Nutritional requirements and methods of feeding low birth weight infants

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Louis Gluck, M.D,, Editor-in-Chief Editorial Board: Thomas E. Cone, Jr., M.D. / Philip R. [ ~ d g ~ t ~ . Frank Falkner, M.D. / Morris Green, M.D,

Volume VII Number 8

June 1977

is Assistant Professor of Pediatrics, Columbia University College of Physicians & Surgeons and Assistant Attending Pediatrician, Babies' Hospital and Vanderbilt Clinic, Columbia-Presbyterian Medical Center. Doctor Hei,'d received the M.D. degree as well as an M.S. in pharmacology from Vanderbilt University, and took much of' his postgraduate training at Columbia-Presbyterian Medical Center. He belongs to several professional societies, among them the Society for Pediatric Research, the American Federation for Clinical Research and the International Society of Parenteral Nutrition.

is Assistant Professor of Pediatrics at the College of Physicians & Surgeons at Columbia University. After graduation from the Medical College of Georgia, he took an internship and residency in pediatrics as well as a fellowship in neonatology at Babies' Hospital, New York. Doctor Anderson's primary clinical intcrcst is in the nutritional management of premature infants.

THE IMPORTANCE of early adequate nutritional management of the low birth weight (LBW) infant is best illustrated by consideration of the metabolic state of the fasted infant. During fasting, energy for continued functioning is derived from endogenous stores of various nutrients. The first such energy source to be utilized is liver glycogen, which is limited in amount and is depleted rapidly. Thereafter, fat stores assume the major burden for providing energy. However, because some tissues have absolute requirements for glucose, protein stores are also called upon. These provide amino acids from which glucose can be synthesized (gluconeogenesis). Thus, the available endogenous stores of fat and protein are the ultimate determinants of the length of time a fasting infant can survive. The body composition of a 1000-gm infant, a 2000-gm infant and a 3500-gm infant are shown in Figure 1. ~ It is obvious that the percentage of body composition comprising both protein and fat, particularly fat, increases with increasing weight. Thus, the 2000-gm infant has more extensive endogenous energy reserves than the 1000-gm infant, and the 3500-gm infant has more exten3

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sive reserves than the 2000-gm infant. This fact applies to the absolute amount of endogenous energy substrate as well as to the amount of substrate per unit of body weight. Thus, the smaller the infant, the more marked is his inability to withstand starvation. The extent of this inability is illustrated in Figure 2, 2 which depicts the maximum estimates of the time each infant might be expected to survive under conditions of both starvation and semiFig 2.-Estimated survival of starved (solid line) and semistarved (broken line) infants weighing 1000, 2000 or 3500 grams at birth. A V A I L A B L E CALORIC RESERVE (Cal/kg)

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starvation. These estimates are based on the assumption that all of the nonprotein (all liver glycogen and all fat) and one-third the protein caloric reserves will be made available at a rate of 50 Cal/kg daily. Thus, under conditions of total starvation, the 1000gm infant has sufficient energy reserves to survive for approximately 4.5 days, the 2000-gin infant has sufficient reserves to survive for approximately 12 days and the term infant has sufficient reserves to survive for approximately a month. Daily provision of glucose intravenously (semistarvation) will prolong surviral. Assuming t h a t exogenous glucose (e.g., 7.5 gm/kg daily, the amount provided by 150 ml/kg daily of a 5% glucose solution or 75 ml/kg daily of a 10% glucose solution) can be added to the endogenous substrates to increase total caloric reserves, survival would be increased by 7, 18 and 50 days, respectively, for the 1000-gm, 2000-gin and 3500-gin infant. These calculations and the assumptions on which they are based obviously lack a high degree of precision. Nonetheless, they serve to depict in a semiquantitative manner the general clinical observations concerning the LBW infant's marked susceptibility to starvation and hence the necessity of careful attention to provision of adequate nutrients. In addition to the practical role of early adequate nutrition for the LBW infant, there is a growing concern t h a t inadequate nutrition at any time during the period of cellular proliferation of the central nervous system may result in a nonrecoupable deficit of central nervous system cells. This concern is based on an accumulating body of evidence obtained primarily in animals ~, 4 but seemingly applicable to the h u m a n as well. 5, ~ Although the total period of cellular proliferation of the human brain covers approximately the first 18 months of life7 and transient deficits apparently can bc reversed if adequate nutrition is provided before the end of this period, 8 little is known concerning the duration of cellular proliferation within specific regions of the central nervous system. This concern is particularly applicable to the premature infant whose brain would have undergone considerable growth during the last part of intrauterine life. In contrast to the situation as late as a decade ago, the factors discussed above are now recognized by neonatologists and the importance of early adequate nutritional management of the LBW infant has become generally accepted. As a result, the general subject of both nutritional requirements of LBW infants and methods for meeting these requirements are areas of active investigation. Nonetheless, such investigation is just beginning and much remains to be learned in both areas. This monograph will focus on the present state of knowledge concerning these areas, and attempts will be made to highlight the important knowledge gaps within each area. 5

NUTRITIONAL REQUIREMENTS Until recently, dictums concerning many of the nutritional requirements of LBW infants were based on the assumption that the requirements were the same as those of the term infant. However, as will become clear, the LBW infant in many instances has different, sometimes special, requirements. Thus, just as the term infant is not a ~'small adult" with respect to nutritional requirements, the LBW infant is not simply a "small infant." Today, there are two major schools of thought concerning the nutritional requirements of the LBW infant. One school sets the requirements of various nutrients at the amounts present in sufficient amounts of human milk, and the other sets requirements of various nutrients at the amounts necessary to allow their accumulation at the intrauterine rate2 -u Although studies show that infants who receive human milk grow as well as those who receive isocaloric amounts of various formulas, TM h u m a n milk contains insufficient amounts of protein, calcium and sodium to allow accumulation of these nutrients at the rate which occurs during the last trimester of gestationl~; thus the two bases for determining nutritional requirements are incompatible. The information that might permit compatibility of the two schools is lacking, i.e., the optimal rate at which the LBW infant should grow. As the reader will undoubtedly detect, lack of this information also hinders the discussions which follow. Although attempts to maintain the intrauterine growth rate are warranted, this goal is rarely achieved; moreover, data to suggest that maintenance of the intrauterine growth rate is either necessary or efficacious are lacking. At least for the short term, a nutritional regimen that prevents catabolism and allows some increment in I ~ ~ d ~ m a s s appears, a priori, to be satisfactoryi ~ers it ~epresents a more realistic goal than maintaining the intrauterine growth rate.

CALORIC REQUIREMENTS Most texts state that LBW infants require at least 120 Cal/kg daily, ~4partitioned into approximately 75 Cal/kg daily for resting expenditure and the remainder for specific dynamic action (10 Cal/kg daily), replacement of inevitable stool losses (10 Cal/kg daily) and growth (25 Cal/kg daily). The 75 Cal/kg daily usually allotted for resting expenditure includes the requirements for maintenance of the basal metabolic rate (approximately 50 Cal/kg daily) as well as additional requirements imposed by activity and response to cold stress. Modern nursery management has probably decreased resting caloric expenditure. With careful control of the environmental temperature, energy expenditure in response to cold stress can be reduced 6

considerably. In fact, oxygen consumption studies of relatively inactive infants maintained in a strictly thermoneutral environment suggest that daily resting caloric expenditure is closer to 50 Cal/kg than 75 Cal/kg. '5 The energy expenditure for specific dynamic action (the difference between resting expenditure of the fed infant and that of the fasted infant) is a function of the composition of the diet. In general, the higher the protein content of the diet the higher the energy required for specific dynamic action. '~, '~ Thus lower protein intakes (see below) would be expected to result in improved efficiency of weight gain (weight gain/caloric intake), provided minimal protein requirements are met. Fecal losses of nutrients, especially fat, appear to be inevitable in the fed infant. The extent of these losses is dependent to some extent on the nature of the fat intake (see Fat Requirements) but approximately 20% of the lipid intake, on average, is not absorbed (approximately 10% of the total caloric intake is lost). The precise caloric requirements for growth are unknown. It has been estimated that approximately 2.5 calories are required for deposition of i gm of tissue. '8 This number is obviously contrived as the caloric requirement for weight gain depends on the composition of the newly synthesized tissue (e.g., deposition of calorically dense fat tissue requires more calories than deposition of lean body mass). With respect to intrauterine weight gain, this figure is reasonable. Thus the caloric cost for the growth that occurs between the 31st and 35th weeks of gestation (1000 gin)' approaches 45 Cal/kg daily. Any such estimate, obviously, is entirely arbitrary and is based on the assumption that adequate amounts of all other nutrients required tbr growth are provided. In this regard it is interesting that clinical studies of caloric intake and weight gain, although showing a correlation up to a toTABLE 1.- CALORIC REQUIREMENTS OF LOW BIRTH WEIGHT INFANTS (IN CAL/KGDAILY) Resting* SDA Stool losses Growth TOTAL~

50- 75 5- 8% of total intake 10% of total intake 25- 45 8 5 - 142

*Estimate includes caloric expenditure for maintenance of basal metabolism plus activity and response to cold stress. %Includessum of restingand growth requirements increased by 15-18% (expenditure for specific dynamic action [SDA] and replacement of stool losses).

tal caloric intake of approximately 150 Cal/kg daily, have not demonstrated an advantage of daily caloric intakes above 150 Cal/kg.,~, o_0 The range of caloric expenditures for each category is summarized in Table 1. Thus, depending on the conditions, the caloric requirement may range from 8 5 - 1 4 2 Cal/kg daily. Obviously, the infant who receives all nutrients parenterally requires fewer calories. Of even greater quantitative importance are the extent of the infant's activity and the environmental conditions under which it is nursed. PROTEIN REQUIREMENTS

Forty years ago most LBW infants, if fed, were fed h u m a n milk. This practice was largely abandoned approximately 30 years ago following the demonstration that protein intakes higher than provided by human milk (that of cow milk or higher) resulted in better weight gains, v Nonetheless, proponents of the adequacy of human milk for LBW infants persisted. The fbrmulas used in the study documenting improved weight gains with higher protein intakes also had greater electrolyte and mineral (ash) contents; thus, it was suggested that the increased weight gain was due to increased water retention secondary to the increased ash intake."" The limited renal function of premature infants, 2'~ plus the high blood urea (or nonprotein nitrogen) concentrations observed in infants receiving higher protein intakes, 24 increased the plausibility of such a relationship. Nonetheless, several years passed before adequate studies to settle this controversy appeared. Kagan et al? '~ showed that both total body water and extracellular fluid of infants receiving high protein, high solute intakes were greater than those observed in patients receiving low solute formulas. In fact, the increase in dry weight (i.e., total weight gain minus increase in total body water) was similar with protein intakes ranging from 2 to 6 gm/kg daily. A few years earlier, Babson et al. 2" had demonstrated that higher protein intakes did not result in greater weight gain unless accompanied by higher solute intakes, but that higher protein intakes were associated with a greater increase in both crown-rump and femur length. Two clinical studies of this era should be mentioned. Davidson et al. 2~ observed better weight gain in infants receiving protein intakes of 4 gm/kg daily than in those receiving 2 gm/kg daily b u t did not demonstrate a superiority of 6 gm/kg daily over 4 gm/kg daily. Snyderman et al. 2s observed similar weight gains with protein intakes ranging from 2 to 9 gm/kg daily. However, infants receiving the higher protein intakes appeared to retain 2 - 3 times more nitrogen than those receiving the lower intakes. Since only 3 - 8% of the observed differences in nitrogen retention 8

could be accounted for by "unmeasured losses" (vomiting, skin losses, small amounts of lost stool, etc.), the authors suggested that the infants receiving the higher protein intakes might have a more "mature" body composition, a questionable asset. On the basis of plasma aminograms and net protein utilization, 2 - 3 gm/kg daily was suggested as an adequate protein intake for premature infants. 29 In the studies mentioned thus far, only the quantity of protein intake was evaluated. Moreover, with the exception of the studies of Snyderman et al., 2s, 2.9 the metabolic consequences of the protein intake were ignored. Recently, R~iihii et al. 12, 30 compared the effects of both quantity and quality of protein intake on growth as well as several metabolic variables in infants weighing under 2100 gin. Subjects were randomly assigned to one of five feeding regimens: (1) pooled human milk; (2)"humanized" cow milk protein (40% casein and 60% whey), 1.5 gm/100 ml; (3) "humanized" cow milk protein, 3 gm/100 ml; (4) cow milk protein (82% casein and 18% whey), 1.5 gin/100 ml; (5) cow milk protein, 3 gin/100 ml. All infants received 117 Cal/kg daily, providing protein intakes of 2.25 and 4.5 gm/kg daily, respectively, from the low and high protein artificial formulas and approximately 2.0 gm/kg daily from human milk. Ash content of the artificial formulas was identical and similar to that of human milk; the artificial formulas were kept isocaloric by varying only carbohydrate concentration in relation to protein concentration. Weight gain from birth to discharge (2400 gm) was somewhat less than the average intrauterine weight gain, but was similar in all groups. The rate of growth from the time birth weight was regained until discharge followed the lower limits of the normal intrauterine growth rate. Although serum albumin concentrations were lower in the group receiving human milk, this group appeared to be as "well hourished" as any of the other groups. Moreover, metabolic imbalances such as hyperaminoacidemia, hyperammonemla, azotemia and acidosis were absent in the infants who received human milk, whereas some or all were common in those who received artificial formulas. From a metabolic standpoint, the group re~ ceiving the lower concentration of "humanized" cow milk protein differed the least from those receiving human milk, whereas the group receiving the higher concentration of cow milk protein differed the most. This study 12, .~0 strongly supports the nutritional adequacy of h u m a n milk for the LBW infant. In addition, it suggests that a daily protein intake of 4.5 gm/kg may be hazardous. Other studies have also conveyed this suggestion. Goldman et al. 3~ followed the neurologic development of LBW infants who received various protein intakes during infancy. A~ 4 - 6 years of age the incidence of strabismus and low IQ scores was considerably greater in those who received daily protein intakes of 6 gm/kg and 9

above t h a n in those who received lower protein intakes. Other studies suggest t h a t the effects of high protein diets in infancy on later neurologic development, if any, are related to excessive intakes of specific amino a c i d s - e . g . , phenylalanine, tyrosine or both.32, 33 The study by R~ih~i et al.'", ~0 is one of the first to explore both q u a n t i t y and quality of protein intakes. The results tend to confirm the historical observation that cow milk, while adequate for h e a l t h y vigorous infants, is inferior to ass milk for the "delicate" or '~sickly" infant2 ~ Ass milk, incidentally, is the only animal milk known to have protein of the same casein-whey ratio as h u m a n milk protein. This century-old observation must have been based purely on clinical grounds. However, in the light of our present knowledge concerning the premature infant's requirements for amino acids, this observation seems particularly astute. For instance, premature infants lack sufficient activity of the enzymes t h a t convert phenylalanine to tyrosine "~'~and methionine to cystine, .~" making these amino acids essential for the premature infant. Calculation of the amounts of various qualities of protein required to provide adequate amounts of cystine illustrates t h a t failure to consider the quality of protein may explain some of the discrepancies of the various studies reviewed earlier. Infants receiving enough h u m a n milk to provide 2 - 3 gm/kg of protein daily would receive 5 1 - 7 6 mg of cystine/kg daily, whereas infants receiving 4 - 6 gm/kg of cow milk protein daily would receive only 4 8 - 72 mg/kg daily. If the a m o u n t of cystine delivered is assumed to be the limiting factor, growth of infants receiving the smaller amount of h u m a n milk would be expected to be similar to those receiving the larger intakes of cow milk protein. It is interesting t h a t Powers 37 speculated in 1935 t h a t the reason infants on cow milk formulas required 20% of their calories as protein, whereas those on h u m a n milk required only 8% of their calories as protein, was that " h u m a n milk protein is largely the complete protein lactoalbumin, while cow's milk protein contains a large amount of casein, which is relatively low in the essential amino acid cystine." In general, daily protein intakes ranging between 2.25 and 2.75 gm/kg appear to be adequate, perhaps even slightly excessive, for most premature infants. The protein, of course, m u s t be of such quality as to provide sufficient amounts of all essential amino acids, including those t h a t are essential only for the prem a t u r e infant. H u m a n milk or humanized cow milk protein appears to meet such requirements to a greater extent t h a n does cow milk protein. Daily protein intakes of up to 4 gm/kg appear to be well tolerated and generally safe for the older, rapidly growing infant. However, in the absence of a demonstrated advantage/'or such a higher protein intake, few reasons for such intakes can be 10

offered. In part, provision of protein in excess of a c t u a l requirements merely taxes the infant's metabolic machinery for disposing of the excess; if this machinery is incapable of responding adequately, azotemia, metabolic acidosis and hyperaminoacidemia can be expected to occur. FAT REQUIREMENTS The only known requirement for fat in human nutrition is to provide essential fatty acids. As initially described, t h e s e included linoleic, linolenic and arachidonic acids; ~s subsequently, it was shown that linolenic and arachidonic acids could be synthesized from linoleic acid. a9 In general, the essential fatty acid requirement can be met by provision of 2 - 4 % of the total calories as linoleic acid. 4~ Since linoleic acid constitutes in excess of 25% of the total fatty acids of most dietary fats, this r e q u i r e m e n t can be met with a diet containing as little as 16% of the total calories of fat. Nonetheless, 4 0 - 5 0 % of the total calories of b o t h natural milks and currently available formulas consists of fat. This fact is necessitated for reasons of p r a c t i c a l i t y - s u b s t i t u t i o n of this fat with sugar would result in a hyperosmolar formula, whereas substitution with protein would result in a protein content far in excess of that tolerated by LBW infants. The role of fat in dietary regimens for LBW infants has received considerable attention for two reasons. First, t h e newborn infant does not absorb fat well and this malabsorption is greater in premature infants. 41 The second reason for the attention paid to the role of fat in infant feeding concerns the effect of fat intake on serum lipid concentrations, particularly serum cholesterol concentration, and the possible effect on the adult development of atherosclerosis.42 In general, the intestinal assimilation of fat consists of three phases43: (1) intraluminal, (2) uptake by the mucosal cell and (3) secretion by the m u c o s a l cell. The intraluminal phase requires both bile acids and pancreatic lipase. The bile acids emulsify the dietary fat, primarily triglyceride, and the pancreatic lipase hydrolyzes triglyceride into free fatty acids, monoglycerides and, to a lesser extent, diglycerides. These products of hydrolysis are then incorporated into the mucosal cell, where triglycerides are reassembled and secreted into the intestinal lymphatics as chylomicrons, which are carried by the thoracic duct to t h e systemic circulation. Compared to term infants, the total bile acid pool of the LBW infant is small. 44 Pancreatic lipase secretion m a y also be somewhat limited in LBW infants, but lipase levels appear to be adequate for hydrolysis. 4~ Mucosal uptake of t;~e products of hydrolysis seems to proceed normally in suckling animals 4c;b u t has not been studied in infants. The status of the process of chylomicron 11

formation and secretion in the premature infant is not known, but there is no suggestion t h a t it is inadequate. Fat absorption by the LBW infant is also affected by the chemical nature of the fat. Fats containing more p o l y u n s a t u r a t e d fatty acids (PUFA), e.g., h u m a n milk fat, are better absorbed t h a n fats containing more saturated fatty acids. 47 The position of t h e fatty acid in the triglyceride molecule also seems to play a role in fat absorption. Palmitic acid, for example, is not well absorbed from the gastrointestinal tract. Thus, since lipase preferentially cleaves fatty acids from the 1 and 3 positions of triglycerides, fats containing palmitic acid in these positions, after hydrolysis, are more likely to be associated with poor overall fat absorption. 4s The 2-monoglyceride of palmitic acid, however, is well absorbed; thus fats containing palmitic acid in the 2 position are b e t t e r absorbed. Triglycerides of short and medium chain fatty acids can be absorbed directly into the portal circulation, regardless of the intralumina] bile salt and lipase activities.49 Thus substitution of a major portion of the fat content of infant formulas with m e d i u m chain triglycerides should result in enhanced absorption. Studies have shown, in fact, that such substitution results in absorption of over 95% of the total fat.5~ ~i This increased absorption, however, has not been demonstrated conclusively to result in improved weight gain# 2 Thus the role of medium-chain triglyceride in routine feeding regimens for L B W infants remains uncertain. The practical importance of the so-called "physiological steatorrhea" of premature infants can be illustrated by an example. Approximately 180 ml/kg of standard infant formula containing 20 Cal/oz is required to provide 120 Cal/kg daily. Delivery of this volume of formula to most L B W infants is extremely difficult. Assuming that fat constitutes 45% of the total calories and the efficiency of fat absorption is only 75%, 13.5 calories would be lost in the stool. Or, a total of only 106.5 calories would be absorbed from the gastrointestinal tract, assuming no malabsorption of other nutrients. O n the other hand, ifthe fat were 9 5 % absorbed, fewer calories would be lost. Or, the same n u m b e r of calories could be absorbed from a smaller volume of formula. Thus, changes in the fat content of infant formulas to increase the efficiency of fat absorption can aid considerably in reducing the total volume of formula required and, in turn, facilitateprovision of adequate calories. Because of the possible relationship of diet in infancy and later development of atherosclerosis,4~ the cholesterol content of infant diets has received considerable attention. Cholesterol is not thought to be an essential nutrient for either the premature or term infant (i.e.,it can be completely synthesized in the body). Thus, L B W infants have no absolute requirement for cholesterol and very little, if any, is present in currently available infant formulas. Natural milks, however, contain abundant amounts of 12

cholesterol; '~3moreover, infants receiving these milks have slightly higher serum cholesterol concentrations than those receiving artificial milks24 This observation has given rise to two arguments. The first concerns the possible deleterious effects of high serum cholesterol concentrations. The other, equally as unproved as the first, suggests that the higher cholesterol intakes of natu, ral milks are desirable. The rationale of this argument is that infants fed low cholesterol diets must depend almost entirely on endogenous synthesis of cholesterol; thus, induction of enzymes necessary for the normal controls of serum cholesterol levels may be limited and serum cholesterol levels in later life might be higher2 ~ Studies in swine show that animals receiving lower cholesterol intake in early life indeed have higher serum cholesterol concentrations when fully grown? ~' However, such studies in humans have failed to demonstrate a conclusive effect of cholesterol content of early feedings on serum cholesterol values at either 1 8 - 24 months or 1 5 - 19 years of age27 Thus, there is no conclusive evidence, at present, that either a high or a low cholesterol content is either beneficial or harmful.

CARBOHYDRATEREQUIREMENTS Metabolism of the central nervous system and the hematopoietic tissue are dependent to a large extent on glucose, b u t glucose can be produced from either exogenously administered protein or endogenous protein stores (gluconeogenesis). Thus, in contrast to the situation with respect to amino acids and essential fatty acids, no absolute requirement for carbohydrate has b e e n demonstrated. However, the status of the various gluconeogenic mechanisms in LBW infants is not completely understood. In fact, the high incidence of hypoglycemia in these infants has been attributed to immaturity of these mechanisms? s Moreover, low carbohydrate diets tend to produce ketosis, especially if protein content is also low; whether this phenomenon occurs in the LBW infant, however, has not been established (it is commonly stated that LBW infants, indeed newbord infants in general, do not develop ketosis). For all of these reasons, approximately 4 0 - 45% of the total caloric content of most dietary regimens, including those designed for LBW infants, is provided as carbohydrate. The type of carbohydrate to be given depends on the digestive capabilities of the gastrointestinal tract of the LBW infant. Most natural milks as well as most commercially available formulas contain lactose as the predominant carbohydrate. Although adult levels of intestinal lactase activity may not be present at birth, activities of this enzyme develop early in fetal life, 5~, 60 and most viable infants tolerate this sugar quite well. Similarly, most viable infants also have sufficient activity of the other disaccharidases to enable them to tolerate these disaccharides as well. In fact, 13

satisfactory clinical progress has been obscrved with formulas which contain only lactose, only sucrose, or mixtures of these sugars. Although data concerning the extent of the LBW infant's ability to transport monosaccharides across the intestinal mucosa are not available, clinical experience suggests that these transport processes are sufficiently active to permit satisfactory clinical progress with formulas which contain only glucose. However, substitution of disaccharides with monosaccharides doubles the osmotic contribution of the carbohydrate content of the formula. W h e t h e r the osmolality, per se, or the demands for transporting only monosaccharides is involved, the incidence of necrotizing enterocolitis is increased in infants who receive formulas containing protein hydrolysate and glucoseY 1 The inclusion of more complicated carbohydrates in the diet of the LBW infant raises further questions. Utilization of these more complicated carbohydrates depend on adequate pancreatic amylase activity, which appears to be limited in the premature infant. 6~ Lactose is probably the preferred sugar for infant formulas. This sugar, reportedly, supports the proliferation of lactobacilli in the intestinal tract2 2 Growth of these organisms, in turn, suppresses growth of certain pathogenic gram-negative organisms, possibly providing some protection against systemic infection with these organisms. 63 The development of a fermentative bacterial flora (predominance of lactobacillus over gram-negative organisms) has been suggested as a responsible factor for the decreased incidence of gram-negative sepsis observed in breast-fed infants2 4 However, most artificial formulas also contain lactose; moreover, h u m a n milk contains a number of other factors (e.g., macrophages, immunoglobulins and specific bacterial growth inhibitors) which, theoretically, are of equal or greater importance in such protection, ~. ~ if indeed such protection is conferred.

FLUID REQUIR]~MENTS Estimates of fluid requirements for LBW infants must include estimates for maintenance requirements plus requirements for synthesis of new tissue incidental to weight gain. Several bases of reference have been suggested for estimating maintenance fluid r e q u i r e m e n t s - e . g . , body weight, body surface area, caloric expenditure. Of these, ca]oric expenditure seems the most relevant in that it focuses attention on the physiologic and nonphysiologic factors most likely to modify fluid r e q u i r e m e n t s e.g., body temperature, ambient temperature, ambient humidity, activity and respiratory rate. "7 In the nongrowing older infant, ]4

the maintenance fluid requirement is approximately i ml/Cal expended. ~'s This allotment replaces insensible w a t e r losses through the lungs and skin as well as obligatory renal and gastrointestinal losses. Insensible water loss varies considerably in all infants, particularly LBW infants. Both pulmonary and cutaneous components of insensible water loss are dependent in large degree o n a m b i e n t humidity, both decreasing as ambient humidity increases. 6~ Under usual nursery conditions, the insensible water loss of t e r m infants is approximately 30 ml/100 Cal. In the very low birth weight infant, however, cutaneous losses appear to be g r e a t e r than this amount, possibly due to altered skin p e r m e a b i l i t y to water. TM Phototherapy, a commonly used modality in L B W inrants with hyperbilirubinemia also increase~ insensible w a t e r losses.7,, 72 Thus, the insensible water loss of the LBW infant almost certainly exceeds that of the older infant, perhaps by as much as twofold, depending on the ambient humidity. Urinary water loss of the LBW infant also varies widely. While even very low birth weight infants can vary the volume of u r i n e excreted according to the solute load and the available water, both renal concentrating and diluting mechanisms are limited. ~ In general, allowance for a urinary volume of 5 0 - 6 0 m l / 1 0 0 Cal allows excretion of the usual range of solute load at u r i n e concentrations of 1 5 0 - 450 mOsm/L, which are easily achieved e v e n b y a very immature kidney. TM Fluid losses via the gastrointestinal tract are minimal if the infant is not being fed. If the infant is fed, however, approximately 10% of the fluid intake is lost in the stool. These losses are even greater in the infant receiving phototherapyT~; whether t h e y are increased in unfed infants receiving phototherapy h a s not been established. Estimating the fluid allowance for growth of the L B W infant is complicated by a number of factors, the most important one b e i n g the rate of growth. Another related factor concerns the w a t e r content of the newly synthesized tissue. Both of these factors a r e further complicated by the so-called physiologic weight loss over the first few days of life. In the term infant, this phenomenon is due chiefly to loss of extracellular fluid. TM While it has been a s s u m e d that such losses also explain the ~r weight loss o f the premature infant, data documenting this assumption a r e lacking. Nonetheless, weight losses of various magnitudes ( u s u a l l y approximately 10% of the birth weight) are observed over the first 1 - 2 weeks of life in most LBW infants, and these losses appear to be independent of nutritional management. Taking a 1500-gin infant (gestational age 31 weeks) as an example and a s s u m i n g continuation of the intrauterine growth rate after an i n i t i a l water loss representing 10% of the birth weight, a weight gain of 850 15

gm would be expected over the first 4 weeks of life.* If this weight gain is assumed to consist of 65% water, the water required for growth will a m o u n t to approximately 10 ml/kg daily. The water requirements for insensible and obligatory losses as well as for growth are reduced by the endogenously produced water of o x i d a t i o n - i . e . , approximately 12 ml/100 Cal, or the a m o u n t required for growth. Thus, the LBW infant, like the term infant, seems to have a m i n i m u m water requirement of i ml/Cal utilized. The fasting infant, therefore, requires at least 75 ml/kg daily, whereas the growing infant requires at least 120 ml/kg daily, assuming total metabolic expenditures of 75 and 120 Cal/kg daily, respectively. However, the very i m m a t u r e infant or the infant undergoing phototherapy may require much more water. In general, 150 ml/kg daily is well tolerated by most infants, whether they are fed enterally or parenterally; up to 200 ml/kg daily has been used without apparent difficulties by some. 77

ELECTROLYTE REQUIREMENTS The approach that will be used to estimate electrolyte requirements of the L B W infant is that used to estimate the fluid requirements-to set the requirements as those required for replacement of obligatory losses plus those required for synthesis of n e w tissue. The obligatory electrolyte losses of the term infant have been estimated as approximately 0.5 m E q of both sodium and chloride and approximately 0.75 mEq of potassium per 100 Calories utilized. TM These estimates probably are reasonable for the LBW infant, as well, although losses are probably greater in infants with increased fluid losses secondary to phototherapy, etc. The requirements for tissue synthesis, of course, depend on the rate of growth. Assuming continuation of the i n t r a u t e r i n e growth rate, the requirement for tissue synthesis will be approximately the amounts which accumulate during the last trimester of pregnancy (Table 2), or approximately 1.0 mEq/kg of sodium and approximately 0.5 mEq/kg each of potassium and chloride daily. If the rate of weight gain achieved is less t h a n the intrauterine rate, the requirements would decrease proportionally. Assuming weight gain a t one-half the i n t r a u t e r i n e rate, for example, the sodium requirement would consist of t h e usual obligatory losses plus one-half the usual requirement for tissue accretion. *In this example it is assumedthat new tissue accretion begins immediately, a nonrealistic assumption, and that the weight gain represents the net effectof fluid loss and tissue accretion. Alternatively,one could assume that the water loss occurs over the first week and new tissue accretion then begins at the intrauterine rate, in which case only 3/4 of the total weight gain would be expected over the ensuing 3 weeks. 16

TABLE 2.-ACCUMULATION OF VARIOUS COMPONENTS DURING THE LAST TRIMESTER OF PREGNANCY* ACCUivfULATIOIN DURING VARIOUS STAGES OF GESTATION COMPONENT

Body Weight (gm)r Water (gm) Fat Igm) Nitrogen (gm) Calcium (gm) Phosphorus (gm) Magnesium (mg) Sodium (mEq) Potassium (mEq) Chloride (mEq) h'on (mg) Copper (rag) Zinc (mg)

26-31 WK

31-33 WK

33-35 WK

35-38 WK

38--40 WK

500 410 25 Ii 4 2.2 130 35 19 30 36 2.1 9.0

500 350 65 12 5 2.6 110 25 24 24 60 2.4 10.0

500 320 85 12 5 2~8 120 40 26 10 60 2.0 8.0

500 240 175 6 5 3.0 120 40 20 20 40 2,0 7.0

500 220 200 7 5 3.0 80 40 20 10 20 2,0 3,0

*Adapted from data of Widdowsor~? 1Body weight of the 26-week fetus is 1000 gm; that of the 40~week f e t u s is 3000 gin.

Thus the minimal daily electrolyte requirements for t h e LBW infant receiving 120 Cal/kg daily are 1.6 mEq sodium, 1.4 mEq potassium and 1.1 mEq chloride. In general, the quantities of potassium and chloride p r e s e n t in the volumes of both h u m a n milk and commonly u s e d formulas usually ingested are sufficient to meet these r e q u i r e m e n t s , even if weight gain approximates that which occurs in utero. However, the sodium content of h u m a n milk (approximately 1.2 mEq/100 Col) may not be sufficient, even if all the sodium p r e s e n t were completely absorbed. MINERAL REQUIREMENTS

Until recently, less attention has been focused on m i n e r a l requirements of LBW infants than on other nutrient requirements. Although considerable data are available on calcium a n d phosphorus contents of infant formulas, the attention paid t h e s e two minerals does not specifically concern nutritional requirements. Rather, this attention is attributable to the frequent occurrence of hypocalcemia in term as well as LBW infants. ~, s0 T h i s condition develops more commonly in infants who receive formulas with a high content of phosphorus relative to calcium (a low calcium-phosphorus ratio); thus emphasis has been placed on the calcium-phosphorus ratio of infant formulas, not o n absolute amounts of either mineral. Experience has shown t h a t a ratio of roughly 2:1 is satisfactory with respect to preventing hypocalcemia. It has been suggested that the nutritional r e q u i r e m e n t s for both major and trace minerals be set at the amount n e c e s s a r y to 17

allow continuation of the rate of accumulation which would have t a k e n place had the infant remained in utero. 8' This concept immediately raises the question of the role of weight gain in det e r m i n i n g mineral requirements: Are the requirements independent of the amount of weight gain or should they be a function of the observed weight gain regardless of how closely it approaches the intrauterine weight gain? In this regard, Forbes has demonstrated,that developmental retention of minerals by t h e human infant as well as some animal species correlates best with the observed weight gain, regardless of the stage of development. 82, 89 The amount of calcium retained during normal intrauterine growth can be calculated from the data shown in Table 2 - a p proximately 14 mEq/day. Since the calcium content of human milk is only 20 mEq/L, it is obvious t h a t the volume of h u m a n milk required to provide this amount of calcium, even assuming 100% rather t h a n the usual maximum 6 0 - 7 0 % absorption from the gastrointestinal tract, is considerably greater t h a n that commonly ingested, or possible to ingest, by most LBW infants. Even at half the usual rate of intrauterine weight gain, the calcium content of h u m a n milk is insufficient to allow retention of the same percentage of calcium as occurs in utero. The low calcium content of h u m a n milk would present few problems with respect to nutritional adequacy were it not that infants fed with h u m a n milk have less dense skeletons radiographically than those who receive larger amounts of calcium24 The situation is further aggravated by the fact that skeletal mineralization is an acidifying process. Based on the stoichiometry of hydroxyapatite deposition ~5or on direct titration of dissolved bone mineral, 86 Kildberg estimates that 20 mEq of acid (H +) is released b y deposition of 1 gm of calcium, or 0.4 m E q H § is released for each m E q of calcium, sT Thus, calcium retention at the in-utero rate (approximately 8 mEq/kg daily) results in release to the body fluids of approximately 3 mEq H+/kg daily. When added to ~he usual daily 3 - 4 mEq/kg of endogenously produced H +, the total H + load presented to the kidney for excretion m a y well exceed the capacity of immature renal acidification mechanisms. Severe acidosis has not been observed in infants receiving calcium supplementation, probably because Ca ~+ supplementation was provided as calcium lactate, s8 However, supplementation with calcium salts of a nonmetabolizable anion (e.g., CaC12) could result in totally different results with respect to the status of blood acid base. Assuming that adequate calcium can be given without producing acidosis, a further problem makes definition of a precise calcium requirement for LBW infants difficult--the absorption of calcium by the gastrointestinal tract. Shaw so studied the calcium absorption of infants receiving h u m a n milk, commonly used in]8

rant formulas and cow milk. Regardless of calcium intake, none retained sufficient calcium to allow accumulation at the intrauterine rate. Calcium retention, in fact, appeared to be almost independent of intake; although intake ranged from 56 to 214 mg/kg daily, retention ranged only from 30 to 60 mg/kg daily (54-31% of the intake). Shaw postulated that the failure to absorb sufficient calcium to allow accumulation at the intrauterine rate was due either to a defect in vitamin D absorption or to an inability to convert vitamin D to 25-hydroxycholeca]ciferol. On the other hand, Day et al. ss demonstrated daily calcium retention of 146.6 mg/kg, approximately the daily intrauterine accumulation, in infants receiving a standard formula plus 147 mg/kg daily of calcium lactate. The total calcium intake of these infants was approximately the same as the highest intake (cow milk) cited by ShawS~; in addition, the vitamin D intake was quantitatively and qualitatively similar in the two studies. Thus it appears that the chemical form of dietary calcium may play a role in the absorption of calcium from the gastrointestinal tract. Alternatively, the type of protein or fat, both of which were different in the two studies, could play a role, Obviously, it is impossible to make a specific recommendation concerning the calcium requirement of the premature infant. While it is well known that skeletal mineralization of infants fed human milk is deficient in comparison with those receiving higher calcium intakes, the clinical significance of this observation is unknown. Nonetheless, it seems reasonable to provide the infant fed h u m a n milk with calcium supplements. Exactly how much and what type of supplement to provide, however, remains uncertain. Although very little is known about the absolute magnesium requirements of LBW infants, the general topic is less confusing than that concerning calcium requirements. The intrauterine rate of accumulation of magnesium averages approximately 6 mg/day. Since h u m a n milk contains only 40 mg/L and since only 6 0 - 70% is absorbed from the gastrointestinal tract, it is unlikely that magnesium retention at the intrauterine rate will occur in infants fed with human milk. Nonetheless, clinical experience with both h u m a n milk and formulas with similar magnesium content has been satisfactory. Magnesium deficiency, in fact, is rare except in gross states of malnutrition '~~ and perhaps with excessive phosphorus intake. 9~ Daily magnesium intakes of 0.25 mEq (3 mg)/kg are often excessive, judged by plasma magnesium concentrations, for premature infants receiving total parenteral nutrition. 92 Considering all these facts, it appears that a magnesium intake similar to that delivered by a reasonable volume of h u m a n milk (e.g., 120 Cal/kg daily) is adequate for most, if not all, LBW infants. However, there is some evidence that the re19

quirement of the infant t h a t is small for gestational age may be more t h a n that of the infant whose size is appropriate for gestational age2 3 Iron requirements depend on the existing body stores and the rate of growth. Thus, the LBW infant has much smaller stores of iron t h a n the term infant and is more susceptible to the developm e n t of iron-deficiency anemia, especially during periods of rapid growth. It has been estimated t h a t the LBW infant's endogenous iron stores, in the absence of exogenous intake, wilt be depleted sometime during the second and third month of life rather than during the fifth:~month of life, as in the term infant. For this reason, it is generally suggested that the LBW infant receive iron supplements or iron-fortified formulas as early as possible. 94 Such supplements, however, increase the infant's susceptibility to vitam i n E deficiency, '~ especially when formulas high in P U F A are fed (see below). In addition, there is evidence that the iron-binding proteins of h u m a n milk (lactoferrin and lactoglobulin), which also have bactericidal properties, lose these properties if saturated with iron. 96 In light of these considerations it seems unnecessary and perhaps undesirable to fortify the formulas of LBW infants with iron during the first 2 months of life. Alternatively, it has been suggested t h a t formulas for LBW infants which contain moderate amounts of P U F A and ample vitamin E be supplemented with 1 mg of iron/100 Cal, and those with higher amounts of P U F A and less vitamin E should contain only 0.15 mg of iron/100 C a l Y Requirements for trace minerals in LBW infants have not been established. In fact, of the m a n y trace minerals that are thought to be necessary for optimal nutrition in man, requirements have been demonstrated for only a few (zinc, copper, iodine). Necessity for other trace minerals (chromium, cobalt, manganese, molybdenum, selenium) has been demonstrated in various animals, and on this basis they have been assumed to be required b y man. Little information is available concerning the LBW infant's requirements for any of the trace minerals. In general, the recommendation for intake of these various minerals has been based either on the amounts provided by h u m a n milk or the amounts recommended for term infants. The Food and Nutrition Board of the National Academy of Sciences-National Research Council recommends a daily zinc intake of 3 mg28 This recommendation is in agreement with the recent proposal by the American Academy of Pediatrics Committee on Nutrition that infant formulas for t e r m infants supply 0.5 mg of zinc/100 Cal. 99 This level of zinc intake, assuming 50% absorption from the gastrointestinal tract, should allow accumulation of zinc at the intrauterine rate. The concentration of zinc in both h u m a n milk and cow milk is approximately 3 - 5 mg/L. Thus, both provide minimally adequate zinc to allow accumulation at the intrauterine rate. 20

Zinc stores are usually high at birth and, regardless of intake, zinc balance is generally negative during the first week of life. '~176 Fomon has accumulated data from balance studies over the first 4 months of life and finds t h a t zinc balance during this time may be slightly negative or slightly positive. ~~ Even when positive, retention rarely exceeds 0.3 mg/day. Thus, it appears t h a t there is little if any increase in total body zinc content over t h e first few months of life, in which case the zinc content of h u m a n milk is certainly adequate. Indeed, zinc deficiency has not been a clinical problem in infants fed h u m a n milk. The daily iodine intake recommended by the Food and Nutrition Board of the National Academy of Sciences-National Research Council is 35 #xgY The minimal requirement recommended by the American Academy of Pediatrics Committee on Nutrition for normal infants is 5/xgll00 Cal, 'j~ which is also the iodine content of h u m a n milk. Since the uptake of radioiodine by the thyroid of premature infants is in the same range as t h a t of children and adults, L~ this recommended intake is probably adequate for the LBW infant as well. The copper requirement of 7- to 9-year-old girls was estimated to be 60 #xg/kg daily. '~ This level of copper is also the recommended level for infant formulas - 6 0 #~g/100 Cal. Although this intake might not allow accumulation of copper at the intrauterine rate, it is approximately the amount delivered by h u m a n milk. Although some have recommended intake of 90 ~g copper/100 Cal for LBW infants s~ to allow accumulation at the intrauterine rate, such intakes are probably not necessary, because of the large hepatic stores of copper. For example, Widdowson has shown that the hepatic copper content of term infants is approximately 12 mg compared with a value of about 8 mg for the adult. TM Copper intake of premature infants has been restricted to 14 #~g/kg daily for 60 days without provoking manifestations of deficiency.l~ The most likely explanation for this fact was that the interva] was too short to exhaust hepatic stores, and this suggests that such stores are as extensive in the preterm as in the term infant.

VITAMIN REQUIREMENTS Specific recommendations concerning either requirements or advisable allowances of vitamins for LBW infants are not available; it is therefore usually suggested t h a t the recommended daily allowances for term infants be given. The recommendations of both the Food and Nutrition Board, National Academy of Sciences-National Research Council and the American Academy of Pediatrics Committee on Nutrition are summarized in Table 3. Infants receiving either h u m a n milk or artificial formulas in amounts to produce adequate growth usually receive sufficient 21

TABLE 3 , - R E C O M M E N D E D ALLOWANCES OF VITAMINS FOR INFANTS UNDER 6 MONTHS OF AGE

VITAMIN A (IU +) D (IU) E (IUI K Qzg) C (rag) Folacin {p~g) Niacin (/.Lg) Riboflavin (p.g) Thiamin (/zg) B6 (/zg) B,2 (~gl Panthothenic acid (p.g) Biotin {~g) Inosito] {mg) Choline (mgl

~RE~OMMENDED ALLOWANCE~ DAILY* PER I00 CAL~" 1400 400 4 35 50 5 400 300 300 0.3

250 40 0.3 4 8 4 250 60 40 35 0.15 300 1.5 4 7

*Food and Nutrition Board, National Academy of SciencesNational Resem-ch Council, 19742 H tAmerican Academy of Pediatrics Committee on Nutrition.'*:* $International units.

amounts of all vitamins, although h u m a n milk (and unfortified cow milk) m a y be deficient in vitamin D. Nonetheless, vitamin supplements are generally recommended since the consumption of sufficient volumes of formula to satisfy vitamin requirements m a y not be attained for several weeks. Moreover, the LBW infant m a y have special needs with regard to certain vitamins, e.g., vitamin E and folic acid. Deficiency of vitamin E with enhanced erythrocyte hemolysis is commonly observed in growing premature infants. '~176 Vitamin E functions as an antioxidant to prevent peroxidation of PUFA in the red cell membrane. Infant formulas utilizing vegetable oils which have higher contents of PUFA result in an increased content of these fatty acids in the erythrocyte membrane, thus increasing the need for v i t a m i n E. I n f a n t formulas containing vegetable oils of high linoleic acid content, therefore, should have a higher vitamin E content. In general, the aim should be to provide 1 International Unit (IU) of vitamin E per gram of linoleic acid, an E-PUFA ratio of 1. Low birth weight infants receiving formulas high in P U F A and given therapeutic doses of iron also have a greater incidence of red cell hemolysis and lower serum vitamin E levels t h a n infants receiving formulas with low levels of iron and PUFA25, ,0,, Thus, not only is there a relationship between vitamin E and polyuns a t u r a t e d fat content of the formula but there also seems to be a 22

relationship between the iron and vitamin E contents of the formula. For this reason it has been suggested that iron supplements either not be given before 2 months of age or t h a t vitamin E content of formulas or vitamin E supplementation be even further increasedY In addition to the above factors which increase the vitamin E r e q u i r e m e n t of LBW infants, these infants have impaired intestinal absorption of vitamin E compared with the term infant. Intakes of vitamin E which are adequate to m ai nt ai n normal serum vitamin E levels in term infants are not sufficient to maintain normal levels in p r e m a t u r e infants. ''~ Water-soluble forms of vit amin E are more easily absorbed and result in higher serum vitamin E levels. TM Thus these forms of vitamin E are recommended. Although not as well established as the situation with respect to vitamin E, there is some evidence that the LBW infant requires more folic acid t han the term infant, u~, H.~ Folic acid functions as a coenzyme in m a n y metabolic reactions, including the synthesis ofpurines and pyrimidines. Thus it is essential for production of new cells. Studies of folate metabolism in p r eter m infants have shown that serum values fall from approximately normal adult levels at birth to levels below this range by a few weeks of age. The levels persist in this range until around 3 months of age before rising again to normal adult levels. H2 This decrease in serum folate values can be prevented by daily oral supplements of 50 t~g, but comparison of groups of pret er m infants supplemented with folate with like groups not supplemented have shown no difference in growth or hemoglobin levels. T M The unsupplemented group, however, had more hypersegmented neutrophils, and erythrocyte folate levels were lower. The hematologic evidence of inadequate folate suggests t hat the folate deficiency affects all growing cells. The recommendation of Dallman for supplementation of LBW infants with 50 t~g dailyJ ~3 therefore, is to be endorsed.

ROLE OF HUMAN MILK IN FEEDING THE LOW BIRTH WEIGHT INFANT W h e t h e r h u m a n milk is nutritionally adequate for the LBW infant has been argued for a number of years but never so vehemently as at the present time. On the one hand, calculations show th at h u m a n milk contains insufficient amounts of various nutrients (protein, calcium and sodium) to allow deposition at the rate which occurs in uter013; nonetheless, the studies of R~hi~ et al.~2, 30 demonstrate t ha t infants receiving h u m a n milk grow as well as those receiving formulas containing larger amounts of the nutrients in question. Moreover, these studies demonstrate the 23

metabolic safety of h u m a n milk in comparison to the other regimens evaluated. The key to this controversy appears to be the definition of"the optimal rate at which LBW infants should grow. Until such definition is available it seems reasonable to view continuation of the intrauterine growth rate as a goal for which to strive. But the lack of evidence for superiority of this rate of growth over t h a t observed in infants receiving h u m a n milk, or even slower rates of growth, m u s t be borne in mind. The intensity of the controversy, currently, is due to an increased awareness of the potential non-nutritional advantages of h u m a n milk. It contains macrophages, lymphocytes, immunoglobulins and other factors which convey local and perhaps systemic i m m u n i t y to the newborn infant. "5, ~ Although the evidence is not conclusive, serious infections seem to be less frequent among breast-fed t h a n among artificially fed infants. ~4 In this regard, the distinction between "breast-fed" and ~infants fed h u m a n milk" m a y be extremely important. A number of the protective components of h u m a n milk are destroyed by h e a t sterilization (e.g., the cellular elements and the immunoproteins) or by freezing (e.g., the cellular elements), both common practices in h u m a n milk b a n k i n g technology. Thus, the advantages of h u m a n milk taken fi'om the breast or given shortly after being expressed from the breast m a y not be apparent in pooled h u m a n milk from milk banks.' ~5 In addition, the composition of h u m a n milk varies with stage of lactation, time of day and whether the milk is the first or the last to be expressed at any particular time. The protein content of h u m a n milk decreases as lactation progresses, reaching concentrations as low as 0.8 gm/100 ml, or less t h a n 1.5 gm/120 Cal. ~16 Fat content, low in the first milk to be released at any lactation period, increases toward the end of the period. 11TThus, i f a h u m a n milk bank contains predominantly the milk of women in advanced stages of lactation, the protein content can be quite low. Similarly, if the bank is composed predominantly of milk that remains after the donor's child has finished nursing, fat content may be quite high. It seems clear t h a t precise recommendations cannot be made concerning the nutritional adequacy of h u m a n milk for the LBW infant. However, h u m a n milk feedings afford the infant the benefit of any protective elements against infection t h a t may be present. Thus it seems reasonable to feed the infant its own mother's milk, preferably at the breast or as soon after it is expressed as possible. If given by nipple or by gavage it should be given without treatment, provided it is expressed in a relatively aseptic fashion. Alternatively, pooled frozen h u m a n milk can be used, provided the composition is rigidly controlled. Little a r g u m e n t can be given for use of heat-sterilized h u m a n milk. 24

DELIVERY OF NUTRIENTS TO LOW BIRTH WEIGHT INFANTS It seems reasonable to assume that the general difficulty encountered in successfully establishing oral feedings in small premature infants is at least partially responsible for the dearth of studies concerning their nutritional requirements. A poor or unsustained suck, ~s an uncoordinated swallowing mechanism, u'~ delayed gastric emptying ~0 and poor intestinal motiiity TM are the neurophysiologic deficiencies accounting for the difficulties. These deficiencies make maintenance of the controlled intakes necessary for careful nutritional studies difficult. In addition, the usual failure to establish a significant enteral intake makes a precise knowledge of nutritional requirements seem irrelevant. Recently, however, methods for delivery of sufficient nutrients solely by the intravenous route (total parenteral nutrition or total intravenous nutrition) as well as methods for continuous infusion of feedings by the gastrointestinal tract (continuous nasogastric or nasojejunal infusions) have been reported. 1~2Utilization of a combination of these available methods of nutrient delivery, allowing the particular clinical problem of an individual infant to be the basis for selection of the particular method, has resulted in improvement of nutrient delivery. Some of the newer methods of nutrient delivery are not used routinely and are worthy of description. They will be described in the context of describing the reported clinical experience with each method. CONTINUOUS TRANSPYLORIC OR INTRAGASTRICINFUSIONS

The use of nasojejunal, or transpyloric, feeding in pediatric patients was first reported by Rhea. '23 Subsequently, Cheek and Staub '2~ reported extensive experience with this method of feeding in LBW infants. The technique includes nasal insertion of a small Silastic catheter enclosed in a more rigid, open-ended catheter. A gold bead is attached to the tip of the Silastic catheter to facilitate passage through the pylorus, and the infant is placed on its right side to further facilitate passage of the tube through the pylorus. Once the tube is in correct position, radiographically, the outer rigid tube is removed, the smaller Silastic catheter is secured in place and formula is infused at a continuous rate by a constant infusion pump. The technique of continuous nasogastric infusion is similar but much simpler. An appropriately sized catheter is placed through the nares into the stomach; once in correct position, the catheter is secured and the formula is infused. With either of these methods, the volume of formula infused 25

initially should be small. Thereafter, depending on the infant's ability to tolerate increasing volumes, the volume can usually be increased rapidly. Both methods overcome the poor suck and uncoordinated swallowing so common in LBW infants. Transpyloric infusions more effectively overcome the problem of delayed gastric emptying. Neither method overcomes the poor intestinal motility common to very low birth weight infants. Studies comparing these two methods of n u t r i e n t delivery have r a r e l y demonstrated advantages of one over the other. *~5,,26 However, Roy et al. '27 demonstrated a difference in n u t r i e n t assimilation t h a t depended on whether the formula was delivered continuously by the transpyloric route or as bolus feeds into the stomach every 2 hours. While neither the volumes delivered to infants weighing approximately 1300 gm nor the infants' weight gains differed, stool frequency and stool fat content were greater in the group who received continuous transpyloric feeds. Although intestinal perforation has been reported in infants receiving continuous nasojejunal feedings, 128, 12~ most were in very small infants in whom polyvinyl rather t h a n Silastic catheters were used. T h a t the polyvinyl catheters become extremely rigid after t h e y have been in place for only a short period of time probably accounts for this complication. In addition, some of the reported perforations occurred shortly after m a n i p u l a t i o n of the indwelling catheter, especially after it was moved forward. Using Silastic catheters, Rhea has used this technique in over 500 patients and perforation has never occurred'3~ thus, if used as he describes, the method appears to be safe. More recently, polyuret h a n e catheters have been used successfully. This m a t e r i a l is more rigid t h a n Silastic, but the rigidity of catheters made of this m a t e r i a l does not increase once they are in place. TM TOTAL PARENTERAL NUTRITION Despite numerous attempts over several decades, it was not until 1966 t h a t delivery of all nutrients exclusively by the parent e r a l route became a reality. 1~2 By infusing a hypertonic mixture of protein hydrolysate and glucose t h r o u g h an indwelling central venous catheter, Dudrick et al. successfully m a i n t a i n e d both h u m a n '32 and a n i m a l subjects 133in positive nitrogen balance and demonstrated t h a t this method of n u t r i e n t delivery sustained normal growth of younger subjects. T M Over the last decade, this method of nutrition has been used widely in m a n y areas of medicine. Although used for provision of n u t r i e n t s to LBW infants,'~5136 the technique cannot be recommended as a routine practice; however, it is a valuable adjunct in selected infants. Any parenteral fluid mixture t h a t will provide sufficient nutrients to promote growth and m a i n t a i n positive nitrogen balance m u s t contain a nitrogen source as well as a caloric source. In ad26

dition, the mixture must contain all other essential nutrients, e.g., electrolytes, minerals and vitamins. Two general types of nitrogen sources are available: hydrolysates of either fibrin or casein or mixtures of crystalline amino acids. Although both provide essential as well as nonessential amino acids, none of the currently available preparations provides an "ideal" amino acid mixture. One of the available crystalline amino acid mixtures in a dose of 2.5 gm/kg daily is recommended. Intakes of 4.0 gm/kg daily have been advocated ~'~4,~:~7. however, this higher intake offers no advantage in terms of either improved nitrogen balance or improved weight gain, and it usually causes azotemia. ~'~sMoreover, plasma concentrations of some amino acids, which reach bothersomely high values with the lower intake, are even higher with higher amino acid intakes. ~s Although f~uctose or a mixture of glucose and fructose is sometimes used, glucose is the most commonly used caloric source. Ethanol has been used TM but its potential hepatic toxicity ~'~.~as well as its variable tolerance from infant to infant '4~ make it undesirable. Intravenous fat preparations have been used for several years outside the United States. ~4', ~,12These preparations, only recently available for use in this country, offer the distinct advantage of providing essential fatty acids; however, their exact role in parenteral nutrition (e.g., only as a source of essential fatty acids or as a major source of calories) has not been clearly defined. Several electrolyte and vitamin additives are available for parenteral use; the amounts required approximate the established oral maintenance requirements. The parenteral requirement ~br minerals, on the other hand, may be significantly different from the oral requirement. Thus, the amounts of various minerals supplied are considerably less than usually recommended. At the present time, trace minerals are rarely included, primarily because precise requirements are not known. Periodic blood or plasma transfusions, used by some to meet requirements for these nutrients, are probably inadequate. Table 4 depicts the composition of a suitable infusate. However, the content of each day's infusate should be determined by a physician after careful assessment of the infant's clinical and biochemical status. The infusates should be prepared frequently (daily or every other day), preferably under laminar flow and by a specially trained pharmacist. The infusate is administered slowly and continuously through a catheter inserted into the superior vena cava via either the external or internal jugular vein (see below). A 0.22/~ Millipore filter is placed in the infusion line as a final filter for debris, microorganisms or both. Constant infusion rate is maintained by use of a constant infusion pump. The LBW infant is unlikely to tolerate the full caloric requirement initially; thus, the initial daily infusate should deliver only 27

TABLE 4.-COMPOSITION OF A SUITABLE PARENTERAL NUTRIENT INFUSATE COMPOIN-EINT

Nitrogen source (hydrolysate or crystalline amino acid mixture) Glucose* Sodium (NaC1) Potassium? Calcium (Ca gluconate) Magnesium (MgSO4) Chloride Phosphorus:': MVI$ TOTALVOLUME

DAILY

AMOUNT

2.5 gm]kg 25- 30 gm/kg 3 - 4 mEq/kg 2- 3 mEq/kg 0.5-1.0 mEq/kg 0.25 mEq/kg 3- 4 mEq/kg 2 mM/kg 1 ml 1 2 0 - 130 ml/kg

*Glucose can be reduced according to amount of intravenous fat emulsion used. Amount provided on initial day should not exceed 15 gm/kg ~see text). tHyperphosphatemia often develops when more than 2 mM/kg daily is used; thus, if potassium intake of more than 2 mEq/kg daily is required, a mixture of KCI and KH2PO, shouldbe used. SUSV. Pharmaceuticals, Tuckahoe, N,Y. This preparation (1 ml) contains adequate amounts of all required vitamins except folic acid, vitamin B,, and vitamin K. These can be added to the daily int'usate {5 t~g vitamin Bj2, 50 /~g folic acid, 500/zg vitamin K); alternatively, vitamin B,2 and vitamin K can be given by intramuscular injections.

1 0 - 15 g m / k g of glucose daily. Glucose c o n t e n t can t h e n be inc r e a s e d g r a d u a l l y to a level of 2 5 - 3 0 g m / k g d a i l y in a c c o r d a n c e w i t h t h e p a t i e n t ' s glucose tolerance. F u l l caloric m a i n t e n a n c e f r o m glucose alone can r a r e l y be achieved in less t h a n 7 - 10 days. I n t r a v e n o u s fat e m u l s i o n s s h o u l d help c o n s i d e r a b l y in this reg a r d , b u t t h e L B W i n f a n t ' s t o l e r a n c e for lipid also s e e m s to v a r y widely, m, 144 T h e m a r k e d v a r i a b i l i t y in metabolic r e s p o n s e s of the p r e m a t u r e i n f a n t n e c e s s i t a t e s f r e q u e n t c h e m i c a l m o n i t o r i n g , a t least u n t i l full caloric m a i n t e n a n c e is achieved. A s u g g e s t e d m o n i t o r ing schedule is g i v e n in T a b l e 5. Obviously, a d h e r e n c e to this s c h e d u l e r e q u i r e s a v a i l a b i l i t y of m i c r o c h e m i c a l methods. Once it seems feasible a n d safe to b e g i n oral feedings, t h e volu m e of i n t r a v e n o u s a l i m e n t a t i o n s o l u t i o n c a n be d e c r e a s e d as o r a l i n t a k e increases. F r o m a strictly p r a c t i c a l v i e w p o i n t , it s h o u l d n o t be d i s c o n t i n u e d t o t a l l y u n t i l a d e q u a t e fluid a n d calories can be provided solely by e n t e r a l feedings. P e r c u t a n e o u s s u b c l a v i a n v e i n p u n c t u r e , the u s u a l m e t h o d for i n s e r t i n g c e n t r a l vein c a t h e t e r s in adults, is difficult as well as h a z a r d o u s in infants. C a t h e t e r s for l o n g - t e r m total p a r e n t e r a l n u t r i t i o n are t h u s u s u a l l y i n s e r t e d t h r o u g h a n e x t e r n a l or inter28

TABLE 5.-SUGGESTED MONITORING SCHEDULE DURING TOTAL PARENTERAL NUTRITION V A R I A B L E S TO B E

MONITORED

,-" S U G G E S T E D I~'REQUENCY 9 I N I T I A L P E R I O D ~: LATER PERIODt

Plasma electrolyte 3-4• Weekly 2-3x Weekly Blood urea nitrogen 3x Weekly 2• Weekly Plasma calcium, magnesium, 3x Weekly 2• Weekly phosphorus Blood glucoses Blood acid-base status 3-4x Weekly 2-3• Weekly Blood ammonia 2x Weekly Weekly Serum protein (electrophoresis Weekly Weekly or albumin/globulin) Liver function studies Weekly Weekly Hemoglobin 2• Weekly 2x Weekly Urine glucose Daily 2x Daily Clinical observations Daily Daily (activity, temperature, etc.) WBC and differential counts As indicated As indicated Cultures As indicated As indicated *Initial period is the period before full glucose intake is achieved, or any period of metabolic Instability. tLater period is the period during which the patient is in a metabolic steady state. +Blood glucose should be monitored closely during periods of glucosuria (to determine the degree of hyperglycemia) and for 2 - 3 days following cessation of parenteral nutrition (to detect hypoglycemia). In the latter instance, frequent Dextrostix determinations constitute adequate screening. n a l j u g u l a r vein cutdown. T h e c a t h e t e r is t h r e a d e d into the super i o r v e n a cava, a n d its p r o x i m a l end is t h e n t u n n e l e d subcutan e o u s l y to exit in the parieto-occipital a r e a of the scalp (Fig 3). E x i t of the c a t h e t e r at this site affords added safety f r o m infect i o n , s o m e f r e e d o m from the infant's w a n d e r i n g hands, and ease of m a i n t e n a n c e of the c a t h e t e r site. T h e c a t h e t e r is o f t e n placed u n d e r g e n e r a l a n e s t h e s i a in a n o p e r a t i n g r o o m setting. H o w e v e r , t h e s e steps are not n e c e s s a r y if the child can be a d e q u a t e l y res t r a i n e d a n d if s i m i l a r s t e r i l i t y can be m a i n t a i n e d elsewhere. Specific steps for c a t h e t e r i n s e r t i o n h a v e b e e n described. '45 R e g u l a r m e t i c u l o u s care of the c e n t r a l venous c a t h e t e r is m a n d a t o r y for prolonged, safe, complication-free use. A p h y s i c i a n or a s p e c i a l l y t r a i n e d n u r s e or technician should dress the c a t h e t e r e x i t site at l e a s t t h r e e t i m e s weekly. T h e occlusive d r e s s i n g m u s t be r e m o v e d a n d the s k i n a r e a cleaned w i t h b o t h d e f a t t i n g and a n t i s e p t i c (Betadine) agents. Antiseptic o i n t m e n t and a fresh occ l u s i v e d r e s s i n g should be reapplied. W i t h m e t i c u l o u s care, a single c a t h e t e r can be used s a f e l y for at least 30 days, often longer. T h e efficacy of t o t a l p a r e n t e r a l n u t r i t i o n in infants w i t h m a j o r a n o m a l i e s of t h e g a s t r o i n t e s t i n a l t r a c t a n d in i n f a n t s with int r a c t a b l e d i a r r h e a l s y n d r o m e s h a s been firmly established. '46 The 29

•

CONSTANT

INFUSION / ~ , _

(/ tl _~_1 PUMP

~ -

~ - -..,~4~-';,~ ="

......... ,.~

\ MILLIPORE FILTER POSITION OF CATHETER Fig 3.--Cornplete setup for administration of total parenteral nutrition. (Reproduced with permission from Sinclair et al.TM)

technique is also useful in selected LBW infants. In these patients, total parenteral nutrition promotes weight gain and positive nitrogen balance until gastrointestinal function is recovered. Daily weight gains of 7 - 2 0 gm/kg and nitrogen balances of 1 0 0 - 250 mg/kg daily can be expected in patients receiving total parenteral nutrition ( 1 1 0 - 1 2 5 Cal/kg daily and 2.5 gm amino acids/kg daily). Generally, the higher values are observed in patients who are malnourished at the onset and experience little or no stress during the period of total parenteral nutrition (e.g., those with intractable diarrheal syndromes). Patients requiring multiple operative procedures or experiencing episodes of sepsis or other illness during total parenteral nutrition exhibit smaller weight gain and less positive nitrogen balance. 2 After a daily caloric intake of greater than 100 Cal/kg is established, LBW infants can be expected to gain approximately 15 gm/kg daily and have positive nitrogen balances in the range of 200 mg/kg daily. '3s M a n y complications have been reported in relation to total parenteral nutrition: These can be divided into three general groups: septic, catheter-related, and metabolic. Since the parenteral nutrition infusate promotes the growth of bacteria and fungi, ~47it must be mixed under strictly aseptic conditions. Failure to do so may result in infusion of a contaminated mixture. A more important factor contributing to high rates of septic complications, however, is failure to maintain meticulous aseptic technique in placement of the catheter and subsequent care of both the catheter and its exit site, ~4~ Most of the catheter-related complications that have been reported, such as malposition, thrombosis and dislodgment, can be 30

p r e v e n t e d by strict a d h e r e n c e to e s t a b l i s h e d principles of placem e n t a n d m a i n t e n a n c e of c e n t r a l vein catheters. For t h e m o s t p a r t , m e t a b o l i c complications a r e r e l a t e d to the c o n t e n t of the p a r e n t e r a l n u t r i e n t solution. A l m o s t all complications i m a g i n a b l e h a v e b e e n reported. T h e ones m o s t often ohs e r v e d are s h o w n in T a b l e 6 along with t h e i r m o s t c o m m o n cause. H y p o g l y c e m i a , t h e m o s t c o m m o n l y e n c o u n t e r e d m e t a b o l i c problem, c a n be m i n i m i z e d b y careful m o n i t o r i n g a n d careful use of s m a l l doses of i n s u l i n (0.25 - 0.50 tL/kg daily). Blood u r e a n i t r o g e n c o n c e n t r a t i o n s e x c e e d i n g 20 mg/100 ml (up to 50 m g / 1 0 0 ml) occur r a r e l y in i n f a n t s r e c e i v i n g daily protein i n t a k e s of 2.5 gm/kg. A c o m p l i c a t i o n t h a t is m o r e frequent, as well as p o t e n t i a l l y m o r e h a z a r d o u s in p r e m a t u r e infants, is t h a t of a b n o r m a l p l a s m a amin o g r a m s . This p h e n o m e n o n is seen with use of any of the curr e n t l y a v a i l a b l e n i t r o g e n sources. E x p e r i e n c e s u g g e s t s t h a t t o t a l p a r e n t e r a l n u t r i t i o n c a n be used w i t h o u t u n d u e r i s k in p r e m a t u r e infants. T h e l o n g - t e r m effects of this t e c h n i q u e , h o w e v e r , c a n n o t be assessed u n t i l experience with it is g r e a t e r . U n t i l such e x p e r i e n c e is available, t o t a l i n t r a v e n o u s a l i m e n t a t i o n c a n n o t be a s s i g n e d a definite role in t h e routine n u t r i t i o n a l m a n a g e m e n t of t h e LBW infant. However, w h e n used TABLE 6.-METABOLIC COMPLICATIONS OF TOTAL PARENTERAL NUTRITION AND THEIR MOST COMMON CAUSE COMPLICATION

Iatrogenic disorders Hyperglycemia

Hypoglycemia Azotemia Electrolyte disorder Mineral (major and trace) disorders Vitamin disorders Essential fatty acid deficiency Disorders due to suboptimal nitrogen Acid-base disorders (hyperchloremic metabolic acidosis) Hyperammonemia Abnormal plasma aminograms Hepatic disorders* Elevated transaminases Hyperbilirubiuemia

USU A L CAUSE

Excessive intake (either excessive concentration or increased infusion rate) Change in metabolic state (sepsis, surgical stress) Sudden cessation of infusion Excessive nitrogen intake Excessive or inadequate intake Excessive or inadequate intake Excessive or inadequate intake Failure to provide essential fatty acids source

Use of' hydrochloride salts of catonic amino acids '~s Inadequate arginine intake Amino acid pattern of nitrogen source Unknown

*Cholestasis, often with hyperbilirubinemia, is encountered frequently. The cause of this disorder is unknown but it seems to be reversible. 31

with adequate precaution, the technique does not seem to entail unacceptable risks, especially for infants unable to tolerate enteral feedings. INTRAVENOUS NUTRIENTS BY PERIPHERAL VEIN

Attempts to provide adequate nutrients solely by peripheral vein infusion are usually unsuccessful for one of two reasons: (1) the necessarily high osmolality of the infusate substantially limits the duration of individual infusion sites; (2) alternatively, the increased volumes of less hypertonic solutions required to deliver adequate nutrients often exceed the infant's tolerance for fluid. Nonetheless, this method has been used with some success. The nutrient mixtures that have been used for peripheral intravenous nutrition, with the exception of glucose concentrations which rarely exceed t0 gin/100 ml, L4:~-~' are similar to those administered via central vein. Intralipid, which delivers 11 Cal/gm without an appreciable osmotic contribution, has also been included in infusates for administration by peripheral vein. ''~ The nutrient mixture is usually infused into one of the peripheral veins on the dorsal aspect of either the hand or fbot or into one of the superficial veins of the scalp. Obviously, caution in placement of the scalp vein needle as well as subsequent meticulous care of the site minimizes local complications. The efficacy of this technique is illustrated by a recent study of Anderson et al. TM This controlled study, conducted during the first week of life in infants weighing less than 2500 gm, compared peripheral intravenous administration of glucose alone and glucose plus amino acids (2.5 gm/kg daily), both regimens delivering 60 Cal/kg daily. Even with this limited caloric intake, most infants who received the regimen of glucose plus amino acids gained small amounts of weight (daily average, 2 gm/kg) and were in positive nitrogen balance (150 mg/kg daily). In contrast, infants who received only glucose lost weight (daily average, 12 gm/kg) and were in negative nitrogen balance - 125 mg/kg daily). Low b i r t h weight infants who received the glucose and amino acid regimen at 3 weeks of age gained approximately 12 gm/kg daily and exhibited positive nitrogen balances averaging 175 mg/kg daily. Mildly elevated plasma levels of some amino acids were observed in the infants who received glucose plus amino acids. In addition, they showed a greater tendency to develop essential fatty acid deficiency. The study, however, shows that the catabolic tendency of the LBW infant during the first week of life can be reversed simply by adding amino acids to the frequently used regimen of intravenously administered glucose (10 gin/100 ml). The daily fluid volume (150 ml/kg) delivered in this study appeared to be well tolerated. Addition of small amounts of an intravenous fat 32

emulsion to this regimen should prevent essential fatty acid deficiency. Moreover, increasing the total caloric intake with this agent might result in this regimen's being as efficacious for shortterm use as total parenteral nutrition by central vein catheter. Although few metabolic complications have been reported with this method of nutrient delivery, such complications should be the same as those observed with total parenteral nutrition by central vein. Septic complications are rarely mentioned as a complication of this technique. Phlebitis or local complications of fluid extravasation (e.g., cutaneous sloughs, superficial infections) have occurred. The greatest problem, however, seems to be maintenance of adequate infusion sites for more than 7 - 1 0 days. INTRAVENOUS SUPPLEMENTATIONOF TOLERATED ORAL FEEDINGS

The simplest form of the technique of supplementing tolerated oral feedings with intravenous infhsions of various nutrients (supplementing tolerated oral feedings with intravenous infusions of 10% glucose) represents the conventional method of feeding premature infants at the present time. More recently, oral feedings have been supplemented with intravenous infusions of glucose and amino acid mixtures ~'~'~,~,~4 or mixtures of glucose, amino acids and lipid; 1~ however, only a few controlled studies have been reported. Bryan et al. ~5~*compared supplemental intravenous infusions of 10% glucose and 3.5% fibrin hydrolysate with supplemental intravenous infusions of only 10% glucose in very small infants (< 1300 gm). Although both total caloric intake and total fluid intake were similar in the two groups, the infants receiving the nitrogen-containing infusion regained birth weight sooner than the control group. In addition, the infants who received the nitrogen-containing infusate had fewer apneic episodes. Pildes et al? '~4 compared intravenous supplementation with a mixture containing 10,5% glucose and 3.4% crystalline amino acids to intravenous supplementation with 5% glucose. In infants weighing between 1000 and 1250 gm, no significant differences in the time required to regain birth weight were observed between the two regimens. However, infants weighing 1250-1500 gm who received the glucose-amino acid mixture regained birth weight sooner (8_+1.8 days) than those who received only glucose (16_+2 days). Weight gain after 21 days was significantly greater in all infants who received the glucose-amino acid mixture, regardless of birth weight. Cashore et al. ~1 supplementing tolerated oral feedings with peripheral intravenous infusions of a mixture of protein hydrolysate, glucose and Intralipid, observed weight gains approaching those which occur in utero. Length and head circumference also increased at approximately the intrauterine rates. The potential complications of this technique include the usual 33

complications of enteral feedings as well as the complications of intravenous nutrition. However, use of the combination of nutrient delivery appears to be somewhat advantageous in that smaller volumes ofenteral feedings can be given, thus decreasing the risk of such complications as aspiration. The most commonly encountered metabolic problem is hyperglycemia. Azotemia was observed by Bryan et al. 1"~,~as well as by Pildes et al., ~54 probably reitecting excessive nitrogen intakes. The problem of abnormal plasma aminograms (hypermethioninemia and hyperg]ycinemia) as reported by Pildes et al. ~54 is likely to occur less frequently once better amino acid mixtures become available.

CONCLUSIONS A number of methods for feeding LBW infants are available. Thus, the physician caring for them should be able to adapt these methods to specific clinical situations so that adequate, if not optimal, nutrition can be provided. Only after this feat is accomplished, can the studies needed to determine optimal nutritional requirements be conducted. REFERENCES 1. Widdowson, E. M.: Growth and Composition of the Fetus and Newborn, in Assail, N.S. (ed.): Biology of Gestation, vol. I[ (New York: Academic Press, Inc., 19681. 2. Heird, W. C., Driscoll, J. M., Jr., Schullinger, J. N., Grebin, B., and Winters, R. W.: Intravenous alimentation in pediatric patients, J. Pediatr. 80:351, 1972. 3. Dickerson, J. W. T., Dobbing, J., al~d McCance, R. A.: The effect of undernutrition on the postnatal development of the brain and cord in pigs, Proc. Roy. Soc., Lond. [Biol.] 166:396, 1966-67. 4. Winick, M., and Noble, A.: Cellular response in rats during malnutrition at various ages, J. Nutr. 89:300, 1966. 5. Winick, M., and Rosso, P.: The effect ofsevcre early malnutrition on cellular growth of human brain, Pediatr. Res. 3:181, 1969. 6. Rosso, P., Hormazabal, J., and Winick, M.: Changes in brain weight, cholesterol, phospholipid and DNA content in marasmic children, Am. J. Clin. Nutr. 23:1275, 1970. 7_ Dobbing, J., and Sands, J.: Quantitative growth and development of human brain, Arch. Dis. Child. 48:757, 1973. 8. Winick, M., Meyer, K. K., and Harris, R. C.: Malnutrition and environmental enrichment by early adoption, Science 190:1173, 1975. 9. O'Donnel[, A. M., Ziegler, E. E., and Fomon, S. J.: Ingestas recomendadas de nutrientes para prematuros en crecimiento, Arch. Argent. Pediatr. 72:126, 1974. 10. Ziegler, E. E., O'Donnell, A. M., Nelson, S. E., and Fomon, S. J.: Body composition of the reference fetus, Growth 40:329, 1977. 11. Cashore, W. J., Sedaghatian, M. R., and Usher, R. H.: Nutritional supplements with intravenously administered lipid, protein hydro]ysate, and glucose in small premature infants, Pediatrics 56:8, 1975. 12. R~ihfi, N. C. R., Heinonen, E., Rassin, D. K., and Gaull, G. E.: Milk protein quantity and quality in low birth weight infants, Pedia*~rics 57:659, 1976. 34

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33. Menkes, J. H., Welcher, D. W., Leir, H. S., Dallas, J., and Gretky, N. E.: Relationship of elevated blood tyrosine to the ultimate intellectual perlbrmance of premature infants, Pediatrics 49:218, 1972. 34. Forsyth, D.: The history ol~ infant feeding fl'om Elizabethan times, Prec. R. Soc. Med. 4:110, 1910-11. 35. RSihii, N. C. R.: Phenylalanine hydroxylase in human liver during development, Pediatr. Res. 7:1, 1973. 36. Sturman, J., Gaull, G., and 1RAih~i, N. C. R.: Absence of cystathionase in human fetal liver: Is cystine essential? Science 169:74, 1970. 37. Powers, G. F.: Infant feeding: Historical background and modern practice, J.A.M.A. 105:753, 1935. 38. Burr, G. 0., and Burr, M. M.: A new deficiency disease produced by the rigid exclusion of fat from the diet, J. Biol. Chem. 82:345, 1929. 39. Aues-Jorgenson, E.: Essential fatty acids, Physiol. Rev. 41:1, 196]. 40. Hansen, A. E., Stewart, R. A., Hughes, G., and Soderhjelm, L.: The relation of linoleic acid to infant feeding, Acta Paediatr. Scand. ISuppl. 137) 51:1, 1962. 4[. Davidson, M., and Bauer, C. H.: Patterns of fat excretion in feces of premature infants fed various preparations of milk, Pediatrics 25:375, 1960. 42. Holman, R. L.: Atherosclerosis: A pediatric nutritional problem? Am. J. Clin. Nutr. 9:565, 1961. 43. Senior, J. R.: Intestinal absorption of fats, J. Lipid Res. 5:495, 1964. 44. Watkins, J. R., Szczepanik, P., Gould, J. B., Klein, P., and Lester, R.: Bile salt metabolism in the human premature infant, Gastroenterology 69:706, 1975. 45. Norman, A., Strandvik, B., and Ojam~ie, O.: Bile acids and pancreatic enzymes during absorption in the newborn, Acta Paediatr. Scand. 61:571, 1972. 46. Holtzapplc, T. G., Smith, G., and Kaldovsky, O.: Uptake, activation, and esterification of fatty acids in the small intesti~e of the suckling rat, Pediatr. Res. 9:786, 1975. 47. Tidwell, H. C., Holt, L. E., Jr., Farrow, H. L., and Neale, S.: Studies in fat metabolism. Ill. Fat absorption in premature infants and twins, J. Pediatr. 6:48[, 1935. 48. Filer, L. J., Jr., Mattson, F. H., and Fomon, S. J.: Triglyceride configuration and fat absorption by the human infant, J. Nutr. 99:293, 1969. 49. Isselbacher, K. J.: Mechanisms of Absorption of Long and Medium Chain Triglycerides, in Senior, J. R. (ed.): Medium Chain Triglycerides (Philadelphia: U. of Penn., 1968), p. 21. 50. Roy, C. C., Ste-Marie, M., Chartrand, L., Weber, A., Bard, H., and Dorsy, B.: Correction of the malabsorp~ion of the preterm infants with a medium chain trigtyceride formula, J. Pediar, r. 86:44~, 1975. 51. Andrews, B. F., and Lorch, V.: Improved fat and calcium absorption in low birth weight infants fed a medium chain triglyceride-containing formula, Pediatr. Res. 8:378, [974. 52. Tantibhedhyangkul, P., and Hashim, S. A.: Medium chain triglyceride feeding in premature infants: Effects on ['at and nitrogen absorption, Pediatrics 55:359, 1975. 53. Maey, I. G., Kelly, H. J., and Sloan, R. E.: The Composition of Milks: A Compilation of the Comparative Composition and Properties of Human, Cow, and Goat Milk, Colostrum and Transitional Milk, publication 254 (Washington, D.C.: Natl. Acad. of Sci.-Nat. Res. Council, 1953). 54. Fomon, S. J., Filer, L. O., Jr., Thomas, L. N., and Rogers, R. R.: Growth and serum chemical values of normal breast fed infants, Acta Paediatr. Scand. (Suppl.) 202:1,1970. 55. Hahn, P., and Koldovsky, O.: Utilization of Nutrients during Postnatal Development (New York: Pergamon Press, 1966). 56. Reiser, R.: Control of adult serum cholesterol by the nutrition of the suckling: A progress report, Circulation (Suppl. II) 44:3, 1971. 36

57. Friedman, G., and Goldberg, S. J.: Concurrent and subsequent serum cholesterols of breast and formula fed infants, Am. J. Clin. Nutr. 28:42, 1975. 58. Gutberlet, R. B., and Cornblath, M.: Neonatal hypoglycemia revisited, 1975, Pediatrics 58:10, 1976. 59. Auricchio, S., Rubino, A., and Murset, G.: Intestinal glycosidase activities in the human embryo, fetus and newborn, Pediatrics 35:944, 1965. 60. Koldovsky, O.: Development of the Functions of the Small Intestine in Mammals and Man (Basel: S. Karger A. G., 1969). 61. Book, L. S., Herbst, J. J., and Jung, A. L.: Necrotizing enterocolitis in infants ibd an elemental formula, Pediatr. Res. 8:379, 1974. 62. Barbero, G. J., Runge, G., Fischer, D., Crawford, M. N., Tortes, F. E., and Gyorgy, P.: Investigations of the bacterial flora, pH and sugar content in the intestinal tract of infants, J. Pediatr. 40:152, 1952. 63. Bullen, C. L., and Willis, A. T.: Resistance of the breast-fed infant to gastroenteritis, Br. Med. J. 3:338, 1971. 64. Winberg, J., and Wessner, G.: Does breast milk protect against septicemia in the newborn? Lancet h1091, t971. 65. Goldman, A. S., and Smith, C. W.: Host resistance t'actx~rs in human milk, J. Pediatr. 82:1082, 1973. 66. Hanson, L. A., Carlsson, B., Ahlstedt, S., Svanberg, C., and Kaijser, B.: Immune Defense Factors in ttuman Milk: In Milk and Lactation, in Kretchnor, N., Rossi, E., and Sereni, F. (eds.): Modern Problems in Pediatrics, vol. 15 (Basel: S. Karger AG, 1973), p. 63. 67. Winters, R. W.: Maintenance Fluid Therapy, in Winters, R. W. (ed.): The Body Fluids in Pediatrics (Boston: Little, Brown and Co., 1973), p. 113. 68. Heird, W. C.: Acid-Base, Fluid, and Electrolyte Disturbances in the Newborn, in Young, D. S., and Ilicks, J. M., (eds.): The Neonate: Clinical Biochemistl:y, Physiology, and Pathology (New York: John Wiley & Sons, Inc., i976}, p. 295. 69. Hey, E. N., and Katz, G.: Evaporative water loss in the new-born baby, J. Physiol. 200:605, 1969. 70. Nachman, R. L., and Esterly, N. B.: Increased skin permeability in preterm infants, J. Pediatr. 79:628, 1971. 71. Wu, P. Y. K. and Hodgman, J. E.: Insensible water loss in preterm infants: Changes with postnatal development and non-ionizing radiant energy, Pediatrics 54:704, 1974. 72. Oh, W., and Karecki, H.: Phototherapy and insensible water loss in the newborn infant, Am. J. Dis. Child. 124:230, 1972. 73. Nash, M. A., and Edelmann, C. M.: The developing kidney: Immature function of inappropriate standard? Nephron 11:71, 1973. 74. Zeigler, E. E., and Fomon, J. J.: Fluid intake, renal solute load, and water balance in infancy, J. Pediatr. 78:561, 1971. 75. Wu, P. Y. K., Lim, R. C., Hodgeman, J. E., Kokosky, M. J., and Taberg, A. J.: Effect of phototherapy in preterm infants on growth in the neonatal period, J. Pediatr. 85:563, 1974. 76. Friis-Hansen, B.: Changes in body water compartments during growth, Acta Paediatr. Scand. (Suppl. 110) 46:1, 1957. 77. Fox, H. A., and Krasna, I. H.: Total intravenous nutrition by peripheral vein in neonatal surgical patients, Pediatrics 52:14, 1973. 78. Pratt, E. L.: Dietary prescription of water, sodium, potassium, calcium, and phosphorus for infants and children, Am. J. Clin. Nutr. 5:555, 1957. 79. Tsang, R., and Oh, W.: Neonatal hypocalcemia in low birth weight infants, Pediatrics 45:773, 1970. 80. Harvey, O., Cooper, L., and Stevens, J.: Plasma calcium and magnesium in newborn babies, Arch. Dis. Child. 45:506, 1970. 81. Shaw, J. C. L.: Parenteral nutrition in the management of sick low birth weight infants, Pediatr. Clin. North Am. 20:333, 1973. 82. Forbes, G. B.: Inorganic chemical heterogony in man and animals, Growth 19:75, 1955. 37

83. Forbes, G. B.: Calcium accumulation by the human fetus (letter), Pediatrics 57:976, 1976. 84. Griscom, N. T., Craig, J. N., and Neuhauses, E. B. D.: Systemic bone disease developing in small premature infants, Pediatrics 48:883, 1971. 85. Kildberg, P.: Clinical Acid-Base Physiology: Studies in Neonates, Infants and Young Children (Copenhagen: Ejnar Munksgaard Forlag, 1968). 86. Raaflaub, J.: Uber die Basizitat der Knochenmineralien, Experientia 17:443, 1961. 87. Kildberg, P., Engel, K., and Winters, R. W.: Balance of net acid in growing infants: Endogenous and transintest~nal aspects, Acta Paediatr. Scand. 58: 34, 1969. 88. Day, G. M., Chance, G. W., Radde, I. C., Reilly, B. S., Park, E., and Sheepers, S.: Growth and mineral metabolism in low birth weight infants. II. Effects of calcium supplementation on growth and divalent cations, Pediatr. Res. 9: 568, 1975. 89. Shaw, J. C. L.: Evidence for defective skeletal mineralization in low birth weight infants: The absorption of calcium and fat, Pediatrics 57:16, 1975. 90. Caddell, J. L., and Goddard, D. R.: Studies in protein-calorie malnutrition. I. Chemical evidence of magnesium deficiency, N. Engl. J. Med. 276:533, 1967. 91. Tsang, R. C.: Neonatal magnesium disturbances, Am. J. Dis. Child. 124:282, 1972. 92. Heird, W. C., MacMillan, R., and Winters, R. W.: Total Parenteral Nutrition in Pediatrics, in Barness, L. (ed.): First Wyeth Nutritional Symposium, 1973. 93. Tsang, R. C., and Oh, W.: Serum magnesium levels in low birth weight infants, Am. J. Dis. Child. 120:44, 1970. 94. Gorten, M. K., and Cross, E. R.: Iron metabolism in premature infants. II. Prevention of iron deficiency, J. Pediatr. 64:509, 1964. 95. Williams, M., Shott, R., O'Neal, P., and Oski, F.: Role of dietary iron and fat on vitamin E deficiency anemia of infancy, N. EngL J. Med. 292:887, 1975. 96. Bullen, J. J., Rogers, H. J., and Griffith, E.: Iron-binding proteins and infections, Br. J. Haematol. 23:389, 1972. 97. American Academy of Pediatrics Committee on Nutrition: Nutritional needs of low birth weight infants, in press. 98. Food and Nutrition Board, National Academy of Sciences-National Research Council'. Recommended daily allowances, 1974. 99. American Academy of Pediatrics Committee on Nutrition: Commen'tary on breast feeding and infant formulas including proposed standards for formulas, Pediatr. 57:278, 1976. 100. Widdowson, E. M.: Trace elements in human development, in Barltrop, D., and Burland, W. L. (eds.): Mineral Metabolism in Paediatrics (Oxford: Blackwell, 1969), p. 85. 101. Bergmann, K. E., and Fomon, S. J.: Trace Minerals, in Fomon, S. J. (ed.): Infant Nutrition (2d ed., Phil'adelphia, W. B. Saunders, 1974), p. 329. 102. Martmer, E. E., Con]gan, K. E., Charbendeau, H. P., and Sosin, A.: A study of the uptake of iodine (I-131) by thyroid of premature infants, Pediatrics 17: 503, 1956. 103. Price, N. O., Bunce, G. E., and Engel, R. W.: Copper, manganese and zinc balance in preadolescent girls, Am. J. Clin. Nutr. 23:218, 1970. 104. Widdowson, E. M., Chart, H., Harrison, G. E., and Milner, R. D. G.: Accumulation of Cu, Zn, Mn, Cr, and Co in the human liver before birth, Biol. Neonate 20:360, 1972. 105. Wilson, J. F., and Lakey, M. E.: Failure to induce dietary deficiency of copper in premature infants, Pediatrics 24:40,1960. 106. Oski, F. A., and Barness, L. A.: Vitamin E deficiency: A previously unrecognized cause of hemolytic anemia in the premature infant, J. Pediatr. 70:211, 1967. 107. Lo, S. S., Frank, D., and Hitzig, W. H.: Vitamin E and haemolytic anemia in premature infants, Arch. Dis. Child. 48:360, 1973. 38

108. Ritchie, J. H., Fish, M. B., McMasters, V., and Grossman, M.: Edema and hemolytic anemia in premature infants: A vitamin E-deficiency syndrome, New Engl. J. Med. 279:1185, 1968. i09. Melhorn, D. K., and Gross, S.: Vitamin E-dependent anemia in the premature infant. I. Effects of large doses of medicinal iron, J. Pediatr. 79:569, 1971. 110. Melhorn, D. K., and Gross, S.: Vitamin E-dependent anemia in the premature infant, II. Relationships between gestational age and absorption of vitamin E, J. Pediatr. 79:581, 1971. 111. Gross, S., and Melhorn, D. K.: Vitamin E-dependent anemia in the premature infant: III. Comparative hemoglobin, vitamin E and erythrocyte phospholipid responses following absorption of either water soluble or fat soluble a-alpha tocopherol, J. Pediatr. 85:753, 1974. 112. Shojaniu, A. M., and Gross, S.: Folic acid deficiency and prematurity, J. Pediatr. 64:232, 1964. 113. Dallman, P. R.: Iron, vitamin E and relate in the preterm infant, J. Pediatr. 851742, 1974. 114. Burland, W- L., Simpson, K., and Lord, J.: Response of low birth weight infants to treatment with relic acid, Arch. Dis. Child. 46:189, 1971. 115. Pitt, J.: Breast milk Ieukocytes, Pediatrics 58:769, 1976. 116. Fomon, S. J., and Filer, L. J.: Milks and Formulas, in Fomon, S. J. (ed.): Infant Nutrition (Philadelphia; W. B. Saunders, 1974), p. 361. 117. Hytten, F. E.: Clinical and chemical studies in human lactation. II. Variation in major constituents during a feeding, Br. Med. J. 11176, 1954. 118. Crump, E. P., Gore, P. M., and Horton, C. P.: The sucking behavior in premature infants, Hum. Biol. 30:128, 1958. 119. Aaeron, G. M., and Kemp, F. H.: A correlation ]aetween sucking pressures and movements of tongue, Acta Paediatr. Scand. 48:261, 1959. 120. Keller, A.: Studies of motility relations of the infant stomach, Nord. Med. 38: 1141, 1948. 121. Takita, S.: Automaticity of the alimentary tract: Observations of the fetal alimentary tract, the so-called ganglion free intestine and the anastomosed organ, Jpn. J. Smooth Muscle Res. 6:79, 1970. 122. Heird, W. C. and Driscoll, J. M., Jr.: Newer methods for feeding low birth weight infants, Clin. Perinatol. 2:309, 1975. 123. Rhea, J. W., Chazzawi, O., and Weidman, W.: Nasojejunal feeding: An improved device and intubation technique, J. Pediatr. 821951, 1973. 124. Cheek, J. A., and Staub, G. F.I Nasojejunal alimentation for premature and full-term infants, J. Pediatr. 82:955, 1973. 125. Pereira, G. R., and Lemons, J.: Comparative study between transpyloric (nasojejunal) and intermittent gavage feeding in small pre-term infants (abstract), Pediatr. Res. 10:346, 1976. 126. Pyati, S., Ramamurthy, R., and Pildes, R. S.: Continuous drip nasogastric (NG) feedings: A controlled study (abstract), Pediatr. Res. 10:349, 1976. 127. Roy, N., Poilnitz, R., Hamilton, R., and Chance, G.: Impaired assimilation of nasojejunal (NJ) feeds in very low birth weight (VLBW) infants (abstract), Pediatr. Res. 10:352, 1976. 128. Bores, S. J., and Reynolds, J. W.I Duodenal perforation: A complication of neonatal transpyloric tube feeding, J. Pediatr. 85:107, 1974. 129. Chen, J. W., and Wong, P. W. K.: Intestinal complications of nasojejunal feeding in low-birth-weight infants, J. Pediatr. 85:109, 1974. 130. Rhea, J. W., Ahmid, M. S., and Mange, E. S.: Nasojejunal (transpyloric) feeding: A commentary, J. Pediatr. 86:451, 1975. 131. Wilkes, G. L., and Sanmels, S. L.: Porous segmented polyurethanes-possible candidates as biomaterials, J. Biomed. Mater. Res., 7:541, 1973. 132. Dudrick, S. J., Wilmore, D. W., Vars, H. M., and Rhoades, J. E.: Long term total parenteral nutrition with growth, development, and positive nitrogen balance, Surgery 64:134, 196839

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