Optimal protein and energy intakes in preterm infants

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Author's personal copy Early Human Development (2007) 83, 831–837

a v a i l a b l e a t w w w. s c i e n c e d i r e c t . c o m

w w w. e l s e v i e r. c o m / l o c a t e / e a r l h u m d e v

Optimal protein and energy intakes in preterm infants Nicholas D. Embleton ⁎ Newcastle Neonatal Service, Royal Victoria Infirmary, University of Newcastle, Newcastle upon Tyne, NE1 4LP, United Kingdom

KEYWORDS Dietary protein; Energy; Nutrient intakes; Preterm infant; Nutritional requirements

Abstract There is compelling evidence that current nutritional practice fails to provide sufficient dietary protein for preterm infants, especially extremely and very low birth weight infants. Nutrient requirements can be estimated by a variety of techniques, but most suggest that these infants will require a protein intake of 3.5–4.0 g/kg/d. Even when these infants are able to tolerate full enteral feeds, most currently available artificial milk formula or breast milk fortifiers will not ensure these protein requirements are met except when fed at high volumes. Energy requirements on the other hand may be currently met, and evidence from controlled studies suggests that intakes higher than 110–135 kcal/kg/d might not be beneficial. The data from studies on neonatal adiposity outcomes, and from studies examining relationship between early growth and later cardiovascular outcome, also suggest that excess nutrient intake might be harmful. In the light of this data, optimal intakes and protein–energy ratios require re-appraisal. © 2007 Elsevier Ireland Ltd. All rights reserved.

1. Assessment of nutritional status Modern neonatal care has enabled the survival of many extremely low birthweight (ELBW b 1000 g) and very low birthweight (VLBW b 1500 g) infants. Two to three decades ago, neonatal intensive care was focused on respiratory and infectious morbidity. Advances in many areas have highlighted the critical importance of nutritional status in determining outcome. Unfortunately, there is no simple static ‘measure’ of nutritional status and no clear consensus on what outcome nutritional manipulation should seek to achieve. Worsening nutritional status (‘malnutrition’) may easily occur without obvious signs. It is difficult to gain consensus on which outcomes or measures of ‘good’ nutritional status should be used in preterm infants despite the clear evidence that nutrition plays a key role in early brain development [1]. An appropriate goal in term

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infants would be to match outcomes (growth, plasma amino acid profiles, cognitive development etc.) of the healthy breast fed infant, but for the preterm infant many suggest aiming for ‘growth’ equivalent to the in-utero reference. This is difficult to achieve, and added to the emerging data on the long term adverse cardiovascular outcomes of early rapid weight gain in infancy, suggest caution [2,3]. The relationship between nutrient intake and growth, weight gain and changing body composition is complex and also involves many non-nutritional factors. Recent data suggest important effects of preterm delivery on adipose tissue distribution that may be related to markers of stress rather than direct effects of excess energy intake [4]. Several controlled trials examining protein and energy intakes in preterm infants have been conducted but, with a few notable exceptions, most focus on short term outcome measures. In isolation, weight is an insensitive marker of growth unless matched with contemporaneous assessment of body composition. There are no good bedside measures of body composition, and all research techniques involve many questionable assumptions. Detailed anthropometry may be as

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Author's personal copy 832 useful as more complex methodologies. Serum measurements are of little use in assessing overall protein and energy status, but measurement of blood glucose, blood urea nitrogen, and some plasma proteins may be useful clinically.

1.1. Protein and nitrogen Proteins are the primary constituents of all living organisms, and consist of amino acids bonded by peptide linkages. Human proteins are composed of only a limited number of amino acids, but despite this are able to combine in an almost limitless number of permutations. This results in proteins of unique sequence and length that allow a myriad of functions. Dietary protein, along with catabolism of body protein, contributes the necessary building blocks for these processes. Despite the pivotal role played by proteins, it is only the presence of nitrogen at a molecular level that distinguishes proteins from carbohydrates and fats. There are some nitrogen containing carbohydrates but they do not appear to play an important role in the overall nitrogen economy. There is, however, no absolute requirement for protein per se, simply a requirement for the building blocks of protein i.e. essential amino acids and an additional source of nitrogen that is usually nonessential amino acids plus some sources of nonprotein nitrogen. From a practical standpoint, however, it is easier to consider nitrogen requirements in terms of equivalent protein (as weight in grams) although the interconversion of grams of amino acids and nitrogen to grams of protein is not entirely straightforward. Where a significant proportion of nitrogen is as nonprotein nitrogen – breast milk contains a significant proportion of its nitrogen as urea – this may significantly overestimate the true protein available [5].

1.2. Energy Energy is required for every process at cellular and organ level. Most energy substrates are converted to adenosine triphosphate which provides cellular energy when hydrolysed to adenosine di-phosphate. Whilst about half of the energy requirements of newborn infants are met by the fat in breast milk, it is worth noting that lipid only provides a small contribution to the fetus where significant amounts of energy are provided by amino acids [6]. Unlike fats and carbohydrates there is no storage pool for amino acids themselves, and protein synthesis requires that the building blocks are all available at the same time. If the necessary dietary complement is not provided then amino acids unable to be used for tissue synthesis will be oxidised and used for energy, or stored as glycogen or fat. Of the 20 human amino acids, 18 are wholly or partially gluconeogenic. Body protein is therefore the largest potential supplier of glucose. This has important implications in preterm infants, as suboptimal energy supply might necessitate the use of essential body proteins as gluconeogenic precursors. Amino acids used as a fuel source are no longer available for protein synthesis.

1.3. Protein requirements Fetal accretion rates and the factorial approach provide a useful basis for defining protein and energy requirements in

N.D. Embleton preterm infants [7]. The seminal studies of Ziegler and others allow us to determine nitrogen accretion during fetal life [8]. Protein increments for the fetus between 25–30 weeks are approximately 2–2.5 g/kg/d. To calculate intake requirements, any losses and inefficiencies must be factored in. Dermal loss of protein, and possibly that in body secretions, is virtually impossible to measure, but probably in the order of 0.1–0.2 g/kg/d. Not all dietary protein is metabolically available – it must first be digested and absorbed – and along with normal turnover of cells lining the gut involves a loss of nitrogen in faeces. Metabolic studies suggest that the inevitable inefficiency of converting enteral protein into body protein is in the order of 10%. This ‘inefficiency’ does not exist when parenteral amino acids are administered (although gut cells will still be shed), but in this situation the balance of administered amino acids is crucial. The fetus exhibits very high levels of protein turnover. Animal studies demonstrate that placental nitrogen supply, as amino acids, far exceed that needed for protein deposition, and it seems likely that many amino acids are therefore oxidised to provide energy. Although there is some simple placental transfer of amino acids, it is clear that the placenta plays a major role in the synthesis, interconversion and utilisation of amino acids [6]. High rates of protein synthesis and breakdown persist in the newborn and result in an obligatory loss of nitrogen in the urine. This inevitable loss is equivalent to a protein loss of b 1.0 g/kg/d in ELBW infants. This suggests that infants born at 25–30 weeks probably require a protein intake of 3.5– 4.0 g/kg/d. Increased requirements due to many factors such as infection and repair of lung tissue, and the additional needs for catch-up growth mean that actual requirements are likely to be somewhat higher [7].

1.4. Energy requirements It is not as easy to define energy requirements using fetal accretion rates. Energy requirements depend on the stage of development and are higher per kg at 24 weeks compared to 36 weeks corrected age. They are also affected by degree of catch-up growth required, differences in body composition (i.e. fat free tissue requires a much higher energy expenditure), and differences in resting energy expenditure. Resting energy expenditure is affected by sleep state and activity levels, environmental factors such as thermoregulation, genetic differences in basal metabolic rate and demands for tissue synthesis. Synthesis of new tissue is energy intense and strongly affected by protein (and other nutrient) intake. Determining protein–energy ratios are as important as the precise energy intake. During the third trimester, lean and fat mass increases and water content decreases. This changing body composition means that optimal protein– energy ratios will be different for infants at 25 weeks, term, and in the postdischarge period. The energy required for protein deposition is approximately 5.5–7.75 kcal/g and for fat is 1.55–1.6 kcal/g [9,10]. Resting energy expenditure does not seem to vary much with gestational age, is approximately 45 kcal/kg/d [11] but may be lower in some babies. Estimated average requirements for new tissue in preterm infants are 4.5–4.9 kcal/g, [9,12] so if the intrauterine weight gain of 17 g/kg/d is to be achieved

Author's personal copy Optimal protein and energy intakes in preterm infants

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[13] 76–83 kcal/kg/d will be needed in addition to the resting energy expenditure. In total this approximates to 120–130 kcal/kg/d of total energy intake. This calculation includes the energy content of the dietary protein.

2. Optimal protein and energy intakes in the first few postnatal days Catabolism of energy and protein stores commences as soon as the continuous placental supply of amino acids, glucose and essential fatty acids abruptly stops. Metabolic adaptation prepares newborn infants for this process, but both glycogen and fat stores are limited in ELBW infants. A 500 g infant at 24 weeks is composed of approximately 90% water with just 50 g of ‘dry’ tissue, of which only a few grams (b 1% total body weight) are fat. Heird has estimated that body stores for an infant weighing 1000 g will only supply sufficient energy for 4–5 days [14]. The earliest parenteral formulations used hydrolysed protein but were associated with numerous problems, and early crystalline amino acid preparations were not designed for preterm infants. Their effects were interpreted alongside data from studies where very high intakes of enteral protein (b6–7 g/kg/d) were associated with adverse outcome [15]. Protein was generally introduced very cautiously. Modern amino acid solutions are able to provide equivalent protein intakes of up to 3.5 g/kg/d commenced immediately after birth in very preterm infants without apparent problem, [16] and administration of 2.5–3.5 g/kg/d of parenteral amino acids as soon as possible after birth is a reasonable recommendation [17]. Plasma amino acid profiles in preterm infants receiving parenteral amino acid solutions do not match that seen in healthy breast fed term infants. Fetal amino acid profiles are however quite different, and the results from babies receiving 3 g/kg/d of parenteral amino acids are remarkably close to these values [18]. Whether this is an appropriate standard is uncertain. A number of studies have examined the relationship between early energy and protein intake, and nitrogen balance in the first week of life [16,18–24]. These are summarised in Fig. 1 where each circle represents the mean group values for preterm infants in observational or controlled studies. None of the studies above noted significant adverse effects of early amino acid provision such as metabolic acidosis or raised urea. Examination of this figure shows, as suggested above, that failure to provide dietary protein will result in a daily negative nitrogen balance of approximately 150 mg/ kg/d (equivalent to 0.9–1.0 g/kg/d protein), and that a protein intake of approximately 1 g/kg/d is necessary to maintain zero nitrogen balance. It also follows that intakes well in excess of 1 g/kg/d of protein are needed to achieve positive nitrogen balance, with ELBW infants probably requiring even more. There are few data relating early intakes to long term outcomes, but observational data suggest benefit [25]. Early nutrient provision that attempts to meet estimated requirements appears both safe and logical, and should be considered standard practice. Typically, preterm infants receive immediate provision of energy as intravenous dextrose solutions, followed by increasing parenteral amino acids intakes, despite there being no good data that step-wise introduction of amino acid provides

Figure 1 Studies examining the relationship between protein intake and nitrogen retention in the first week of life. Each circle represents the mean value for a study group of preterm infants (n = 9–16). Large circle represents study group n = 66–69. Legend identifies primary author: see references [16,18–24] for details.

any advantage. There are wide ranging practices concerning the use of intravenous lipid and the introduction of enteral feeds, but many receive enteral milk in the first few days. These gradual increases in intakes of protein and energy result in an inevitable nutrient deficit. The cumulative deficit is calculated by assuming a daily requirement of 120 kcal/kg energy and 3 g/kg protein and subtracting this from the actual daily intake received. Fig. 2 shows that in infants b 31 weeks gestation this deficit totals approximately b 18 g/kg of protein by the end of the 2nd postnatal week [26]. The energy deficit is b600 kcal/kg. Additional daily needs for catch-up depend on the time over which the deficit is regained [27]. To recoup this protein deficit over the following 8 weeks would require an additional daily protein intake of 0.3–0.4 g/kg/d. If deficits are calculated assuming a protein need of 4 g/kg/d, both the cumulative deficit and the additional needs for ‘catch-up’ almost double.

2.1. Antiproteolytic effect of energy and protein, and the role of individual amino acids Increasing glucose supply reduces proteolysis in adults, primarily through promotion of insulin production. In ELBW infants, increasing glucose supply also increases insulin production but seems to have little effect on proteolysis calculated from stable isotope studies [28]. Denne and coworkers, have shown that intravenous amino acids suppress proteolysis by up to 20% in term infants without concomitant effects on glucose or insulin production [28–30]. In contrast, both ELBW and VLBW infants, show little, if any, proteolytic suppression at amino acid intakes of 2.5 g/ kg/d despite adequate amounts of glucose and lipid [31]. Others have confirmed that the primary effect of amino acid provision on net nitrogen balance is caused by promotion of synthesis rather than suppression of proteolysis [32]. Exogenous insulin did reduce proteolysis, but there was an unexpected parallel decrease in protein synthesis that meant there was no net change in protein balance [33]. Glutamine plays a key role in several metabolic processes, and many have suggested that it should be considered conditionally essential in preterm neonates. Current parenteral

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Figure 2 Cumulative protein deficit in infants b 31 weeks for postnatal days 0–13 from Ref. [26]. Bars represent recommended intake of 3 g/kg (crossed bars) and actual intakes (dotted bars) above the line, and cumulative deficit (solid bars) below the line. By the end of the 2nd postnatal week the protein deficit is approximately 18 g/kg.

amino acid solutions do not contain glutamine. Kalhan and coworkers have used stable isotope kinetics to show that supplemental glutamine decreases the rate of appearance of several key amino acids, suggesting suppression of whole-body proteolysis [34–36]. A large controlled trial of glutamine supplementation of parenteral nutrition showed no overall effect on weight gain [37]. In a further study, it was hypothesised that increased provision of amino acids would increase de novo glutamine synthesis, but results were equivocal [35]. In summary, there appear to be no currently available clinical techniques that result in significant suppression of proteolysis. Adequate provision of energy and amino acids is therefore essential to ensure positive nitrogen balance. Many other amino acids play important individual roles, but detailed discussion is beyond the scope of this chapter. Indeed, the list of amino acids previously considered nonessential that are now considered conditionally indispensable seems to continually increase. Nitrogen retention can be improved (∼30 mg/kg/d) by the addition of cysteine hydrochloride to infants receiving cysteine-free parenteral solutions. However, metabolic acidosis seems to be more common and there are no long term data to suggest that such supplementation should yet become routine practice [38]. Dietary taurine intake, might explain differences in longer term neuro-developmental benefit, but is the only important amino acid that is not a constituent of protein [39].

3. Optimal intakes in the subsequent postnatal weeks Whilst the first few postnatal days are vitally important, most preterm infants receive much more nutrition via the enteral as compared to the parenteral route. There is overwhelming evidence to support the use of breast milk, but for many VLBW infants, and for all ELBW infants it will not meet nutrient needs alone. Optimal protein and energy intakes will then require the use of breast milk fortifiers and/ or low birthweight formula. Poor growth in the postnatal period has been documented in several studies, is likely to be related, at least in part, to inadequate supply of protein and energy and is associated with worse neuro-developmental outcome. Lucas and co-

workers are the only group to have adequately tested the long term effects in controlled trials. They have shown conclusively that feeding preterm infants with a term formula compared to a formula designed for preterm infants prior to discharge, results in worse developmental and long term cognitive outcome during childhood [40]. Similar effects were observed when the formulae were used as supplements to maternal breast milk. It is not possible to know what precise constituents or combinations were responsible for the effects, but it is clear that inadequate nutrition for just a few weeks is likely to result in permanent disadvantage. It is important to note that in these trials, the control infants i.e. those receiving a term formula, were not deliberately malnourished. They continued to grow but presumably accrued significant nutrient deficits.

3.1. Enteral energy requirements in stable preterm infants Clinical studies suggests that energy intakes ≤ 100 kcal/kg/d will not meet the needs of some preterm infants prior to discharge, but where protein–energy ratios are adequate (N 3–3.6 g/100 kcal) a lower limit of N 100 kcal/kg/d might be safe [41]. Metabolisable energy intake is usually about 90% of total dietary energy, but fat malabsorption is common in preterm infants, so feeding at these lower intakes might only be safe when the breast milk, fortifier and/or formula used are ‘well absorbed’. These lower intakes may result in a fat mass percentage closer to both intrauterine references and normal term infants. Given the limitations of using weight as a valid measure of growth, and differences in fat:lean mass ratios, the overall aim of assessing energy intakes may be better focused on achieving optimal lean mass accretion. Studies have shown that whilst higher intakes (140–150 kcal/kg/d) appear safe in the short term, there is limited evidence of improved linear growth that might be a proxy for lean mass or nitrogen accretion, and fat mass deposition appears excessive [41–44]. Nonprotein–energy source affects nitrogen retention. Carbohydrate appears more effective than fat at sparing protein oxidation, and may result in improved linear growth. However, studies at energy intakes of 155 kcal/kg/d with

Author's personal copy Optimal protein and energy intakes in preterm infants higher ratios of carbohydrate:fat showed substantially greater fat deposition than intrauterine references [44]. Few preterm infants require an intake much in excess of 120 kcal/kg, [45] and a reasonable range of energy intake for healthy growing preterm infants with adequate protein intake is in the range 110–135 kcal/kg/d. In infants where growth appears inadequate and there is no evidence of fat malabsorption, increasing energy intake may not be appropriate as it is more likely that other nutrients, especially protein, are rate limiting on growth.

3.2. Enteral protein requirements in stable preterm infants Protein requirements vary much more than those for energy during the 2nd and 3rd trimester. Although the factorial approach suggests that protein requirements are likely to be 4 g/kg/d or higher, most studies reviewed in a recent metaanalysis have compared ‘low’ (b 3 g/kg) to ‘high’ (3–3.9 g/ kg) intakes, and there are very few studies specifically examining ‘very high’ (≥ 4 g/kg) intakes [46]. There is marked heterogeneity in formula composition, duration of study and patient group, many studies have methodological issues, and few have long term follow up data. Short term data suggest that intakes higher than 3 g/kg/d are needed but there are too few data to know what the optimal protein intake might be for most ELBW infants. In the meta-analysis only two studies reported ‘very high’ intakes of protein and both noted associated problems (4.5 g/kg/d [47] and 6–7.2 g/kg/d [15]). Raiha noted an increased incidence of metabolic acidosis that resolved when infants were converted back to breast milk [47]. Goldman noted a significant increase in low IQs among infants b 1300 g fed the very high intakes [15]. Both these studies were conducted more than 30 years ago. In a more recent study, preterm infants were enrolled at approximately 33 weeks corrected gestation and fed one of three isocaloric formulae (80 kcal/100 mL) until 12 weeks postterm. Protein–energy ratios of 3.3 g, 3 g and 2.7 g/ 100 kcal provided protein intakes of between 3.5 g to 4.5 g/ kg/d [48]. Whilst there was evidence of improved early growth with the higher protein–energy ratio (until 36 weeks corrected), no differences in weight or length gain, or body composition were detected at the time of the primary outcome at 12 weeks. This study suggested that higher protein intakes might be beneficial in the predischarge period, but that a protein–energy ratio N 2.7 g/100 kcal offered no advantage in the postdischarge period. It is noteworthy that even though protein intakes in the postdischarge period were in excess of 5–6 g/kg/d for some infants, metabolic acidosis, or abnormal plasma amino acid profiles were not observed in those with raised serum urea. Further study has examined the effect of increased dietary protein on growth and metabolic balances in VLBW infants randomised in a cross-over design to isocaloric formulae (80 kcal/100 mL) with protein–energy ratios of 3 g v 3.6 g/100 kcal [49]. This resulted in protein intakes of 3.8 g and 4.6 g/kg/d. No infants developed raised urea or metabolic acidosis. Higher protein intakes were associated with improved nitrogen retention (40 mg/kg/d), weight gain (8 g/d) and fractional weight gain (6 g/kg/d). These data demonstrate that a protein–energy ratio of 3.6 g/100 kcal is

835 safe and efficacious in the short term, but long term effects on growth require confirmation in a large controlled trial. Preterm infants are generally discharged when they are able to demand oral feeds by breast or bottle despite there being no logical reason why that should signal the end of continuing nutritional assessment. Most infants will have weights below their birth centile, many will grow poorly in the first year of life and many will achieve lower scores on cognitive testing in the future. Are these in any way connected? Several large trials have examined the role of specialised ‘postdischarge’ formula, but whilst all have demonstrated benefits on various aspects of growth none have shown clear neuro-cognitive benefit [50–52]. It seems though, that in at least one study, differences in growth were achieved largely by differences in protein intake [53]. Infants appeared to regulate their intake volumes on caloric density, so whilst energy intakes were identical between those consuming a standard and preterm formula, protein intakes (and protein–energy ratios) were greater.

3.3. Practical implications and the use of breast milk There is no doubt that there are substantial advantages offered by using breast milk. It may not be appropriate therefore to make a simplistic comparison between macronutrient requirements in formula and breast fed infants. Nonprotein nitrogen in breast milk as urea almost certainly contributes to the overall nitrogen economy. Protein quality or source may be important in other respects. Many studies seem to suggest that protein hydrolysate formulae are associated with slightly less nitrogen retention, greater urinary excretion of amino acids and differences in plasma amino acid profiles [54]. Whether this has clinical implications is uncertain. Nitrogen and energy retention may also be adversely affected by the addition of breast milk fortifiers. Given the large variability in nutrient composition of breast milk it is also difficult to know how much fortifier to provide. Some have proposed analysing individual aliquots of breast milk but this technique is not routinely available [55]. A more recent study suggested using periodic determinations of serum urea as a guide to protein intake, and adjusting the intake of fortifier and supplemental protein accordingly. This resulted in better weight gain and head growth compared to a control group receiving standard fortification [56].

4. Conclusions Preterm infants are nutritionally vulnerable and careful management of their energy and protein requirements is essential if their outcome is to be optimised. However, any potential short term growth benefits from increasing intakes of protein and energy need to be considered alongside the potential for adverse long term metabolic adaptation [3]. Some have suggested a more cautious approach to promoting ‘catch-up’ growth. However, these long term epidemiological studies have demonstrated that the catch-up observed occurs in term infants feeding ‘ad lib’. If infants regulate intake on calories can rapid catch-up be prevented? Appropriate nutritional management primarily in the predischarge period, may prevent nutrient deficits occurring or persisting at discharge. If adequate nutrition is being achieved there may

Author's personal copy 836 be little or no catch-up needed. Conversely, inadequate attention to nutrient intakes in early postnatal life will result in poor growth, cognitive compromise, and potentially create the conditions whereby rapid growth may adversely affect long term metabolic outcome.

N.D. Embleton

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Acknowledgements/Conflict of Interest [21]

Dr Embleton has received grants from Royal Numico, SHS International and Nutricia to support research examining nutritional requirements in preterm infants, but has received no personal payment, and has no other financial relationship with these organisations. No commercial organisation was involved in the preparation of this manuscript.

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