordingto CGA and not postnatal age, and early nutritional deficits relate tothe latter. For example, a group of infants at 26weeks of CGAwill bea variety of different postnatal ages (0e3 weeks) which are asso-ciated with a very wide range of nutritional deficits (confirmed bythe large variation in protein intake data at lower gestations in thisstudy). Nevertheless, these data provide a vital insight into thepotential mechanisms of head growth failure that require furtherinvestigation.

7. Amino acids and early metabolic adaptation

The fetus receives large quantities of AAs across the placenta tomeet intrauterine growth rates. One of the arguments against early,

C. Morgan / Seminars in Fetal & Neonatal Medicine 18 (2013) 160e165 163

aggressive AA administration is that VPIs are in a catabolic state inthe first few days after birth and are therefore unable to utiliseprotein for growth. However, several studies26e28 clearly indicatethat positive nitrogen balance may be achieved by starting AAimmediately after birth, even in the first 48 h. Extreme prematurityused to be frequently associated with hyperkalaemia and fluid andelectrolyte protocols still advocate delayed potassium supplemen-tation. Recent evidence suggests that early AA administration isassociated with a positive potassium balance and a reduction inhyperkalaemia.81 AAs stimulate endogenous insulin secretion26

and this may affect plasma potassium levels directly as well as bypromoting growth.

Hyperglycaemia is a frequent problem in VPIs82 and is associ-ated with higher mortality and morbidity.83,84 Early AA adminis-tration is associatedwith less insulin-treated hyperglycaemia in thefirst 2 weeks of life.53 The mechanism is unclear but could involvethe AA stimulation of the insulineIGF-1 axis26 and/or prevention ofkey AA deficiencies, such as arginine.85 Arginine is one AA that is aparticularly potent secretagogue for insulin,86 and the PN-dependent preterm infant is vulnerable to arginine deficiency.87

Thus interrupting AA supply, even for short periods (24 h) afterbirth, may actually impair postnatal metabolic adaptation in VPIsrather than relieving the metabolic burden.

8. Amino acid formulations in neonatal PN

Early protein intake in VPIs comprises total intravenous AAs(parenteral) and enteral protein. Although there has been muchdebate about the individual AA constituents in neonatal PN, therehas been little change in neonatal parenteral AA formulations formore than two decades. Therefore current AA formulations predaterecent recommended protein intakes and the evidence supportingAA administration immediately after birth. There have been rela-tively few studies of individual AA levels28,34,88,89 in VPIs followingcontemporary nutritional strategies. AA administration immedi-ately after birth prevents the sharp fall in the plasma levels of mostindividual AAs seen with delayed introduction.24 In general, indi-vidual plasma AA levels in the first 2 weeks of life (the main PN-dependent period) are at or above the upper limit of the refer-ence population (Fig. 1) for each AA.34,88e90 However, it is notknown what the ‘normal’ individual AA plasma levels for VPI

Fig. 1. Day 9 plasma amino acid (AA) levels in infants born <27 weeks of gestation. Bars desthe median, and the lighter bar the quartile above the median. Values expressed as a percentmonths.90 Thus, the entire IQR for plasma levels of tyrosine (Tyr), cysteine (Cys), glutamine(bold line at 100%).

should be or what levels should be used to define deficiency ortoxicity.

The last major change in AA formulationwas the introduction ofneonatal PN because of the risks of hyperphenylalaninaemia andhypertyrosinaemia resulting from non-neonatal parenteral AAsources. Current neonatal parenteral AA formulations are theoret-ically based on the individual AA composition of human milkprotein or cord blood AA levels. However, there is difficulty inattaining certain AA levels in PN because of poor solubility or sta-bility. Thus, tyrosine, cystine and glutamine PN content is very low,often leading to correspondingly low plasma AA acid levels in PN-dependent preterm infants (Fig. 1). Whereas all these AAs can besynthesised in humans, inadequate metabolic pathways in VPIsmay render these AAs conditionally essential.24 Paradoxically,optimising nutritional strategy can result in aggravation of thisapparent deficiency because nutritional interventions are oftencomplex and have other metabolic/therapeutic implications (e.g.insulin-treated hyperglycaemia and hypotyrosinaemia).89 Someindividual AAs, such as glutamine, play such a central role inmetabolic and inflammatory pathways that this has led to hy-potheses that neonatal glutamine supplementation may reduce therisk of several preterm complications.88 Despite multiple RCTs,there is no evidence of clinical benefit from additional parenteral(or enteral) glutamine supplementation.91 Nevertheless, single AAdeficiency has the potential to undermine high-protein nutritionalstrategies by limiting protein synthesis. This situation also has thepotential to cause high (and so potentially toxic) plasma levels ofother AAs that cannot be utilised for protein synthesis because ofthe imbalance in AA supply.

Arginine also plays a central role in key metabolic and inflam-matory pathways, notably the urea cycle and nitric oxide synthesis.Arginine deficiency is well recognised in PN-dependent preterminfants, and probably reflects increased metabolic demand andimpaired synthetic pathways.87 By contrast with tyrosine, cysteineand glutamine, PN content of arginine is much higher than that ofhuman milk92 and yet arginine deficiency (as measured by lowplasma levels) still occurs (Fig. 1). There is a wide variation inneonatal PN arginine content (between 1.5 and 3 times that of hu-man milk)75 with clear evidence that higher arginine contenttranslates into higher arginine levels. Lowplasma arginine levels areassociated with hyperammonaemia,93 necrotising enterocolitis,94

cribe the interquartile range (IQR) with the darker bar representing the quartile belowage of the median plasma AA level in a reference population of healthy infants aged <6(Gln), arginine (Arg) and asparagine (Asn) lies below the reference population median

C. Morgan / Seminars in Fetal & Neonatal Medicine 18 (2013) 160e165164

hyperglycaemia85 and respiratory morbidity,87 and arginine PNsupplementation (equivalent to 4 times human milk content) hasbeen shown to reduce necrotising enterocolitis in one study.95

The complexity of neonatal parenteral AA formulation andmanufacture is clear. Current parenteral AA formulations need ur-gent re-evaluation in light of recent nutrient recommendations, asoptimising protein intake is likely to increase sensitivity to AAimbalance in the PN formulation, aggravating both deficiency andpotentially toxic levels of individual AAs. Few neonatal servicesroutinely monitor plasma AA levels.22 However, until morecontemporary evidence is available, it would seem prudent tomonitor plasma AA levels for a period before and after a change inparenteral AA policy.

Practice points

� Postnatal nutritional deficits can be significantly

reduced by close attention to all aspects of neonatal PN

policy.

� Achieving actual protein intakes >3 g/kg/day in PN-

dependent preterms is difficult in the first week of life

and requires AAs to be introduced within 4e6 h of birth.

� There is increasing evidence that early AA intake

(particularly in the first 2 weeks) has benefits for head/

brain growth and long-term neurodevelopmental

outcome.

� Amino acid administration immediately after birth

quickly achieves a positive nitrogen balance and is

associated with enhanced electrolyte balance and

blood glucose control.

� A period of regular plasma AA monitoring may be

justified by neonatal services, particularly where major

changes in PN policy or AA formulation are being

contemplated.

Research directions

� Definitive randomised controlled trial evidence evalu-

ating the link between early nutritional (particularly AA)

intake, early head/brain growth and long-term neuro-

developmental outcome is required.

� The biological mechanisms whereby AAs modulate

postnatal metabolic adaptation need to be further

explored.

� The balance of individual AAs in neonatal PN formula-

tions that minimises potential toxicity and deficiency,

while maximising protein synthesis and growth, needs

further investigation.

Conflict of interest statement

None declared.

Funding sources

None.

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