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REVIEW ARTICLE

Workshop Summary: Nutrition of the Extremely Low Birth Weight Infant

William W. Hay, Jr, MD*; Alan Lucas, MD‡; William C. Heird, MD§; Ekhard Ziegler, MD¶; Ephraim Levin, MDi; Gilman D. Grave, MDi; Charlotte S. Catz, MDi; and Sumner J. Yaffe, MDi

ABBREVIATIONS. ELBW, extremely low birth weight; NEC, necrotizing enterocolitis; IUGR, intrauterine growth-restricted; RER, respiratory exchange ratio; LA, linoleic acid; EFA, essential fatty acid; LNA,a-linolenic acid; BPD, bronchopulmonary dyspla-sia; AA, arachidonic acid; DHA, docosahexaenoic acid; GI, gastro-intestinal; IGF-I, insulin-like growth factor I; EGF, epidermal growth factor; MEN, minimal enteral nutrition.

O

ver the past decade many exciting advances

have been made with regard to the survival, medical care, and outcome of extremely low birth weight (ELBW) infants (those who weigh

,1000 g at birth). Yet the growth of these infants continues to lag considerably after birth.1

Further-more, this postnatal lag of growth is related to long-term growth and neurodevelopmental delays at least through school age2–5and, possibly, into adulthood.6

These major deficits define critical needs for further information about the nutritional requirements for growth of ELBW infants, how they should be fed, and whether improved growth and developmental outcomes can be achieved with earlier and more aggressive postnatal nutrition.

To address these critical needs, a Workshop was sponsored by the National Institute of Child Health and Human Development in September 1997. This Workshop Summary, updated in December 1998, presents consensus views of the Workshop attendees about current information on the nutritional require-ments of ELBW infants, how well these requirerequire-ments are met by current feeding practices, and the extent to which current nutritional practices in the early postnatal period contribute to the generally poor outcome of these infants. The Summary concludes with recommendations for research to fill gaps in knowledge and resolve controversies in knowledge and current practice that should lead to improved

nutrition, growth, and developmental outcome of ELBW infants.

The premise of the Workshop was that optimal nutrition of ELBW infants should meet the unique and changing nutrient requirements of these infants and support growth that mimics normal fetal growth.7Unfortunately, this goal is seldom met. On

the one hand, extremely preterm birth results in seemingly insurmountable impediments to growth, including the stress of relatively frequent pathophys-iologic events (eg, hypotension, hypoxia, acidosis, infection, surgical interventions), pharmacologic treatments (eg, corticosteroids) and physiologic im-maturity (eg, limited intestinal motility). On the other hand, there is concern that early aggressive feeding will produce pathology, principally necrotiz-ing enterocolitis (NEC), but also potential toxicity to the central nervous system and other organs from elevated plasma concentrations of amino acids, glu-cose, fatty acids, and/or their metabolic products. Furthermore, many ELBW infants already are signif-icantly growth restricted at birth8 –11and because this

might represent successful adaptation of the fetus to nutrient insufficiency, readaptation to higher and perhaps qualitatively unique nutrient intakes may be required before growth can resume, a consequence suggested by animal studies.12,13

CURRENT FEEDING PRACTICES AND THEIR CONSEQUENCES

Inadequate Growth

Several clinical management practices contribute to inadequate nutrition and, hence, inadequate growth of ELBW infants.14 Most are controversial

and lack rigorous testing against desirable outcomes. One is volume restriction. For many ELBW infants, total fluid intake is routinely limited, especially in the early postnatal period, often to,120 mL/kg/d. Current formulas, human milk supplements, and in-travenous nutrient mixtures are too dilute to provide sufficient nutrients, especially protein, when fed at such rates. Another is the practice of increasing in-takes to increase body weight only after weight has reached a plateau or decreased, virtually ensuring that infants will grow at less than their potential. Uncertainty about the actual nutritional require-ments for normal metabolism and desired rates of growth also may contribute to such limited nutrient intakes. Whatever the reasons, it is clear that many ELBW infants do not achieve sufficient nutrient in-From the *Department of Pediatrics of the University of Colorado Health

Sciences Center, Denver, Colorado; the ‡MRC Childhood Nutrition Re-search Centre of the Institute of Child Health, University College London, London, United Kingdom; the §Children’s Nutrition Research Center and the Department of Pediatrics of the Baylor College of Medicine, Houston, Texas; the ¶Department of Pediatrics of the University of Iowa, Iowa City, Iowa; and theiCenter for Research for Mothers and Children, National Institute of Child Health and Human Development, Bethesda, Maryland. Names of the Workshop participants can be found in the Appendix. Received for publication Jan 25, 1999; accepted Apr 26, 1999.

Reprint requests to (W.W.H.) University of Colorado Health Sciences Cen-ter, 4200 E Ninth Ave, Box B-195, Denver, CO 80262. E-mail: bill.hay@uchsc.edu

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take to produce rates of growth that could be con-sidered adequate, let alone optimal. Although inad-equacies of other nutrients, including the micro-nutrients, cannot be ruled out as additional causative factors, global undernutrition of both protein and energy is by far the most plausible cause of nutrition-related suboptimal outcome of ELBW infants.

Inadequate Development

There is considerable evidence that inadequate early nutrition can have a strongly negative impact on long-term outcome. For example, malnutrition at a vulnerable period of brain development results in a decreased number of brain cells as well as deficits in behavior, learning, and memory.15 Later

develop-ment of obesity, insulin resistance, hypercholesterol-emia, hyperlipidhypercholesterol-emia, and diabetes also has been associated with low maternal protein intake and high maternal carbohydrate intake during pregnancy and lactation.16 In contrast, there is much less evidence

that enhanced early nutrition can have a strongly positive impact on long-term outcome. Only one ma-jor study has addressed this possibility. In that study, random assignment of human preterm infants to a standard term formula rather than a nutrient-enriched preterm formula as sole diet or as supple-ment to mother’s own expressed milk during hospi-talization was associated with major developmental disadvantages at 18 months postterm, especially in intrauterine growth-restricted (IUGR) infants.17 At

school age, those assigned to the term formula also had a significantly lower verbal IQ and a higher incidence of frank cognitive and neuromotor impair-ment.18Clearly this single study needs confirmation,

and there is great need for additional large, random-ized trials to test the impact of various improvements in diet and feeding of ELBW infants on long-term outcome.

CURRENT KNOWLEDGE REGARDING SPECIFIC NUTRIENT REQUIREMENTS

Although achievement of the normal rate of fetal growth is the standard for judging the adequacy of nutritional intakes of ELBW infants,7 there is little

direct evidence in human fetuses of the composition and amount of nutrient intakes that support normal fetal growth. Such information is vital to help deter-mine the postnatal nutritional requirements neces-sary to achieve intrauterine rates and composition of growth in infants born at equivalent stages of very early development. Several experimental approaches have been used to estimate these requirements. For example, direct measurements of the rates of fetal nutrient uptake, utilization, turnover, and accretion of body nutrient components have been made in fetal sheep.19 Such studies have shown that the late

sec-ond, early third trimester ovine fetus uses about 8 to 10 mg/min/kg of glucose, which interestingly is about the maximum rate of glucose that is tolerated by ELBW human infants at comparable gestational ages.20 Other studies have defined the basal energy

requirements of the ovine fetus as 50 kcal/d/kg, also similar to that of preterm human neonates.21,22 The

early third trimester fetal sheep also uses about 6.25

g/d/kg of amino acids.23,24When scaled to the

frac-tional growth rate of lean body mass characteristic of the normally growing human fetus at the same stage of development,25this rate of amino acid utilization

is about 3.6 to 4.8 g/d/kg. This rate is similar to the required intake (4.0 g/d/kg) estimated for ELBW infants by the factorial method and greater than the rate of amino acid or protein intake that these infants usually are fed.26 Furthermore, with current human

milk or formula feeding regimens, it is practically impossible to achieve protein intakes that are neces-sary to achieve and maintain the desired rates of growth.26 Such observations support the position

that ELBW infants need greater nutrient intakes than customarily fed and define the need for further study of protein requirements and the development and response to feeding of more concentrated food mix-tures.

Amino Acids and Protein

ELBW infants receiving glucose alone lose in ex-cess of 1.2 g/d/kg of endogenous protein. This re-flects markedly increased rates of protein breakdown relative to the already high rates of protein synthesis. Provision of amino acids, even if total energy intake is low, spares endogenous protein stores by enhanc-ing the rate of protein synthesis, thereby decreasenhanc-ing the difference between rates of proteolysis and pro-tein synthesis.27–29Providing intravenous amino acid

and energy intakes as low as 1.1 to 1.5 g/d/kg and 30 kcal/d/kg changes protein balance from substan-tially negative to zero or slightly positive.30A higher

energy intake decreases proteolysis to some extent and higher intakes of both protein and energy result in net protein anabolism.30 Despite such evidence,

many ELBW infants do not receive even such modest intravenous amino acid and energy intakes during the first several days of life, virtually assuring devel-opment and continuation of a catabolic state. Addi-tional, much larger studies are clearly needed to confirm the potentially beneficial effects of earlier and greater protein intake on producing a more pos-itive protein balance.

Even if total protein intake is adequate, however, a number of factors may limit its utilization. One major factor is an inadequate intake of a single essential (indispensable) or conditionally essential amino ac-id.31 The latter include tyrosine, cysteine, taurine,

histidine, glycine, glutamine, and arginine. A suffi-cient amount of all nonessential amino acids also are required to maintain an appropriately balanced in-take of amino acids; otherwise, essential amino acids are diverted to their production and away from pro-tein synthesis.

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condition-ally essential amino acids, glutamine, cyst(e)ine, and tyrosine, are not found in currently available intra-venous amino acid mixtures. Glutamine and cys-t(e)ine are unstable in solution but can be added to infusates on a daily basis; tyrosine, however, is rela-tively insoluble.

The amount of these amino acids needed also is unclear.32–35 Moreover, even if these were known,

acceptable strategies for increasing the amino acid contents of parenteral amino acid mixtures must be defined. For example, increasing the phenylalanine intake might increase availability of tyrosine but also can produce hyperphenylalaninemia and its poten-tially adverse effects on brain development. Use of

N-acetyltyrosine (a more soluble form of tyrosine) appears to help provide tyrosine requirements but its bioavailability is limited.36Tyrosine peptides such as

glycyltyrosine are a more promising form of soluble tyrosine37 but these have not been studied in

neo-nates.

Energy Requirements and Energy Balance

Most studies of energy expenditure in ELBW in-fants have used indirect calorimetry. Other methods (eg, direct calorimetry, doubly labeled water, heart rate monitoring, and labeled bicarbonate infusion) have major limitations when used in ELBW infants. The variability with indirect calorimetry is due pri-marily to the low rates of oxygen consumption and carbon dioxide production of ELBW infants.38Errors

of measurement of oxygen consumption up to 5% are often reported and the error in measurement may be even larger if the infant is receiving supplemental oxygen and/or is ventilated and has leaks around the endotracheal tube.39Thus, although it seems

ob-vious that measurements of energy flux and energy balance should be made more frequently in ELBW infants to test for their energy responses to different diets and methods of feeding (as well as medical care and disease states), considerable improvement in cal-orimeter design is needed before there can be more widespread application of calorimetry measure-ments.

Indirect calorimetry also has been used to estimate the contribution of carbohydrate and fat to energy metabolism, but such estimates include potential er-rors in determination of the respiratory exchange ratio (RER) and substrate metabolic interconver-sions. The assumption that the relation between ox-ygen consumption and carbon dioxide production is a constant for different rates of substrate utilization is not valid in growing infants. Even the addition of stable isotopes to quantify the carbon substrate used for energy production has limitations. For example, estimates of glucose utilization from respiratory cal-orimetry and from oxidation of13C-glucose are

com-parable at RER between .76 and .90, but the contri-bution of glucose to energy production is higher than estimates from respiratory calorimetry at RER ,.76 and less at RER..90. The discrepancy at lower RERs is thought to represent the contribution of glucone-ogenesis, which is included as protein oxidation in RER, whereas the discrepancy at higher RERs is thought to be attributable to lipogenesis.40

Indirect calorimetry estimates of energy expendi-ture of ELBW infants indicate that daily energy ex-penditure ranges from 60 to 75 kcal/d/kg.41 The

higher energy expenditure of ELBW infants is re-lated, in part, to their higher rates of growth and, hence, greater needs for synthesis of new tissue. ELBW infants also can have higher energy losses from heat and evaporative exchange attributable to their thin skin and high surface-to-mass ratio. Respi-ratory distress, sepsis, and some medications (eg, caffeine, insulin, and dexamethasone) also appear to increase energy expenditure.38,42 However, there is

considerable controversy about the actual energy ef-fects of these and other conditions and medications in ELBW infants. Resolution of such controversy needs considerably more study and more wide-spread application of measurements of caloric ex-penditure.

Lipids

Absolute lipid requirements are limited to the re-quirements for essential fatty acids (EFAs), ie, from 1% to 4% of total energy intake as linoleic acid ([LA], 18:2v6) and approximately 1% of total energy intake asa-linolenic acid ([LNA], 18:3v3). However, higher lipid intakes are necessary to achieve total body en-ergy balance and support normal growth. Although lipid comprises about 50% of the nonprotein energy content of both human milk and formulas, both of which contain LA and LNA, customary limitation of enteral intake precludes these sources for early post-natal supply of the EFAs.

Parenteral lipid emulsions also can provide non-protein energy and EFAs. However, use of such emulsions in ELBW infants often is delayed or lim-ited by concerns that lipid intolerance— either de-creased clearance (inde-creased plasma triglyceride con-centrations) or decreased utilization (increased plasma free fatty acid concentrations), both of which are more common in ELBW preterm and IUGR in-fants—may have adverse effects. These include im-paired oxygenation, imim-paired lung function (ventila-tion-perfusion ratio), increased risk of lung disease (particularly bronchopulmonary dysplasia [BPD]), impaired immune function, and increased free bili-rubin levels. In addition, clearance of an equivalent amount of triglyceride is slower if infused as a 10% rather than a 20% emulsion because of the interfer-ence of phospholipids, which are in relatively greater abundance in the 10% solutions.43

Several studies have examined the effects of lipid emulsion on the incidence and severity of respiratory morbidity. Some have shown no effects and others have shown adverse effects.44 – 49 The effect of lipid

emulsion on immune function also is uncertain; there is no conclusive evidence of deleterious in vivo ef-fects,50but deleterious in vitro effects have been

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encephalopa-thy. However, displacement of bilirubin from albu-min is albu-minimal at fatty acid/albualbu-min ratios,4.1 and higher ratios are unlikely. Further, clinical studies have shown that infusion of lipid at rates up to 3 g/d/kg does not increase plasma concentrations of free fatty acids or free bilirubin.51

Available parenteral lipid emulsions contain large proportions of LA and LNA. Failure to provide LA results in biochemical signs of deficiency within 72 hours,52but this can be prevented by administration

of as little as .5 g/d/kg of available lipid emulsions. These emulsions do not contain arachidonic acid (AA, 20:4v6) and docosahexaenoic acid (DHA, 22: 6v3); thus, concerns have been expressed about availability of sufficient amounts of these fatty acids for the developing central nervous system. In this regard, plasma, liver, lung, and kidney lipid levels of both AA and DHA fall during infusion of lipid emul-sions, although the short-term effect on brain lipid levels is relatively small.53 The long-term effects of

lower intakes of AA and DHA on brain development are unknown but should be determined given the large contribution of these EFAs to brain growth and development at this early state of development.

Adverse effects of parenteral lipid emulsions sec-ondary to an inappropriate overall fatty acid compo-sition also must be considered.54 In comparison to

normal tissue and to plasma lipids and human milk, currently available emulsions have a very high con-tent of LA and LNA but a very low concon-tent of satu-rated (16:0) and monounsatusatu-rated (18:1) fatty acids. Unfortunately, there is no consensus for the appro-priate range of any of these fatty acids or the long-chain polyunsaturated fatty acids (LC-PUFAs) in plasma (or tissue) lipids. This is unfortunate because dietary fat is an important determinant of membrane lipid composition, a variety of membrane-associated functions, eicosanoid metabolism, and possibly cen-tral nervous system development. Other problems, eg, lipid peroxidation and free radical formation at-tributable to increased incorporation of polyunsatu-rated fatty acids (ie, 18:2v6, 18:3v3) into tissue lipids, also are possible and need further study.

LC-PUFAs

Whether LC-PUFAs should be added to formulas and/or parenteral lipid emulsions intended for ELBW infants remains highly controversial. Some, but not all, studies have indicated that both term and preterm infants fed human milk and LC-PUFA-sup-plemented formulas might have better visual devel-opment and neurodeveldevel-opmental outcomes than in-fants fed unsupplemented formulas.5 Thus, several

agencies and individuals have recommended that infant formulas, particularly preterm formulas, be supplemented with DHA and AA.56 –59The amounts

usually suggested are those of human milk. Others feel that recommendations to supplement formulas with DHA and AA are premature, especially in light of studies that show no improvement in visual and/or neurodevelopmental outcome. There is rea-sonable evidence to support this more cautious po-sition. For example, LC-PUFAs are present in human milk but the amounts are variable and seem to reflect

the LC-PUFA content of maternal plasma which, in turn, reflects maternal diet. This suggests that there is no specific mammary gland mechanism for main-taining a narrow range of concentrations of these fatty acids in human milk, making it difficult to determine specific amounts with which to supple-ment formulas. Furthermore, although DHA is the predominant fatty acid in the retina, retinal DHA content can be maintained by adequate intakes of LNA.60 Also, although the LC-PUFAs are the

pre-dominantv3 andv6 fatty acids in brain, the relation-ship between the plasma lipid content of these fatty acids (which reflect dietary intake) and the brain content is poorly defined. In fact, data from animal and cell culture studies suggest that the major por-tion of DHA deposited in the developing brain may be synthesized within the brain.61,62In addition to the

lack of consistent evidence that LC-PUFAs improve either visual acuity or neurodevelopmental outcome, there are unresolved problems with assessing both visual acuity and neurodevelopmental outcome dur-ing infancy.

A number of safety issues concerning the various sources of LC-PUFAs also remain to be addressed. LC-PUFAs are highly bioactive compounds. They are precursors of eicosanoid and they enhance as well as depress transcription of genes encoding a number of important metabolic enzymes.63

More-over, DHA and AA cannot be added to formulas as fatty acids but must be added as components of lipids. Several sources of such fatty acids are avail-able but some are considered novel for infant formu-las and are untested with respect to long-term safety. Also, the available LC-PUFA sources differ in struc-ture and, hence, may not be metabolically equivalent. Furthermore, studies in which DHA was obtained from fish oil have shown slower rates of growth in low birth weight infants (not all were ELBW).64,65It is

not known whether the level of dietary DHA, the absence of AA, an imbalance of DHA and AA, or some contaminant from the fish oil led to the slower rate of growth.

Glucose

Although the absolute glucose requirement of term infants is limited to that necessary to prevent hypoglycemia, about 3 to 4 mg/min/kg (or less),66

ELBW infants often require more. However, the ab-solute requirement for glucose (or carbohydrate) is probably much less than the usual amounts given to ELBW infants (often in excess of 12 to 14 mg/min/ kg) as part of enteral and intravenous nutrition reg-imens. Actual measurements of glucose utilization and production rates in ELBW infants, even shortly after birth, average from 6 to 10 mg/min/kg.67These

rates are slightly higher than in term infants, in part because the brain-to-body-weight ratio of the ELBW infant is higher and in part because total energy requirements are higher.

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adipos-ity and to increased carbon dioxide production. Whether such consequences are of clinical signifi-cance or lead to poor outcomes needs to be resolved. Most studies have shown a negative correlation be-tween hepatic glucose production of healthy preterm infants and plasma levels of glucose and insulin.68

Infusion of glucose alone (.6 to 7 mg/min/kg), but particularly with insulin or with amino acids, causes an almost complete suppression of glucose produc-tion in most infants. Fatty acids also regulate plasma glucose concentration by decreasing peripheral glu-cose uptake and, via their oxidation, by increasing enzymatic activity within the gluconeogenic path-way. Unless hypoglycemia is significant, however, the impact of lipids on the rate of glucose production is limited relative to its effect on decreasing glucose utilization. Overall, much more information is needed concerning the interaction of lipid supply, plasma triglyceride and free fatty acid concentra-tions, and glucose metabolism. In addition, mecha-nisms to enhance and sustain gluconeogenesis in ELBW infants, eg, early intravenous amino acid in-fusion, need to be studied and developed.

Hypoglycemia in ELBW infants continues to be a common and difficult problem to manage. A major component of this problem is the actual definition of hypoglycemia. Recent cordocentesis studies in nor-mal human fetuses over the second half of gestation demonstrate that fetal plasma glucose concentration is.50 to 55 mg/dL.69These values are the same as

the lower 95th percentile confidence limits for nor-mal preterm infants.70They also are just greater than

the threshold value reported by Lucas et al71 below

which repeated measurements of low glucose con-centrations are associated with increased risk of mental and motor developmental delay. Based on this evidence, the 50 to 55 mg/dL glucose concentra-tion range should be the lower limit for ELBW pre-term infants. Whether or not strict adherence to keeping glucose concentrations above this range will improve neurodevelopmental outcome, however, re-mains to be proven.

Hyperglycemia also is a common problem in ELBW infants. The causes remain poorly defined and controversial, as do current therapeutic ap-proaches. Although many studies have shown that glucose and insulin can suppress glucose produc-tion in ELBW infants, others have shown persistent glucose production in ELBW infants despite intra-venous glucose infusions.72–74A few studies

possi-bly included infants with stress-induced glucose production and some may have included results of intravenous lipid infusion, which tends to enhance glucose production and diminish glucose utiliza-tion. In others, reasons are less clear, but may include relative insulin resistance. In contrast, early infusion of amino acids may actually de-crease glucose production, inde-crease insulin secre-tion, and enhance insulin acsecre-tion, thus limiting the need for exogenous insulin.75

Trace Minerals

Currently, the importance of iron, zinc, copper, and selenium in nutrition of ELBW infants is well

established.76 The importance of iodine, manganese,

molybdenum, chromium, fluoride, and cobalt also is recognized, but deficiency states are not a current concern in the United States. Vanadium, boron, ar-senic, silicon, lead, and nickel may be important, but a need for these minerals has not been established.

Several lines of evidence suggest that ELBW in-fants probably require more zinc than term inin-fants. For example, increasing dietary zinc from moderate to high levels over the first year of postnatal life has been shown to improve growth and motor develop-ment as well as developdevelop-ment and function of the immune system, especially in ELBW infants with IUGR.77,78 In addition, acute zinc deficiency occurs

more readily in the ELBW preterm infant.79,80 Also,

optimization of maternal zinc status during preg-nancy appears to reduce the incidence of prematuri-ty.81,82Despite increased zinc needs, the ELBW infant

has a remarkable ability to conserve endogenous zinc (bound to hepatic metallothionein) by 30 to 32 weeks postconceptional age.83 Hence, the need for zinc is

very modest until rapid growth is established. Whether increased zinc supply can augment in-creased protein and energy intake to promote growth more rapidly and earlier remains unknown. Although the optimal range of zinc intake remains incompletely defined, it appears to be limited. Too much zinc, for example, impairs immune function and interferes with copper metabolism.77

Less is known about the ELBW infant’s need for other trace minerals. The optimal iron intake, partic-ularly that to be administered in conjunction with erythropoietin therapy, is still uncertain. The effi-ciency of utilization of fetal hepatic copper stores, including the extent of reabsorption of endogenous copper that has been secreted in the bile, also is not known.84Both iron and copper are potent oxidants in

biological systems, and the ELBW infant is especially vulnerable to oxidant stress. Selenium, on the other hand, is an essential component of one of the gluta-thione peroxidase enzymes and, hence, is an impor-tant antioxidant. Recent reports have linked sele-nium deficiency in ELBW infants with impaired pulmonary function and, possibly, retinopathy.85

Inositol

Inositol and phosphoinositides mediate trans-membrane signaling, are lipotrophic growth factors, and serve as sources of AA. Inositol is present in human milk and infants fed human milk have higher serum concentrations than formula-fed and/or par-enterally-fed infants.86 – 88 However, few data are

available regarding the clinical impact of inositol supplementation. One study reported improved respiratory and surfactant function in preterm in-fants with respiratory distress syndrome who re-ceived supplemental inositol,88 suggesting that

ino-sitol might potentiate glucocortocoid-induced

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Nucleotides

Nucleotides are components of nucleic acids and precursors of many important physiologic media-tors. They are present in human milk as nucleic acids, nucleosides, nucleotides, and related meta-bolic products. Numerous studies in animals have demonstrated beneficial effects of dietary nucleotide supplements on growth, development, and function of the gastrointestinal (GI) and immune systems.89 –91

The role of nucleotides and the amounts needed by ELBW infants requires further study.

Choline

Choline is a component of important phospholip-ids and a precursor for the biosynthesis of acetylcho-line and betaine (a source of labile methyl groups). A clinical choline deficiency syndrome has not been defined in humans, although patients receiving cho-line-free nutritional regimens may develop liver dys-function similar to that observed in choline-deficient animals that is reversible by the addition of choline to the diet or by the use of lipid emulsions that contain phosphatidylcholine. Choline may also facil-itate spatial memory, which is temporally related to prenatal cholinergic neurogenesis and postnatal syn-aptogenesis,92 transmembrane signaling, neuronal

apoptosis, neuronal synthesis/release of acetylcho-line,93and neural function after injury.94Despite such

apparent importance in development, the ELBW in-fant’s need for choline remains undefined.

MILKS, FORMULAS, AND FEEDING PRACTICES Human Milk Versus Formula

Human milk has unique nutritional components, contributes to host defense, exerts trophic effects on the GI tract, and promotes maternal-infant bond-ing.95 However, there are major concerns about its

nutritional adequacy for ELBW infants. Supplemen-tation with calcium and phosphorus is necessary to produce normal biochemical indices of mineral ho-meostasis and sodium supplementation is necessary for normalization of plasma sodium concentration. Also, protein supplementation of human milk is nec-essary to improve rates of weight gain and indices of protein nutritional status in ELBW infants.96,97

Opti-mal supplementation regimens remain to be defined and tested.

Clinical studies of ELBW infants fed fortified ver-sus unfortified human milk indicate that intakes of protein and minerals as well as rates of gain in weight and length are greater in those fed fortified human milk.98 –100Indices of protein and mineral

nu-tritional status also are more appropriate and balance data indicate that net nutrient retention rates ap-proach intrauterine rates. In contrast, ELBW infants fed fortified human milk versus preterm formula have markedly lower rates of weight- and length-gain as well as lower rates of increase in skinfold thicknesses.100 The lower rates of growth may be

related to the roughly 30% lower rates of fat absorp-tion of infants fed fortified human milk versus pre-term formula.101Fortified human milk must be fed at

approximately 180 mL/d/kg, however, if ELBW

in-fants are to achieve adequate growth, nutrient reten-tion, and biochemical indices of nutritional status. There still are safety concerns with fortification of human milk, especially with cow milk proteins. Such a practice may increase the rate of sepsis and NEC.102

In contrast, there is good evidence that human milk feeding of preterm infants provides significant pro-tection from infection and NEC103 Both of these

ob-servations require confirmation.

Growth Factors in Human Milk

Mammalian colostrum and milk contain a variety of growth factors. Their concentrations vary among species and according to the stage of lactation. The biological importance of these growth factors to the ELBW neonate is not known. A central question is whether their presence in milk simply represents spillover of factors involved in mammary gland function or whether they provide important benefits to the infants who ingest them.104

Of the many growth factors that have been de-tected in human milk, insulin-like growth factor-I (IGF-I) and epidermal growth factor (EGF) are likely candidates for enhancing the development of the GI tract.104,105 IGF-I concentration is two- to threefold

higher in human colostrum than in mature milk but declines sharply after 2 to 4 days of lactation. Al-though present in bovine milk, IGF-I is not detectable in infant formulas. However, IGF-I mRNAs are ex-pressed throughout the GI tract, indicating that the peptide may be produced (and may act) locally.106

Parenteral administration of IGF-I to animals sub-jected to intestinal resection, total intravenous nutri-tion, glucocorticoids, and intestinal transplantation causes increases in crypt cell proliferation, protein synthesis, mucosal thickness, and intestinal length. However, enteral administration of physiologic con-centrations of IGF-I in formula has smaller effects.107

Thus IGF-I may not be an essential component of the milk of normal, healthy infants but it may have ther-apeutic benefits for infants with compromised GI function. EGF also is present in human milk and its concentration also is higher in colostrum (6 –70 nmoles/L) than in mature milk (3–20 nmoles/L). Weanling rats fed formula supplemented with EGF have accelerated small intestinal regrowth after in-testinal resection.108 EGF also enhances healing of

stress-induced gastric ulcer109 and increases villus

length and lactase activity of rotavirus-damaged pig-let small intestine.109

Effects of Early Enteral Feeding on GI Development

Because of the assumed association between feed-ing and NEC, many ELBW infants are not fed durfeed-ing the early days and weeks of life.110 However, this

necessitates extensive intravenous nutrition, which has been associated with poor intestinal growth, cho-lestasis, osteopenia, and sepsis. To minimize these complications of intravenous feeding, small volumes of human milk or formula are often fed to promote intestinal growth and development. Numerous ani-mal studies have shown that this practice, ie, mini-mal enteral nutrition (MEN),111 maintains mucosal

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studies have demonstrated benefits of MEN without adverse consequences.112 Documented benefits of

MEN include higher plasma concentrations of GI hormones, a more mature motility pattern, a lower incidence of cholestasis, and better as well as sooner tolerance of enteral feedings.111–114Clear evidence for

the relative advantages of various types of MEN (eg, dilute versus full strength formula; continuous ver-sus bolus infusion; rate of volume increase; specific formula or formula component) is not available and will require many more large, randomized trials.

CONCLUSIONS: RESEARCH PRIORITIES

From the foregoing, it is clear that much is known about the nutritional requirements of ELBW infants. However, it also is clear that many, perhaps all, of these infants experience poor growth, or no growth, for the first several days to weeks of life. Thus, by the time they begin growing they have incurred deficits of sufficient magnitude to make catch-up growth virtually impossible, particularly with currently available formulas. Further, there is considerable ev-idence that these early growth deficits have long lasting effects including short stature and poor neu-rodevelopmental outcomes. Why, then, if so much is known about the probable nutritional requirements of these infants, does growth continue to be inade-quate? The problem seems to be that the data estab-lishing probable requirements have come from short-term studies in selected groups of infants. Few studies have evaluated these probable requirements and strategies for delivering them to large groups of infants who are characteristic of the total population of ELBW infants. Further, until data from such stud-ies are available, nutritional management and, hence, growth of these vulnerable infants are not likely to improve appreciably.

Considering this, the Workshop participants unan-imously agreed that the most urgent research need was large scale, relatively long-term studies evaluat-ing the short- and long-term metabolic, growth, and neurodevelopmental responses of ELBW infants to earlier and more aggressive nutritional management. The long-term aim of such studies should be to de-fine strategies that support the desired rates of growth. Specific studies should test specific nutri-tional interventions in ELBW infants (eg, high pro-tein intake; quality of propro-tein intake). These studies also should determine if it matters whether ELBW infants receive improved nutrition. Major outcomes should include short- and long-term mortality as well as the type, rate, and severity of specific mor-bidities, length of hospital stay, and long-term growth and development. The Workshop partici-pants strongly recommended that investigators be primarily concerned with endpoints that have obvi-ous clinical meaning.

The Workshop participants also stressed the need for additional research to further refine the effects of specific nutritional interventions and to ascertain the metabolic mechanisms that determine how nutrients are used to support normal growth and develop-ment. Examples of questions that should be an-swered include, but are not limited to, the following:

1. What is the optimal mixture, rate of delivery, and route of administration of specific macronutrients (amino acids, glucose, and lipids)?

2. What are the systemic metabolic and growth re-sponses and the rere-sponses of selected organs (eg, the GI tract and the lung) to anabolic hormones such as insulin, IGF-I, growth hormone, and EGF? 3. Can nutrients and/or anabolic hormones limit the adverse effects on metabolism and growth sec-ondary to specific diseases (eg, sepsis), stress (eg, surgery), and treatments (eg, dexamethasone for BPD) associated with increased protein break-down, hyperglycemia, and growth failure? 4. What are the requirements for essential and

con-ditionally essential amino acids, EFAs, LC-PUFAs, trace elements, and conditionally essen-tial nutrient co-factors (eg, inositol, choline, nucleotides)?

APPENDIX

Participants of the National Institute of Child Health and Human Development (NICHD) Workshop: Nutrition of the Extremely Low Birth Weight Infant

Co-Chairs:William W. Hay, Jr, University of Colorado Health Sciences Center, Denver, CO; Alan Lucas, Institute of Child Health, London, UK

Organizing Committee:William W. Hay, Jr, University of Col-orado Health Sciences Center, Denver, CO; Alan Lucas, Institute of Child Health, London, UK; William C. Heird, Baylor College of Medicine, Houston, TX; Ekhard Ziegler, University of Iowa, Iowa City, IA; Sumner Yaffe, Charlotte Catz, Gilman Grave, and Ephraim Levin, NICHD.

Other Workshop Participants:Scott Denne, University of In-diana, Indianapolis, IN; Patti Thureen, University of Colorado Health Sciences Center, Denver, CO; Sheila Innis, University of British Columbia, Vancouver, BC, Canada; Ruth Morley, Univer-sity of Melbourne, Melbourne, Australia; Maureen Hack, Case Western Reserve University, Cleveland, OH; Richard Ehrenkranz, Yale University, New Haven, CT; Albert Aynsley-Green, Univer-sity College Hospital, London, UK; Satish Kalhan, Cleveland Met-ropolitan Medical Center, Cleveland, OH; David Rassin, Univer-sity of Texas Medical Branch, Galveston, TX; John Benson, Ross Products Division, Abbott Laboratories, Columbus, OH; Michael Hambidge, University of Colorado Health Sciences Center, Den-ver, CO; Jane CarDen-ver, University of South Florida College of Medicine, Tampa, FL; Louis Underwood, University of North Carolina, Chapel Hill, NC; Pietr Sauer, Groningen University, Groningen, The Netherlands; Josef Neu, University of Florida, Gainesville, FL; Richard Schanler, Baylor College of Medicine, Houston, TX.

ACKNOWLEDGMENTS

This Workshop was supported in part by an educational grant from Ross Products Division, Abbott Laboratories, Columbus, Ohio.

This work was sponsored by the Center for Research for Moth-ers and Children, National Institute of Child Health and Human Development, NIH, Bethesda, Maryland.

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1999;104;1360

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Levin, Gilman D. Grave, Charlotte S. Catz and Sumner J. Yaffe

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