Acta PEdiatr Scand Suppl374: 58-66, 1991
Malnutrition in the Premature Infant EKHARD E. ZIEGLER From Department oj‘Pediatrics, Coilege af’Medicine, University of lowa, Iowa City, Iowa
ABSTRACT. Ziegler, E. E. (Department of Pediatrics, College of Medicine, University of Iowa, Iowa City, Iowa). Malnutrition in the premature infant. Acta Paediatr Scand Suppl374: 58,1991. During the first few days of life, the ill premature infant is usually subjected to acute semistarvation because the provision of nutritional support is considered cumbersome and unnecessary. However, the absence of readily recognizable adverse effects of semistarvation does not rule out the existence of significant short-term adverse effects, nor does it rule out possible adverse sequelae in the long run. Similar concerns pertain to the later neonatal period, during which nutritional deprivation is less severe but of longer duration. Evidence is presented that qualitative malnutrition, characterized by inadequate intake of protein and relatively excessive intake of energy, is common with current feeding regimens and is responsible for increased body fat deposition in growing small premature infants. Key words: premature infant, acute semistawation, prolonged undernutrition, qualitative malnutrition, late sequefae.
The nutritional problems of the preterm infant are not commonly considered under the rubric of childhood malnutrition. Survival or preterm infants depends on the availability of relatively sophisticated and costly medical care. Such care is more readily available in industrialized than in developing countries. Nutritional deprivation of the preterm infant is therefore largely a problem of industrialized countries. Childhood malnutrition, on the other hand, occurs most commonly in developing countries. Yet, there are strong commonalities. Both conditions share as their immediate cause insufficient intakes of protein and energy, although the reasons for insufficient intakes are completely different. Both affect growth. And most importantly, both conditions share the potential for lifelong adverse consequences. The long-term consequences of nutritional deprivation of the premature infant are essentially unknown. Because of the complexity of the premature infant’s medical problems, which have their own potential for adverse outcomes, it may be inherently impossible to separate the long-term effects of nutritional deprivation from the sequelae of illnesses. Some of the short-term effects of nutritional deprivation are readily recognized (i.e., effects on growth), while others are not. It can be argued that whenever there are short-term consequences, there is a risk of long-term consequences. It follows logically that amelioration of short-term consequences, for example through improved nutritional management, will reduce the risk of longterm consequences. Thus, the following discussion is based on the premise that improving short-time nutrition-related outcomes through improved nutritional support will have the effect of reducing the risk of long-term adverse consequences. Preterm infants are often critically ill and confront the neonatologist with complex problems requiring intensive medical management. Under these circumstances the provision of nutritional support is perceived to be non-essential and unduly cumbersome. Consequently, current medical practice dispenses with nutritional support during the first few days of life, and in doing so routinely subjects the preterm infant to semistarvation. This is done in the presumptio? that short-term nutritional deprivation is inconsequential, if not beneficial. The purpose of this
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Malnutrition in the premature infant
discussion is to point out that the presumption of inconsequentiality is based mainly on clinical impressions and that data supporting the safety of the practice are virtually nonexistent. Following the acute semistarvation during the early days of life, ill preterm infants commonly go through a prolonged period during which nutrient intakes are adequate to cover ongoing losses, but are not adequate to support growth. Although information on the longer-term consequences of this milder but protracted undernutrition is beginning to emerge, current knowledge remains fragmentary. Again, the safety, or lack thereof, of current practices remains to be established. Increased awareness of the plight of the preterm infant is a prerequisite for an intensified search for solutions to the many unsolved nutritional problems. While it is not inconceivable that current practices are indeed safe with regard to long-term sequelae, proving such safety would require large efforts. Efforts could be spent far more productively on the development of improved nutritional management modalities that aim at minimizing nutritional deprivation during the immediate neonatal period.
Acute semistarvation: The immediate neonatal period During the first few days of life, many preterm infants require intense medical management. Life-threatening disorders of the respiratory, cardiovascular, central nervous, renal and hemostatic systems are common and are frequently complicated by infections and by fluid-electrolyte instability. These medical problems command the neonatologist’s full attention. As mentioned earlier, during the first 2 to 4 days of life, nutritional support other than glucose and electrolytes is considered dispensible. Thus, in addition to the stress of acute life-threatening illness, the infant must also cope with the metabolic stress imposed by abrupt cessation of the influx of nutrients which it enjoyed as a fetus until the time of birth. The sudden transition from an anabolic situation to semistarvation requires major metabolic and endocrine adjustments, whose main features have been characterized (1) but whose exact regulatory mechanisms are but incompletely understood. Most of the available information has been obtained with the use of animal models (2,3,4) or from study of term infants ( 5 , 6, 7) and very few data have been obtained directly in preterm infants (8, 9). Because of their limited metabolic reserves, preterm infants are less able than term infants to endure semistarvation, and extrapolation from findings in term infants to the preterm infant is therefore of limited validity. Metabolic stress is clinically “silent”, i.e., it produces no clinical signs and does not affect the course of illnesses in a clinically recognizable manner. The neonatologist therefore regards the provision of nutritional support as non-urgent and defers attention to nutritional support until the more pressing medical problems are brought under control. The absence of clinically apparent adverse consequences may, however, be deceptive. Illnesses are often serious and the general course is usually so stormy that signs of metabolic stress may easily go unrecognized. Moreover, possible effects of semistarvation on the course of illnesses, etc. are not likely to be recognized by simple observation. Therefore, the more subtle early effects and any later effects can be identified only by controlled trials that are specifically designed to look for such effects. In 1963, Usher (10) presented the results of a landmark study that revolutionized the management of preterm infants. Before Usher’s study, administration of intravenous fluids to preterm infants was not routinely practiced. Usher showed that the administration of a glucose-bicarbonate solution beginning within three hours of birth reduced the mortality among premature infants with respiratory distress to less
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than half the mortality of control infants who received no intravenous fluids. The profound beneficial effects of a relatively simple (by today’s standards) regimen would not have been appreciated, had it not been for Usher’s controlled study. More importantly, the poor outcome associated with the old regimen would have escaped recognition. Today, it is unlikely that such dramatic improvements in mortality could be achieved by upgrading existing nutritional regimens. But important effects are nevertheless conceivable. It must be emphasized that the absence of readily apparant adverse effects of current practices does not justify the presumption of adequacy and compiacency is not in order as long as appropriately designed controlled trials have not been performed. Complacency regarding the provision of nutritional support is unfortunately fostered by the formidable technical obstacles that must be overcome in providing nutritional support. For a variety of reasons, the gastrointestinal tract is initially not available for nutrient administration. Therefore, the parenteral route must be relied upon exclusively. Numerous obstacles are encountered in the parenteral administration of nutrients, including technical difficulties in securing adequate vascular access, metabolic derangements such as abnormal glucose metabolism, unstable fluid and electrolyte homeostasis, and impaired renal function. It is understandable that under these circumstances the provision of nutritional support is considered unduly cumbersome. For reasons that are not well understood (see later), during the first few days the amount of energy that can be administered in the form of glucose without causing hyperglycemia is often less than the energy the infant is expending. Thus, the infant may be in negative energy balance for several days, in addition to being in negative balance for all other nutrients with the exception of electrolytes. By the time more complete nutritional support is instituted, a substantial negative balance of energy and of most nutrients has been incurred.
Subacute undernutrition: The later neonatal period Some form of parenteral nutrition is usually initiated by 2 to 4 days of age. Initially at least, the objective is to provide maintenance nutrition, i.e., to replace ongoing losses of nitrogen, minerals and vitamins. Although regimens are far from uniform, there seems to be agreement that provision of complete nutritional support (i.e., support that meets maintenance and growth requirements) need not, or should not, be attempted at this early stage. But as the days pass, such complete support becomes increasingly the goal. Because it is impossible to provide complete intravenous support through peripheral veins, percutaneously inserted small-bore central venous catheters are increasingly used (1 1, 12). This method of securing vascular access makes it technically more feasible to provide complete parenteral nutrition. But even with satisfactory vascular access, complete nutrient intakes and satisfactory growth are for a variety of reasons not readily achieved. The more common reasons include restriction of fluid intake, use of diuretics and intervening complications such as infections. Another reason is failure to provide adequate intakes of amino acids and of other nutrients mostly for fear of metabolic complications, but perhaps at times also out of ignorance concerning nutrient requirements. Fig. 1 illustrates the disappointing results obtained in spite of aggressive provision of nutritional support. The figure depicts daily body weights during the first 70 days of life of a preterm infant born at 27 weeks gestational age weighing 920 g, who was cared for at the author’s institution. Included as reference is the weight curve the infant would probably have followed in utero according to the standards of
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Acta Paediatr Scand Suvvl 374
2600
-
6I
/
2400 2200 2Ooo-
6 1800Y
2
.P 1600-
5 1400: lo00 1200
ooo€00
Fig. I . Body weight of female infant born at 27 weeks gestation. Solid squares indicate expected intrauterine weight based on the data of Usher & McLean (1 3). Glucose = intravenous glucose; NVN = neonatal venous nutrition solution; Lipids = intravenous lipid immulsion; HM = human milk.
1 0 5 1 0 1 5 2 0 2 5 3 0 3 5 4 0 4 5 5 0 5 5 6 0 6 5 7 0 Age (days)
Glucose NVN Lipids HM 0
I
0
r
I
Usher & McLean (1 3). The infant’s diagnoses included hyaline membrane disease, patent ductus arteriosus, septicemia, and necrotizing enterocolitis. It is evident that weight gain did not occur until after 32 days of age, despite intensive efforts to provide parenteral nutrition. These efforts were hampered by the necessity to restrict fluid intake and by severe fluid and electrolyte instability. Even after full feedings of fortified human milk were established, weight gain remained slow, so that by 70 days of age a weight deficit of about 1 kg had accrued. The course of this infant is representative of many infants of similar size and maturity. Growth arrest of several weeks duration, which is not at all uncommon, provides compelling proof of undernutrition, but does, of course, not provide clues as to the cause(s) of undernutrition. Some short-term consequences of growth arrest and slow growth rate, such as prolongation of hospitalization, are readily apparent. Other effects, such as impaired humoral and cellular immunity, must be surmised to occur based on evidence from animal experiments (14) and from observations in malnourished human subjects (1 5). Preterm infants are known to be highly susceptible to infections, but whether poor nutrition plays a causal role in this regard remains unknown, although such a role seems very probable. Of great concern is the possibility that undernutrition may have long-lasting untoward effects, especially on cognitive development. In a well-designed prospective study involving over 500 preterm infants, Lucas and associates have determined the effect of two enteral feeding regimens on later developmental achievement. During the neonatal period, the two regimens led to substantially different rates of growth (1 6). Upon follow-up at 9 months of age (1 7) as well as 18 months of age ( I 8), the feeding regimen that produced the lesser rate of neonatal growth was associated with significantly lower developmental scores. Although it remains to be seen whether these effects persist at older ages, it is also important to note that the degree of undernutrition associated with the inferior feeding regimen was mild
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compared to the degree of undernutrition exemplified by the case presented in Fig. 1.
Parenteral nutrition: Limitations and challenges As the case in Fig. 1 illustrates, nutritional support must initially rely exclusively or predominantly on the parenteral route. In current clinical practice, administration of amino acids, minerals and vitamins is initiated at 2 to 4 days of age, and administration of fat emulsions is begun several days later. This pattern is dictated by practical and technical considerations rather than a rational approach to the infant’s nutritional needs. Consequently, there is considerable room for improvement, practical or technical obstacles notwithstanding. In particular, there seems to be precious little justification for the semistarvation (glucose and electrolytes only) imposed during the first few days of life. Immediate provision of nutrients at a level comparable to the in-utero level is clearly a utopian goal at the present time. Unachievable as it may be, as a long-term goal it may serve as a useful point of reference. Steps in the direction of this goal have been taken. Rivera et al. (I 9) and Saini et al. (20) have shown that the administration of amino acids can safely be initiated within the first 24 hours of life. Saini et al. (20) also demonstrated improved nitrogen balance. But much further study is required to delineate the metabolic consequences of early aggressive nutritional support and to establish its practical feasibility. While it is entirely possible that the benefits of early nutritional intervention will turn out to be marginal, it is also conceivable that such intervention may produce large and/or unexpected benefits. Glucose intolerance is typically present from the outset and often persists for some time (8). It has the effect of limiting energy intakes, often to levels below maintenance needs (i.e., less than energy expenditures). Glucose intolerance results from persistence of glucose production and decreased peripheral insulin sensitivity (9). The cause of this derangement of glucose homeostasis is unknown, but there is reason to believe that it is caused by the metabolic/endocrine response to starvation. Preliminary observations suggest that the early administration of amino acids ameliorates glucose intolerance (1 9). A better understanding of the mechanism(s) leading to glucose intolerance will be a prerequisite for designing strategies to overcome the problem of negative energy balance. Since the infant possesses little body fat, the energy deficit must be made up primarily from catabolism of body protein. Early administration of amino acids may conserve body protein, not only by providing substrate for increased protein synthesis, but also by enabling higher intakes of glucose, which, in turn, may minimize protein catabolism. Delivery of adequate amounts of calcium and phosphorus by the parenteral route is practically impossible because of solubility limitations. The problem is compounded by the calciuretic effect of the diuretics that are commonly employed. Thus, demineralization of the skeleton, which probably begins immediately after birth, all too often reaches severe degrees and may progress to the stage of frank rickets especially in those infants who achieve rapid growth rates. Although healing of rickets usually occurs without complications, data presented by Lucas et al. (21) suggest that rickets may be associated with shorter stature later in life. Enteral nutrition: The threat of necrotizing enterocolitis The time of introduction of enteral feedings is determined by a multitude of factors and considerations, most of which have one common denominator: the risk of necrotizing enterocolitis (NEC). Because of the risk of NEC, enteral feedings are
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Acta Paediatr Scand Suppl 374
0
._
-;
--
(3 l o t
1
2 3 4 Protein/energy (g/lOO kcal)
5
Fig. 2. Gain in fat-free weight of preterm infants in relation to protein concentration of feedings. All infants received 120 kcal/kg.day. Value at lowest proteinlenergy ratio pertains to human milk, all other values pertain to formulas. Drawn from data of Kagan et al. (29). X o n ordinate indicates estimated value for fetus (30).
often withheld for prolonged periods of time (22), a practice that also dictates the use of parenteral nutrition support for extended periods. Thus, the threat of necrotizing enterocolitis has a profound influence on the nutritional management of preterm infants. Necrotizing enterocolitis is the pathological response of the immature intestine to a wide range of injurious stimuli (23). Since it is a potentially devastating disease with high mortality, prevention has become the major focus of attention. Although controlled trials have shown that early enteral feeding does not increase (24) and may actually decrease the risk of necrotizing enterocolitis ( 2 5 ) , delayed introduction of enteral feedings remains the principal preventive strategy employed by neonatalogists. Because of the many limitations of parenteral nutrition in the preterm infant, any delay in the introduction of enteral feedings causes a prolongation of the period of suboptimal nutrition.
Enteral nutrition: Protein inadequacy and energy excess The infant whose weight curve is presented in Fig. 1 was fed her own mother’s milk fortified with a commercially available fortifier (Enfamil Human Milk Fortifier, Bristol-Meyers Co., Evansville, IN) and received a generous intake of energy. Yet, this infant’s weight gain was less than expected on the basis of her presumed growth potential. The requirement for protein of the small preterm infant has been estimated to be 3.6 g/kg-day or 4.0 g/100 kcal (26). Data from a number of trials with formulas providing different levels of protein (for example, 27, 28) are in substantial agreement with this estimate. The protein concentration of human milk is such that the protein requirement is met only by milk produced during the first one or two weeks of lactation. Milk produced subsequently provides protein intakes that are substantially below the requirement, even with appropriate fortification. Thus, the preponderance of the available evidence leads to the conclusion that fortified human milk as well as formulas, including those specifically designed for preterm infants, provide intakes of protein that are limiting for growth of the small preterm infant. In the presence of an adequate intake of energy, protein intake determines the rate of gain in fat-free body mass. A feeding with a protein content that is suboptimal relative to its energy content thus causes reduced gain in fat-free mass, even when fed to provide an adequate energy intake. When fed at a level that provides an adequate protein intake, such a feeding leads to adequate gain in fat-free mass, but excessive energy intake leads to increased gain in fat mass. This scenario is compati-
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L
.-u)
al 3
Fig. 3. Gain in fat as percentage 20-
*
g .c
0
:[
g) 10m
c
LL
1
1
I
of total weight gain of preterm infants in relation to protein concentration of feedings. All infants received 120 kcal/kg-day. Value at lowest proteidenergy ratio pertains to human milk, all other values pertain to formulas. Drawn from data of Kagan et al.
ble with data from several recent studies (27,28). However, only the data of Kagan et al. (29) provide direct evidence. These investigators fed groups of preterm infants banked human milk or one of four formulas varying in protein concentration. Energy intake was uniformly 120 kcal/kg-day. Total body water was determined in each infant at 6 days of age and again at 28 days of age. Although Kagan et al. (29) did not calculate gain in fat-free body mass, the investigators provided detailed data for each infant so that calculation of fat-free mass is possible. Fig. 2 presents the mean gain in fat-free mass for each feeding group in relation to the proteidenergy ratio of the feedings. It is evident that gain in fat-free mass increased with increasing proteidenergy ratio of the feedings up to a value of 2.9 g/100 kcal, at which point fat-free gain reached a value slightly exceeding that of the fetus of similar size (30). The feeding that produced the lowest gain in fat-free mass was human milk. Fortification of human milk had not been introduced at the time this study was performed. Corresponding data for fat mass gain, expressed as percent of total weight gain, are presented in Fig. 3. It is evident that the feedings that produced the lowest gains in fat-free mass produced the highest relative gains in fat mass. It may be concluded that even at modest energy intakes, when protein intake limits gain in fat-free mass, a relative excess of energy intake may lead to increased fat deposition. As pointed out earlier, with current feeding regimens protein intakes are usually inadequate for small preterm infants (i.e., limiting for gain in fat-free mass) while energy intakes are relatively excessive. As a consequence of this qualitative malnutrition, most small preterm infants accumulate more fat than they would have accumulated in utero. Increased fat deposition may offer some advantages in the short term, e.g., increased thermal insulation. Its long-term consequences are unknown.
Conclusion In 1974, Shaw, an early proponent of aggressive parenteral nutritional support for preterm infants, concluded that the “low-birth-weight infant .. . appears to be suffering from malnutrition” (3 1). Since then, substantial progress has been made in the provision of nutritional support, primarily through expanded utilization of parenteral administration modalities. ’41~0,the nutritional needs of the preterm infant are perhaps better understood today than in 1974. But today also more and smaller infants are surviving and the challenge to provide nutritional support has increased in complexity and certainly in quantity. In 1990, the preterm infant is still
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Malnutrition in the premature infant
suffering from malnutrition, although perhaps in different ways than in 1974. Much has yet to be accomplished before victory over malnutrition in the premature infant may be proclaimed.
REFERENCES 1. Bassett JM. Hormones and metabolic adaptation in the new born. Proc Nutr SOC1989; 48: 263-269. 2. Ogata ES, Holliday MA. The effects of starvation, glucose infusion, and normal feeding, on muscle protein synthesis and catabolism in the newborn guinea pig. Biol Neonate 1976; 29: 247-256. 3. Cowett RM, Czech MP, Susa JB, Schwartz R, Oh W. Blunted muscle responsiveness to insulin in the neonatal rat. Metabolism 1980; 29: 563-567. 4. Kliegman RM, Morton S. The metabolic response of the canine neonate to twenty-four hours of fasting. Metabolism 1987; 36: 52 1-526. 5. Frazer TE, Karl IE, Hillman LS, Bier DM. Direct measurement of gluconeogenesis from [2,3-'3C,]alanine in the human neonate. Am J Physiol 1981; 240: E615-E621. 6. Denne SC, Kalhan SC. Glucose carbon recycling and oxidation in human newborns. Am J Physiol 1986; 25 1 : E71-E77. 7. Denne SC, Kalhan SC. Leucine metabolism in human newborns. Am J Physiol 1987; 253: E608-E615. 8. Cowett RM, Oh W, Pollak A, Schwartz R, Stonestreet BS. Glucose disposal of low birth weight infants: Steady state hyperglycemia produced by constant intravenous glucose infusion. Pediatrics 1979; 63: 389-396. 9. Cowett RM, Oh W, Schwartz R. Persistent glucose production during glucose infusion in the neonate. J Clin Invest 1983; 71: 467-475. 10. Usher R. Reduction of mortality from respiratory distress syndrome of prematurity with early administration of intravenous glucose and sodium bicarbonate. Pediatrics 1963; 32: 966-975. 1 1. Shaw JCL. Technical problems in parenteral nutrition of the premature infant. Acta Chir Scand 1981; Suppl 507: 258-268. 12. Durand M, Ramanathan R, Martinelli B, Tolentino M. Prospective evaluation of percutaneous central venous silastic catheters in newborn idants with birth weights of 510 to 3 920 grams. Pediatrics 1986; 78: 245-250. 13. Usher R, McLean F. Intrauterine growth of live-born Caucasian infants at sea level: Standards obtained from measurements in 7 dimensions of infants born between 25 and 44 weeks of gestation. J Pediatr 1969; 74: 901-910. 14. Harris MC, Douglas SD, Lee JC, Ziegler MM, Gerdes JS, Polin RA. Diminished polymorphonuclear leukocyte adherence and chemotaxis following protein-calorie malnutrition in newborn rats. Pediatr Res 1987; 21: 542-546. 15. Chandra RK, Newberne PM. Nutrition, immunity and infection mechanisms of interactions. New York and London: Plenum Press, 1977. 16. Lucas A, Gore SM, Cole TJ et al. Multicentre trial on feeding low birthweight infants: effects of diet on early growth. Arch Dis Child 1984; 59: 722-730. 17. Lucas A, Morley R, Cole TJ et al. Early diet in preterm babies and developmental status in infancy. Arch Dis Child 1989; 64: 1570-1578. 18. Lucas A, Morley R, Cole TJ et al. Early diet in preterm babies and developmental status at 18 months. Lancet 1990; 335: 1477-1481. 19. Rivera Jr A, Bell EF, Stegink LD, Ziegler EE. Plasma amino acid profiles during the first three days of life in infants with respiratory distress syndrome: Effect of parenteral amino acid supplementation. J Pediatr 1989; 115: 465-468. 20. Saini J, Macmahon P, Morgan JB, Kovar IZ. Early parenteral feeding of amino acids. Arch Dis Child 1989; 64: 1362-1 366. 21. Lucas A, Brooke OG, Baker BA, Bishop N, Morley R. High alkaline phosphatase activity and growth in preterm neonates. Arch Dis Child 1989; 64: 902-909. 22. Brown EG, Sweet AY. Preventing necrotizing enterocolitis in neonates. JAMA 1978; 240: 2452-2454. 23. Kliegman RM, Fanaroff A. Necrotizing enterocolitis. N Engl J Med 1984; 310: 10931103. 5-918329
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24. Ostertag SG, LaGamma EF, Reisen CE, Ferrentino FL. Early enteral feeding does not affect the incidence of necrotizing enterocolitis. Pediatrics 1986; 77: 275-280. 25. LaGamma EF, Ostertag SG, Birenbaum H. Failure of delayed oral feedings to prevent necrotizing enterocolitis. Am J Dis Child 1985; 139: 385-389. 26. Ziegler EE. Protein requirements of preterm infants. In: Fomon SJ, Heird WC, eds. Energy and protein needs during infancy. New York: Academic Press, 1986: 69-85. 27. Kashyap S, Forsyth M, Zucker C, Ramakrishnan R, Dell RB, Heird WC. Effects of varying protein and energy intakes on growth and metabolic response in low birth weight infants. J Pediatr 1986; 108: 955-963. 28. Kashyap S, Schulze KF, Forsyth M et al. Growth, nutrient retention, and metabolic response in low birth weight infants fed varying intakes of protein and energy. J Pediatr 1988; 113: 713-721. 29. Kagan BM, Stanincova V, Felix NS, Hodgman J, Kalman D. Body composition of premature infants: relation to nutrition. Am J Clin Nutr 1972; 25: 1153-1 164. 30. Ziegler EE, O’Donnell AM, Nelson SE, Fomon SJ. Body composition of the reference fetus. Growth 1976; 40: 329-341. 31. Shaw JCL. Malnutrition in very low birth-weight, pre-term infants. Proc Nutr SOC1974; 33: 103-1 1 1 .
(E. E. Z.) Department of Pediatrics University of Iowa Hospital Iowa City, Iowa 52242, USA
Malnutrition in the Premature Infant EKHARD E. ZIEGLER From Department oj‘Pediatrics, Coilege af’Medicine, University of lowa, Iowa City, Iowa
ABSTRACT. Ziegler, E. E. (Department of Pediatrics, College of Medicine, University of Iowa, Iowa City, Iowa). Malnutrition in the premature infant. Acta Paediatr Scand Suppl374: 58,1991. During the first few days of life, the ill premature infant is usually subjected to acute semistarvation because the provision of nutritional support is considered cumbersome and unnecessary. However, the absence of readily recognizable adverse effects of semistarvation does not rule out the existence of significant short-term adverse effects, nor does it rule out possible adverse sequelae in the long run. Similar concerns pertain to the later neonatal period, during which nutritional deprivation is less severe but of longer duration. Evidence is presented that qualitative malnutrition, characterized by inadequate intake of protein and relatively excessive intake of energy, is common with current feeding regimens and is responsible for increased body fat deposition in growing small premature infants. Key words: premature infant, acute semistawation, prolonged undernutrition, qualitative malnutrition, late sequefae.
The nutritional problems of the preterm infant are not commonly considered under the rubric of childhood malnutrition. Survival or preterm infants depends on the availability of relatively sophisticated and costly medical care. Such care is more readily available in industrialized than in developing countries. Nutritional deprivation of the preterm infant is therefore largely a problem of industrialized countries. Childhood malnutrition, on the other hand, occurs most commonly in developing countries. Yet, there are strong commonalities. Both conditions share as their immediate cause insufficient intakes of protein and energy, although the reasons for insufficient intakes are completely different. Both affect growth. And most importantly, both conditions share the potential for lifelong adverse consequences. The long-term consequences of nutritional deprivation of the premature infant are essentially unknown. Because of the complexity of the premature infant’s medical problems, which have their own potential for adverse outcomes, it may be inherently impossible to separate the long-term effects of nutritional deprivation from the sequelae of illnesses. Some of the short-term effects of nutritional deprivation are readily recognized (i.e., effects on growth), while others are not. It can be argued that whenever there are short-term consequences, there is a risk of long-term consequences. It follows logically that amelioration of short-term consequences, for example through improved nutritional management, will reduce the risk of longterm consequences. Thus, the following discussion is based on the premise that improving short-time nutrition-related outcomes through improved nutritional support will have the effect of reducing the risk of long-term adverse consequences. Preterm infants are often critically ill and confront the neonatologist with complex problems requiring intensive medical management. Under these circumstances the provision of nutritional support is perceived to be non-essential and unduly cumbersome. Consequently, current medical practice dispenses with nutritional support during the first few days of life, and in doing so routinely subjects the preterm infant to semistarvation. This is done in the presumptio? that short-term nutritional deprivation is inconsequential, if not beneficial. The purpose of this
Acta Paediatr Scand Suppl 374
Malnutrition in the premature infant
discussion is to point out that the presumption of inconsequentiality is based mainly on clinical impressions and that data supporting the safety of the practice are virtually nonexistent. Following the acute semistarvation during the early days of life, ill preterm infants commonly go through a prolonged period during which nutrient intakes are adequate to cover ongoing losses, but are not adequate to support growth. Although information on the longer-term consequences of this milder but protracted undernutrition is beginning to emerge, current knowledge remains fragmentary. Again, the safety, or lack thereof, of current practices remains to be established. Increased awareness of the plight of the preterm infant is a prerequisite for an intensified search for solutions to the many unsolved nutritional problems. While it is not inconceivable that current practices are indeed safe with regard to long-term sequelae, proving such safety would require large efforts. Efforts could be spent far more productively on the development of improved nutritional management modalities that aim at minimizing nutritional deprivation during the immediate neonatal period.
Acute semistarvation: The immediate neonatal period During the first few days of life, many preterm infants require intense medical management. Life-threatening disorders of the respiratory, cardiovascular, central nervous, renal and hemostatic systems are common and are frequently complicated by infections and by fluid-electrolyte instability. These medical problems command the neonatologist’s full attention. As mentioned earlier, during the first 2 to 4 days of life, nutritional support other than glucose and electrolytes is considered dispensible. Thus, in addition to the stress of acute life-threatening illness, the infant must also cope with the metabolic stress imposed by abrupt cessation of the influx of nutrients which it enjoyed as a fetus until the time of birth. The sudden transition from an anabolic situation to semistarvation requires major metabolic and endocrine adjustments, whose main features have been characterized (1) but whose exact regulatory mechanisms are but incompletely understood. Most of the available information has been obtained with the use of animal models (2,3,4) or from study of term infants ( 5 , 6, 7) and very few data have been obtained directly in preterm infants (8, 9). Because of their limited metabolic reserves, preterm infants are less able than term infants to endure semistarvation, and extrapolation from findings in term infants to the preterm infant is therefore of limited validity. Metabolic stress is clinically “silent”, i.e., it produces no clinical signs and does not affect the course of illnesses in a clinically recognizable manner. The neonatologist therefore regards the provision of nutritional support as non-urgent and defers attention to nutritional support until the more pressing medical problems are brought under control. The absence of clinically apparent adverse consequences may, however, be deceptive. Illnesses are often serious and the general course is usually so stormy that signs of metabolic stress may easily go unrecognized. Moreover, possible effects of semistarvation on the course of illnesses, etc. are not likely to be recognized by simple observation. Therefore, the more subtle early effects and any later effects can be identified only by controlled trials that are specifically designed to look for such effects. In 1963, Usher (10) presented the results of a landmark study that revolutionized the management of preterm infants. Before Usher’s study, administration of intravenous fluids to preterm infants was not routinely practiced. Usher showed that the administration of a glucose-bicarbonate solution beginning within three hours of birth reduced the mortality among premature infants with respiratory distress to less
59
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than half the mortality of control infants who received no intravenous fluids. The profound beneficial effects of a relatively simple (by today’s standards) regimen would not have been appreciated, had it not been for Usher’s controlled study. More importantly, the poor outcome associated with the old regimen would have escaped recognition. Today, it is unlikely that such dramatic improvements in mortality could be achieved by upgrading existing nutritional regimens. But important effects are nevertheless conceivable. It must be emphasized that the absence of readily apparant adverse effects of current practices does not justify the presumption of adequacy and compiacency is not in order as long as appropriately designed controlled trials have not been performed. Complacency regarding the provision of nutritional support is unfortunately fostered by the formidable technical obstacles that must be overcome in providing nutritional support. For a variety of reasons, the gastrointestinal tract is initially not available for nutrient administration. Therefore, the parenteral route must be relied upon exclusively. Numerous obstacles are encountered in the parenteral administration of nutrients, including technical difficulties in securing adequate vascular access, metabolic derangements such as abnormal glucose metabolism, unstable fluid and electrolyte homeostasis, and impaired renal function. It is understandable that under these circumstances the provision of nutritional support is considered unduly cumbersome. For reasons that are not well understood (see later), during the first few days the amount of energy that can be administered in the form of glucose without causing hyperglycemia is often less than the energy the infant is expending. Thus, the infant may be in negative energy balance for several days, in addition to being in negative balance for all other nutrients with the exception of electrolytes. By the time more complete nutritional support is instituted, a substantial negative balance of energy and of most nutrients has been incurred.
Subacute undernutrition: The later neonatal period Some form of parenteral nutrition is usually initiated by 2 to 4 days of age. Initially at least, the objective is to provide maintenance nutrition, i.e., to replace ongoing losses of nitrogen, minerals and vitamins. Although regimens are far from uniform, there seems to be agreement that provision of complete nutritional support (i.e., support that meets maintenance and growth requirements) need not, or should not, be attempted at this early stage. But as the days pass, such complete support becomes increasingly the goal. Because it is impossible to provide complete intravenous support through peripheral veins, percutaneously inserted small-bore central venous catheters are increasingly used (1 1, 12). This method of securing vascular access makes it technically more feasible to provide complete parenteral nutrition. But even with satisfactory vascular access, complete nutrient intakes and satisfactory growth are for a variety of reasons not readily achieved. The more common reasons include restriction of fluid intake, use of diuretics and intervening complications such as infections. Another reason is failure to provide adequate intakes of amino acids and of other nutrients mostly for fear of metabolic complications, but perhaps at times also out of ignorance concerning nutrient requirements. Fig. 1 illustrates the disappointing results obtained in spite of aggressive provision of nutritional support. The figure depicts daily body weights during the first 70 days of life of a preterm infant born at 27 weeks gestational age weighing 920 g, who was cared for at the author’s institution. Included as reference is the weight curve the infant would probably have followed in utero according to the standards of
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2600
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6I
/
2400 2200 2Ooo-
6 1800Y
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.P 1600-
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Fig. I . Body weight of female infant born at 27 weeks gestation. Solid squares indicate expected intrauterine weight based on the data of Usher & McLean (1 3). Glucose = intravenous glucose; NVN = neonatal venous nutrition solution; Lipids = intravenous lipid immulsion; HM = human milk.
1 0 5 1 0 1 5 2 0 2 5 3 0 3 5 4 0 4 5 5 0 5 5 6 0 6 5 7 0 Age (days)
Glucose NVN Lipids HM 0
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Usher & McLean (1 3). The infant’s diagnoses included hyaline membrane disease, patent ductus arteriosus, septicemia, and necrotizing enterocolitis. It is evident that weight gain did not occur until after 32 days of age, despite intensive efforts to provide parenteral nutrition. These efforts were hampered by the necessity to restrict fluid intake and by severe fluid and electrolyte instability. Even after full feedings of fortified human milk were established, weight gain remained slow, so that by 70 days of age a weight deficit of about 1 kg had accrued. The course of this infant is representative of many infants of similar size and maturity. Growth arrest of several weeks duration, which is not at all uncommon, provides compelling proof of undernutrition, but does, of course, not provide clues as to the cause(s) of undernutrition. Some short-term consequences of growth arrest and slow growth rate, such as prolongation of hospitalization, are readily apparent. Other effects, such as impaired humoral and cellular immunity, must be surmised to occur based on evidence from animal experiments (14) and from observations in malnourished human subjects (1 5). Preterm infants are known to be highly susceptible to infections, but whether poor nutrition plays a causal role in this regard remains unknown, although such a role seems very probable. Of great concern is the possibility that undernutrition may have long-lasting untoward effects, especially on cognitive development. In a well-designed prospective study involving over 500 preterm infants, Lucas and associates have determined the effect of two enteral feeding regimens on later developmental achievement. During the neonatal period, the two regimens led to substantially different rates of growth (1 6). Upon follow-up at 9 months of age (1 7) as well as 18 months of age ( I 8), the feeding regimen that produced the lesser rate of neonatal growth was associated with significantly lower developmental scores. Although it remains to be seen whether these effects persist at older ages, it is also important to note that the degree of undernutrition associated with the inferior feeding regimen was mild
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compared to the degree of undernutrition exemplified by the case presented in Fig. 1.
Parenteral nutrition: Limitations and challenges As the case in Fig. 1 illustrates, nutritional support must initially rely exclusively or predominantly on the parenteral route. In current clinical practice, administration of amino acids, minerals and vitamins is initiated at 2 to 4 days of age, and administration of fat emulsions is begun several days later. This pattern is dictated by practical and technical considerations rather than a rational approach to the infant’s nutritional needs. Consequently, there is considerable room for improvement, practical or technical obstacles notwithstanding. In particular, there seems to be precious little justification for the semistarvation (glucose and electrolytes only) imposed during the first few days of life. Immediate provision of nutrients at a level comparable to the in-utero level is clearly a utopian goal at the present time. Unachievable as it may be, as a long-term goal it may serve as a useful point of reference. Steps in the direction of this goal have been taken. Rivera et al. (I 9) and Saini et al. (20) have shown that the administration of amino acids can safely be initiated within the first 24 hours of life. Saini et al. (20) also demonstrated improved nitrogen balance. But much further study is required to delineate the metabolic consequences of early aggressive nutritional support and to establish its practical feasibility. While it is entirely possible that the benefits of early nutritional intervention will turn out to be marginal, it is also conceivable that such intervention may produce large and/or unexpected benefits. Glucose intolerance is typically present from the outset and often persists for some time (8). It has the effect of limiting energy intakes, often to levels below maintenance needs (i.e., less than energy expenditures). Glucose intolerance results from persistence of glucose production and decreased peripheral insulin sensitivity (9). The cause of this derangement of glucose homeostasis is unknown, but there is reason to believe that it is caused by the metabolic/endocrine response to starvation. Preliminary observations suggest that the early administration of amino acids ameliorates glucose intolerance (1 9). A better understanding of the mechanism(s) leading to glucose intolerance will be a prerequisite for designing strategies to overcome the problem of negative energy balance. Since the infant possesses little body fat, the energy deficit must be made up primarily from catabolism of body protein. Early administration of amino acids may conserve body protein, not only by providing substrate for increased protein synthesis, but also by enabling higher intakes of glucose, which, in turn, may minimize protein catabolism. Delivery of adequate amounts of calcium and phosphorus by the parenteral route is practically impossible because of solubility limitations. The problem is compounded by the calciuretic effect of the diuretics that are commonly employed. Thus, demineralization of the skeleton, which probably begins immediately after birth, all too often reaches severe degrees and may progress to the stage of frank rickets especially in those infants who achieve rapid growth rates. Although healing of rickets usually occurs without complications, data presented by Lucas et al. (21) suggest that rickets may be associated with shorter stature later in life. Enteral nutrition: The threat of necrotizing enterocolitis The time of introduction of enteral feedings is determined by a multitude of factors and considerations, most of which have one common denominator: the risk of necrotizing enterocolitis (NEC). Because of the risk of NEC, enteral feedings are
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0
._
-;
--
(3 l o t
1
2 3 4 Protein/energy (g/lOO kcal)
5
Fig. 2. Gain in fat-free weight of preterm infants in relation to protein concentration of feedings. All infants received 120 kcal/kg.day. Value at lowest proteinlenergy ratio pertains to human milk, all other values pertain to formulas. Drawn from data of Kagan et al. (29). X o n ordinate indicates estimated value for fetus (30).
often withheld for prolonged periods of time (22), a practice that also dictates the use of parenteral nutrition support for extended periods. Thus, the threat of necrotizing enterocolitis has a profound influence on the nutritional management of preterm infants. Necrotizing enterocolitis is the pathological response of the immature intestine to a wide range of injurious stimuli (23). Since it is a potentially devastating disease with high mortality, prevention has become the major focus of attention. Although controlled trials have shown that early enteral feeding does not increase (24) and may actually decrease the risk of necrotizing enterocolitis ( 2 5 ) , delayed introduction of enteral feedings remains the principal preventive strategy employed by neonatalogists. Because of the many limitations of parenteral nutrition in the preterm infant, any delay in the introduction of enteral feedings causes a prolongation of the period of suboptimal nutrition.
Enteral nutrition: Protein inadequacy and energy excess The infant whose weight curve is presented in Fig. 1 was fed her own mother’s milk fortified with a commercially available fortifier (Enfamil Human Milk Fortifier, Bristol-Meyers Co., Evansville, IN) and received a generous intake of energy. Yet, this infant’s weight gain was less than expected on the basis of her presumed growth potential. The requirement for protein of the small preterm infant has been estimated to be 3.6 g/kg-day or 4.0 g/100 kcal (26). Data from a number of trials with formulas providing different levels of protein (for example, 27, 28) are in substantial agreement with this estimate. The protein concentration of human milk is such that the protein requirement is met only by milk produced during the first one or two weeks of lactation. Milk produced subsequently provides protein intakes that are substantially below the requirement, even with appropriate fortification. Thus, the preponderance of the available evidence leads to the conclusion that fortified human milk as well as formulas, including those specifically designed for preterm infants, provide intakes of protein that are limiting for growth of the small preterm infant. In the presence of an adequate intake of energy, protein intake determines the rate of gain in fat-free body mass. A feeding with a protein content that is suboptimal relative to its energy content thus causes reduced gain in fat-free mass, even when fed to provide an adequate energy intake. When fed at a level that provides an adequate protein intake, such a feeding leads to adequate gain in fat-free mass, but excessive energy intake leads to increased gain in fat mass. This scenario is compati-
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L
.-u)
al 3
Fig. 3. Gain in fat as percentage 20-
*
g .c
0
:[
g) 10m
c
LL
1
1
I
of total weight gain of preterm infants in relation to protein concentration of feedings. All infants received 120 kcal/kg-day. Value at lowest proteidenergy ratio pertains to human milk, all other values pertain to formulas. Drawn from data of Kagan et al.
ble with data from several recent studies (27,28). However, only the data of Kagan et al. (29) provide direct evidence. These investigators fed groups of preterm infants banked human milk or one of four formulas varying in protein concentration. Energy intake was uniformly 120 kcal/kg-day. Total body water was determined in each infant at 6 days of age and again at 28 days of age. Although Kagan et al. (29) did not calculate gain in fat-free body mass, the investigators provided detailed data for each infant so that calculation of fat-free mass is possible. Fig. 2 presents the mean gain in fat-free mass for each feeding group in relation to the proteidenergy ratio of the feedings. It is evident that gain in fat-free mass increased with increasing proteidenergy ratio of the feedings up to a value of 2.9 g/100 kcal, at which point fat-free gain reached a value slightly exceeding that of the fetus of similar size (30). The feeding that produced the lowest gain in fat-free mass was human milk. Fortification of human milk had not been introduced at the time this study was performed. Corresponding data for fat mass gain, expressed as percent of total weight gain, are presented in Fig. 3. It is evident that the feedings that produced the lowest gains in fat-free mass produced the highest relative gains in fat mass. It may be concluded that even at modest energy intakes, when protein intake limits gain in fat-free mass, a relative excess of energy intake may lead to increased fat deposition. As pointed out earlier, with current feeding regimens protein intakes are usually inadequate for small preterm infants (i.e., limiting for gain in fat-free mass) while energy intakes are relatively excessive. As a consequence of this qualitative malnutrition, most small preterm infants accumulate more fat than they would have accumulated in utero. Increased fat deposition may offer some advantages in the short term, e.g., increased thermal insulation. Its long-term consequences are unknown.
Conclusion In 1974, Shaw, an early proponent of aggressive parenteral nutritional support for preterm infants, concluded that the “low-birth-weight infant .. . appears to be suffering from malnutrition” (3 1). Since then, substantial progress has been made in the provision of nutritional support, primarily through expanded utilization of parenteral administration modalities. ’41~0,the nutritional needs of the preterm infant are perhaps better understood today than in 1974. But today also more and smaller infants are surviving and the challenge to provide nutritional support has increased in complexity and certainly in quantity. In 1990, the preterm infant is still
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suffering from malnutrition, although perhaps in different ways than in 1974. Much has yet to be accomplished before victory over malnutrition in the premature infant may be proclaimed.
REFERENCES 1. Bassett JM. Hormones and metabolic adaptation in the new born. Proc Nutr SOC1989; 48: 263-269. 2. Ogata ES, Holliday MA. The effects of starvation, glucose infusion, and normal feeding, on muscle protein synthesis and catabolism in the newborn guinea pig. Biol Neonate 1976; 29: 247-256. 3. Cowett RM, Czech MP, Susa JB, Schwartz R, Oh W. Blunted muscle responsiveness to insulin in the neonatal rat. Metabolism 1980; 29: 563-567. 4. Kliegman RM, Morton S. The metabolic response of the canine neonate to twenty-four hours of fasting. Metabolism 1987; 36: 52 1-526. 5. Frazer TE, Karl IE, Hillman LS, Bier DM. Direct measurement of gluconeogenesis from [2,3-'3C,]alanine in the human neonate. Am J Physiol 1981; 240: E615-E621. 6. Denne SC, Kalhan SC. Glucose carbon recycling and oxidation in human newborns. Am J Physiol 1986; 25 1 : E71-E77. 7. Denne SC, Kalhan SC. Leucine metabolism in human newborns. Am J Physiol 1987; 253: E608-E615. 8. Cowett RM, Oh W, Pollak A, Schwartz R, Stonestreet BS. Glucose disposal of low birth weight infants: Steady state hyperglycemia produced by constant intravenous glucose infusion. Pediatrics 1979; 63: 389-396. 9. Cowett RM, Oh W, Schwartz R. Persistent glucose production during glucose infusion in the neonate. J Clin Invest 1983; 71: 467-475. 10. Usher R. Reduction of mortality from respiratory distress syndrome of prematurity with early administration of intravenous glucose and sodium bicarbonate. Pediatrics 1963; 32: 966-975. 1 1. Shaw JCL. Technical problems in parenteral nutrition of the premature infant. Acta Chir Scand 1981; Suppl 507: 258-268. 12. Durand M, Ramanathan R, Martinelli B, Tolentino M. Prospective evaluation of percutaneous central venous silastic catheters in newborn idants with birth weights of 510 to 3 920 grams. Pediatrics 1986; 78: 245-250. 13. Usher R, McLean F. Intrauterine growth of live-born Caucasian infants at sea level: Standards obtained from measurements in 7 dimensions of infants born between 25 and 44 weeks of gestation. J Pediatr 1969; 74: 901-910. 14. Harris MC, Douglas SD, Lee JC, Ziegler MM, Gerdes JS, Polin RA. Diminished polymorphonuclear leukocyte adherence and chemotaxis following protein-calorie malnutrition in newborn rats. Pediatr Res 1987; 21: 542-546. 15. Chandra RK, Newberne PM. Nutrition, immunity and infection mechanisms of interactions. New York and London: Plenum Press, 1977. 16. Lucas A, Gore SM, Cole TJ et al. Multicentre trial on feeding low birthweight infants: effects of diet on early growth. Arch Dis Child 1984; 59: 722-730. 17. Lucas A, Morley R, Cole TJ et al. Early diet in preterm babies and developmental status in infancy. Arch Dis Child 1989; 64: 1570-1578. 18. Lucas A, Morley R, Cole TJ et al. Early diet in preterm babies and developmental status at 18 months. Lancet 1990; 335: 1477-1481. 19. Rivera Jr A, Bell EF, Stegink LD, Ziegler EE. Plasma amino acid profiles during the first three days of life in infants with respiratory distress syndrome: Effect of parenteral amino acid supplementation. J Pediatr 1989; 115: 465-468. 20. Saini J, Macmahon P, Morgan JB, Kovar IZ. Early parenteral feeding of amino acids. Arch Dis Child 1989; 64: 1362-1 366. 21. Lucas A, Brooke OG, Baker BA, Bishop N, Morley R. High alkaline phosphatase activity and growth in preterm neonates. Arch Dis Child 1989; 64: 902-909. 22. Brown EG, Sweet AY. Preventing necrotizing enterocolitis in neonates. JAMA 1978; 240: 2452-2454. 23. Kliegman RM, Fanaroff A. Necrotizing enterocolitis. N Engl J Med 1984; 310: 10931103. 5-918329
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24. Ostertag SG, LaGamma EF, Reisen CE, Ferrentino FL. Early enteral feeding does not affect the incidence of necrotizing enterocolitis. Pediatrics 1986; 77: 275-280. 25. LaGamma EF, Ostertag SG, Birenbaum H. Failure of delayed oral feedings to prevent necrotizing enterocolitis. Am J Dis Child 1985; 139: 385-389. 26. Ziegler EE. Protein requirements of preterm infants. In: Fomon SJ, Heird WC, eds. Energy and protein needs during infancy. New York: Academic Press, 1986: 69-85. 27. Kashyap S, Forsyth M, Zucker C, Ramakrishnan R, Dell RB, Heird WC. Effects of varying protein and energy intakes on growth and metabolic response in low birth weight infants. J Pediatr 1986; 108: 955-963. 28. Kashyap S, Schulze KF, Forsyth M et al. Growth, nutrient retention, and metabolic response in low birth weight infants fed varying intakes of protein and energy. J Pediatr 1988; 113: 713-721. 29. Kagan BM, Stanincova V, Felix NS, Hodgman J, Kalman D. Body composition of premature infants: relation to nutrition. Am J Clin Nutr 1972; 25: 1153-1 164. 30. Ziegler EE, O’Donnell AM, Nelson SE, Fomon SJ. Body composition of the reference fetus. Growth 1976; 40: 329-341. 31. Shaw JCL. Malnutrition in very low birth-weight, pre-term infants. Proc Nutr SOC1974; 33: 103-1 1 1 .
(E. E. Z.) Department of Pediatrics University of Iowa Hospital Iowa City, Iowa 52242, USA
