Many years ago it was not necessary for pediatricians to pay close attention to the details of infant nutrition while obtaining satisfactory results. The success of neonatal intensive care, however, has changed this situation. Full-term and large premature infants have grown well and thrived on a variety of feeding substances (most often proprietary infant formulas) which have remained largely unchanged throughout this period. This approach to infant nutrition was extrapolated to growing numbers of small premature infants surviving primarily due to technical advances in supportive care. As a result, clinically significant nutrition deficiency diseases have become increasingly apparent in premature nurseries across the country. It is now generally recognized that the needs of small premature infants are quite different from those of full-term babies and that it is necessary to develop a clearer understanding of these specialized needs and to identify optimal substances and techniques for meeting them. Over the last decade an increasing number of neonatalogists have focused on the definition of nutritional requirements for infants of varying gestational ages as well as the evaluation of conventional feeding substances. Out of this research has come an improved but incomplete understanding of the role nutrition plays in the developing fetus. The role of breast milk in the nourishment of the premature infant has received extensive attention. In addition, manufacturers of proprietary infant formulas have developed new products which are specifically intended to deal with the special problems presented by young premature infants. The purpose of this article is to outline areas of new knowledge concerning the nutritional requirements and the digestive tract functioning of premature infants, and to consider these in the context of new product formulation. We propose a rational approach to feeding which will be flexible enough to be generally applied to both large and small prematures.
GOALS AND OBJECTIVES
An historic goal in the feeding of premature infants has been to duplicate the weight gain expected had the infant remained in utero until term. Early, rapid weight gain along intrauterine growth curves, however, has been difficult to achieve, and when accomplished, has often proved to be simple water retention. In 1955, Kaganet al1 showed that a formula of high ash content caused water retention rather than the expected nitrogen retention. Babson and Bramhall2 later showed that both high protein and high ash diets produced weight gain, but later linear growth occurred only with the high protein diet. More recently, formula feeding has been shown to triple the rate of fat accretion in preterm infants when compared to fetal fat accretion rates.3 Consequently, the duplication of weight gain alone cannot be considered to adequately reflect nourishment of a premature infant. Formula composition and its effect on tissue composition of the infant must be evaluated.
CALCULATED DAILY RATES OF ACCUMULATION OF VARIOUS SUBSTANCES BY THE FETUS AT DIFFERENT PERIODS OF GESTATION5
Body composition changes radically throughout gestation. The relative proportions of major body compartments (eg, fat, bone, and water) change significantly during the last trimester. The early work of Widdowson and Spray4 in 1951 analyzed whole body composition of fetuses of varying weights and gestational ages. It was found that many substances accumulate at exponential rates between the 25th and 35th week of gestation.
Table 1 shows the daily rates of accretion of nitrogen, fat, water and minerals during the third trimester. While many substances accumulate at a fairly constant rate (eg sodium, potassium, magnesium, and water), rapid skeletal mineralization requires increasing amounts of calcium and phosphorus as the fetus approaches term. Similarly, the rate of fat accretion also rises more rapidly near term. These data may be used as a basis for evaluating the ability of enteral feedings and parenteral solutions to provide nutrients in the proper amounts for the premature infant of a given gestational age.
With these data in mind, it is probably appropriate to reformulate our goal for feeding of the premature infant. Our ideal objective should be to duplicate both fetal growth rates and fetal body composition.
Gastrointestinal immaturity alters both GI motility and enzyme availability and may decrease the effectiveness of enteral feeding in prematurity. Symptomatic motility disturbances most often involve the upper gastrointestinal tract. Limited gastric capacity is often complicated by delayed or incomplete emptying resulting in many of the common deterrents to feeding: gastric residuals, abdominal distention, and regurgitation. In the presence of these symptoms, it is quite common to respond by restricting feedings. More subtle, but of equal importance to motility disorders are problems which may result in malabsorption. Prematures have both quantitative and qualitative deficiencies of many enzymes as well as bile salts. Most notably, deficiencies of pancreatic lipase, lactase, and bile acids may make it difficult to achieve normal retention of fat and lactose, the predominant carbohydrate in milk.
Starvation and semi-starvation eras of premature feeding have resulted in the re-emergence of classical nutrient deficiency diseases, among them rickets6'7 and iron deficiency anemia.8 The severe weight loss and poor regaining of weight seen in the sub-optimally fed premature can be classified as clinical marasmus. Furthermore, malnutrition clearly compromises host defense mechanisms and immune competence;9 this factor may have important repercussions in the susceptibility of the infant to necrotizing enterocolitis.
We must, therefore, reconsider our goals and objectives in the feeding of premature infants. It has been difficult to duplicate intrauterine growth velocity ex-utero. However, it may be possible to duplicate the composition of the fetal body which would have been attained by intrauterine nourishment. While the problems associated with gastrointestinal tract immaturity suggest restrained progression of enteral feeding, critically needed energy and essential substrates must be provided. The principal objective is to adequately nourish the infant by enteral means. Parenteral nutrition may be necessitated either as a result of substance intolerance or malabsorption. The effectiveness of the feeding program is evaluated by means of physical measures (body weight, length, and head circumference) as well as by clinical observations and laboratory tests. If we knew the relationship between feeding composition and body composition, it would be easy to select an ideal feeding substance. Our present understanding of this relationship is most complete concerning mineral metabolism. Knowledge about amino acids and fatty acids, however, is much less complete. Consequently, clinicians are left to make an important feeding decision which cannot be completely substantiated by scientific data.
Premature infants are not a homogenous group. The enzymatic and functional deficiencies of im maturity exist as a spectrum which changes as the infant grows and ages. For example, lactase activity in the premature infant remains less than 30% of the normal term infant through 34 weeks post-conception; at this point it increases rapidly to reach normal levels at 38 to 40 weeks. It is noteworthy, however, that despite this seeming deficiency, lactose malabsorption is rarely a problem in prematures. The activities of sucrase, maltase and isomaltase, the other major disaccharidases, are well developed by 24 weeks of gestation, at 60% of the normal term activity levels. These latter disaccharidases are substrate inducible. Sugar or starch present in the diet can increase the activity of these enzymes beyond the levels expected for post-conceptional age. The small stomach capacity and uncoordinated gut motility which cause unpredictable gastric emptying may be an acute problem in the under 1000 g premature, but is of less concern in the 140Og infant. The implications of such assets and liabilities to the feeding of premature infants have resulted in major changes in their feeding.
Human milk, long the standard of quality for infant feeding, contains nutrients in highly digestible, absorbable, and utilizable form for the healthy term baby. A new awareness of the unique qualities, both nutritional and immunologic, of human milk has led to a re-examination of its use in the premature nursery. Table 2 lists some of the unique components of breast milk, along with their functions. While human milk is well tolerated by premature infants, a comparison of the nutrient accretion rates in utero with the composition of human milk readily demonstrates a small number of important deficiencies. This comparison makes it clear that small premature infants fed an exclusive diet of breast milk would receive inadequate quantities of calcium, phosphorus, iron, copper and zinc.10 The caloric density of human milk (20 kcal/oz) may result in slow growth if the infant is unable to tolerate sufficient fluid to meet caloric requirements. Conversely, some investigators'1-13 have reported increased concentrations of protein, fat, sodium, and chloride in preterm mothers' milk, seeming to correspond to the infants' increased need for these nutrients. According to B. Lindblad, M. D. (conversation, June 1982), "lacto-engineering" involves adding a fraction of lyophilized pooled breast milk protein to the infant's own mother's milk. This has been shown to produce growth at intrauterine rates in a very small number of low birthweight infants; its wider application remains to be examined.
ENERGY AND FLUID
The crux of the dilemma of feeding low birthweight infants is reached in the attempt to provide an adequate amount of each nutrient in the small volumes which can be managed by the premature gastrointestinal tract. While absolute energy expenditure of individual babies may vary due to exogenous and endogenous factors, typical caloric expenditure is estimated to be in the range of 95 to 120 kcal/ kg/ day (Table 3). A significant proportion of this energy expenditure is required for growth. Cold stress, physical activity and increased cardiopulmonary work as well as nutrient composition and route of administration will also affect the overall adequacy of energy intake. In general, enteral caloric intakes of 110 to 150 kcal/ kg/ day can be expected to support growth at a consistent rate. Parenteral intakes may be somewhat lower. Calorie dense formulas (81 kcal/ di) are frequently used to achieve this level of caloric intake in the very low birthweight infant. Fluid requirements are individual decisions, unique to each baby's condition and treatment. In practice, fluid is often initially administered at 100 cc/kg/day and adjusted upward or downward.
If breast milk is used as the sole source of calories, it is necessary to provide 179 cc/kg/day in order to deliver 120 kcal/ kg/ day. If a calorie-dense formula (81 kcal/dl) is used, then 148 cc/kg of fluid are required for an equal number of calories. In both of these situations, fluid loads may be too high. Severe respiratory distress, clinically significant patent ductus arteriosus and acute tubular necrosis are all common clinical problems of premature infants which may require restrictions of fluid intake.
HUMAN BREAST MILK
The subtleties of breast milk composition have yielded significant information regarding protein nutrition. Protein quality is an indicator of how efficiently a protein source may be used to promote both positive nitrogen balance and growth, in the absence of protein maldigestion. The major protein of human milk is whey, which is known to have a high nutritive value by all common measures of protein quality. Formulas based on cow milk may be modified by the addition of whey to more closely resemble the protein composition of human milk. These humanized formulas offer improved protein quality and more essential amino acids. The relative percentages of whey and casein in solution also affect the physicochemical properties of these proteins when exposed to gastric secretions. Breast milk or a "humanized "formula containing 60% whey forms a soft, easily digested and easily propulsed curd in the stomach. Conversely, the standard infant feeding containing 82% casein forms a harder, more rubbery curd, which appears to be a significant factor in the incidence of lactobezoar formation.15 Clearly, ease of digestion and high protein quality are beneficial characteristics of infant feeding.16
The provision of fat is important to provide essential fatty acids and a concentrated source of calories. Marginal lipase activity and a contracted bile salt pool conspire to impair the absorption of fat in very premature infants. It has been estimated that 85% of the fat may be absorbed from the vegetable oil sources used in proprietary formulas. This represents a significant loss of energy when formula intake is marginal. Improved total energy delivery and net caloric retention may result if a passively absorbed form of fat such as medium chain triglyceride oil ( MCT oil) is used as part of the fat content, or when breast milk is mixed with formula.'7 Linoleic acid, an essential fatty acid, must comprise at least 1 % of the total caloric requirement to prevent essential fatty acid deficiency. Therefore, a vegetable oil containing long chain polyunsaturated fatty acids must also be included in the diet when MCT oil is used as a caloric source.18
Serum values of calcium, phosphorus, magnesium and zinc may not adequately reflect nutritiona1 status in terms of body stores and tissue growth. Calcium, phosphorus, and magnesium are deposited in the bone matrix in large amounts during the last trimester. If the objective in the feeding of premature infants is to achieve proper body composition, it is essential to provide the quantity of these three minerals which will produce third trimester-like bone growth and mineralization. The calcium salts commonly present in formula are poorly absorbed from the premature small intestine, and breast milk contains insufficient calcium and phosphorus to produce the desired bone growth even when calorie intake is optimal. Consequently, infant feedings should be enriched with calcium and phosphorus during periods of rapid linear growth. Unfortunately, there is not yet available a wellabsorbed liquid calcium/ phosphorus supplement for the breast milk-fed premature infant. Mixtures of breast milk and premature infant formulas may partially ameliorate this problem.
While electrolyte imbalances are fairly rare and sodium and potassium needs are well met, iron nutrition and the trace elements zinc and copper deserve mention. Zinc and copper are present in adequate quantities in most infant formulas as well as in colostrum and early milk. However, the concentrations of zinc and copper in human milk undergo a significant decline throughout lactation,19 and may rapidly become inadequate to meet trace element needs in the growing premature infant. Similarly, the iron content of human milk cannot meet the requirements of the premature, despite the enhanced absorption of iron from human milk. Iron supplementation with a ferroussulfate preparation (2 mg/ kg/ day) begun at two to four weeks of life in preterm infants is recommended to minimize the duration of the anemia of prematurity classically seen at two months of age.8 This level of supplementation is unlikely to induce the membrane lipid peroxidation and hemolytic anemia that had been previously seen in infants supplemented with formulas containing 12 mg of iron per liter.20
ESTIMATE OF CALORIC EXPENDITURE DURING THE NEONATAL PERIOD14
Vitamin supplementation is generally adequate in any enteral formula which is taken in sufficient amounts to meet normal energy needs. Vitamin D, in the form of AC-D drops should be given to all premature infants.
Vitamin E administration has become a controversial topic in the wake of recent reports linking pharmacologic doses of vitamin E with partial or full resolution of retrolental fibroplasia.21 Vitamin E functions primarily as an antioxidant, preventing peroxidative damage to cell membrane lipids. Highly variable absorption of vitamin E in the premature infant makes it difficult to determine appropriate dosages to achieve therapeutic serum levels. The very small premature infant and the infant exposed to oxygen may benefit from supplemental vitamin E to minimize the sequelae of potential retrolental fibroplasia.
PREMATURE INFANT FORMULAS
The past two years have seen the introduction of proprietary infant formulas designed expressly for the premature infant. The compositions of these formulas reflect both the special nutritional requirements of the premature infant and the functional immaturity of their small intestines. A premature formula is characterized by an increased caloric density (24 kcal/oz) to allow higher calorie intake. Addition of whey protein to duplicate the ratio of whey to casein found in human milk provides higher quality protein and results in a more digestible curd. Medium chain triglyceride oil replaces a portion of the fat content to improve absorption and retention of fat. Glucose polymers, which are partially hydrolyzed starches, are easily digested and absorbed by low birthweight infants. The use of glucose polymers as a part of the carbohydrate source results in an iso-osmotic formula. The exact vitamin and mineral concentrations of premature formulas vary among the preparations, but are, in general, increased to compensate for decreased volume intake. These formulas may be used exclusively or in combination with breast milk until the infant weighs between 1700 g and 1000 g, and is tolerating increasing volumes of feedings well. Table 4 illustrates some of the formulas available for infants, their compositions, indications for use and appropriate supplemental products.
In order to be successful in the feeding of small premature infants it is important to provide the proper substances by the proper method. Considering the content and net retention of nutrients, for infants under 1000 g, it becomes abundantly clear that despite its advantages, breast milk alone is inadequate. Infants in this weight group may be fed initially with half-strength (12 kcal/oz) premature formula, to be advanced to full strength after 24 hours. When breast milk is available, it may be given alternately or mixed with 24 kcal/oz premature formula. Once it is clear that consistent growth is occurring and increasing amounts of formula are well tolerated, premature formula may be discontinued in favor of breast milk or routine infant formula.
Feeding methods may vary, depending on the age and abilities of the particular infant. Gavage feedings by continuous infusion or bolus may be required by the very small premature infant. Nipple feeding is usually possible when the infant has reached a post-conceptional age of 34 weeks or more. Offering a pacifier during gavage feedings in younger prematures has been found to facilitate the eventual transition to full nipple feedings. A soft rubber nipple is generally used for early feedings to allow the infant to obtain milk with less effort.
Gavage feeding by continuous infusion offers some advantages in the smallest of prematures. The small volume infused at any given time presents a minimal volume load to the stomach, reducing the likelihood of large gastric residuals, vomiting, and aspiration of formula. The infusion rate may be increased as the infant's stomach capacity and tolerance of formula dictate. Infants should be fed via a perfusion pump which can be adjusted to accurately deliver volumes as small as 1 cc per hour when continuous infusion is employed.
Two types of tubes are commonly used for gavage feeding. Those made of polyvinyl chloride (PVC) are inexpensive and easily inserted. However, on prolonged exposure to duodenal secretions, these tubes harden, making safe removal difficult. Bowel perforation has occasionally been reported when these tubes were manipulated after being in place for along period of time. PVC tubes should be changed every 24 to 48 hours to minimize these risks. Silastic tubes do not suffer from the disadvantages of PVC tubes when used for nasogastric feedings, and are therefore preferred for long-term use. Silastic tubes are more pliable, requiring greater skill to insert, and are also more expensive.
Feeding problems are common in the intensive care nursery. Formula intolerance frequently results from difficulty in achieving normal gut motility. Signs of poor gastric emptying, and abdominal distention are symptomatic of both abnormal gut motility, and more seriously, early sepsis. Slowing infusion rates or discontinuing the infusion for a short time may be all that is necessary until such signs subside. When formula intolerance is persistent, or coupled with guaiac positive stools, bilious residuals, apnea, or lethargy, a further investigation is imperative. The role of feeding in necrotizing enterocolitis is unclear. For the purpose of this discussion, we have overlooked the interrelationships between enteral feeding and NEC. Should it become apparent that enteral feeding is to be replaced by parenteral in infants at high risk for NEC the approach outlined is still applicable at the point enteral feeding is commenced.
The achievement of adequate growth in the premature infant is evaluated by serial measures of body weight, length, and head circumference. Plotting these measurements on one of many available infant growth charts will identify whether growth is occurring consistently along a normal curve. Growth may not, however, occur at the expected percentile when compared to term infants. Therefore, the use of fetal growth curves is preferred until the infant reaches a postconceptional age of 40 weeks. After this point, chronological age should be corrected for prematurity. Careful attention must be paid to the provision of formula, breast milk, and supplemental preparations in sufficient quantity when evaluating growth. When growth and/ or ability to take nourishment enterally falls below established minimum standards, parenteral nutrition is required.
The increased survival of premature infants has led to the recognition of nutritional deficiency states when conventional feeding substances have been used. These problems have resulted both from requirements for individual nutrients which exceed those of full-term infants as well as functional immaturity of the gastrointestinal tract. In overcoming the functional or physical limitations of the premature infant's Gl tract, special techniques of feeding may be required. An understanding of the limitations and requirements which small premature infants present, coupled with knowledge of the assets and liabilities associated with individual feeding substances is essential to the successful enteral nourishment of premature infants.
1 Kagan BM, Hess JH, Lundeen E, et al: Feeding premature infants: A comparison of various milks. Pediatrics 1955; 15:373-382.
2 Babson SG, Bramhall JL: Diet and growth in the premature infant. J Pediatr 1969; 74:890-900.
3 Reichman B, Chessey P, Putet G, et al: Diet, fat accretion and growth in premature infants. N EnglJ Med 1981; 305:1495-1500.
4 Widdowson EM, Spray CM: Chemical development in utero. Arch Dis Child 1951; 26:205-214.
5 Shaw JCL: Parenteral nutrition in the management of sick low birthweight infants. Pediatr Clin North Am 1973; 20:333.
6 Steichen JJ , Gratton TC, Tsang RC: Osteopenia of prematurity: The cause and possible treatment. J Pediatr 1980; 96:528-534.
7 Hoff N, Haddad J, Teitelbaum S. et al: Serum concentrations of 25-hydroxy vitamin D in rickets of extremely premature infants. J Pediatr 1979; 94: 460466.
8 Lundstrom U, Silmes MA, Dallman PR: At what age does iron supplementation become necessary in low-birthweight infants? J Pediatr 1977;91:878-883.
9 Dionigi R, Gnes F, Bonera A, Dominion! L: Nutrition and infection. Journal of Parenteral and Enteral Nutrition 1979; 3:62-68.
10. Forbes GB: Nutritional adequacy of human breast milk for premature infants, in Lebenthal E. (ed): Textbook of Gastroenterology and Nutrition in Infancy. New York, Raven Press. 1981. pp 321-329.
11 Atkinson SA. Rudde IC, Chance GW, et al: Macromineral content of milk obtained during early lactation from mothers of premature infants. Early Hum Dev 1980;4:15-14.
12 Gross SJ, David RJ, BaumanL,TomarelliRM:Nutritionalcompositionof milk produced by mothers delivering preterm. J Pediatr 1980; 96:641-644.
13 Schanler RJ, Oh W: Composition of breast milk obtained from mothers of premature infants as compared to breast milk obtained by donors. J Pediatr 1980;96:679-681.
14. Driscoll JM Jr, Heird WC: Maintenance fluid therapy during the neonatal period, in Winters RW (ed): The Body Fluids in Pediatrics. Boston. Little Brown & Co, 1973.
15 Schreiner RL. Brady MS, Ernst JA. et al: Lack of lactobezoars in infants given predominantly whey protein formulas. Am J Dis Child 1982; 136:437-439.
16 Davidson M. Bauer CH, Levine SZ. et al: Feeding of premature infants. Pediatrics 1964; 33:945.
17 Hernell O: Human milk lipases. Presented at the Second International Symposium on Infant Nutrition and the Development of the Gastrointestinal Tract. Niagara Falls. Canada, Jane 1982.
18 Davidson M, Levine SZ, Bauer CH. et al: Relation of dietary protein, fat, and electrolytes to rates of weight gain, clinical courses and serum chemical concentrations. J Pediatr 1967; 70:695.
19 Vuori E. Kuitonen P: The concentrations of copper and zinc in human milk. Acta Paediatr Scand 1979; b8: 33-37.
20 Williams ML Shott RJ. O'Neal PL, et al: Role of dietary iron and fat on vitamin E deficiency anemia of infancy. N Engl J Med 1975; 292:887-890.
21 Hittner H M. Godio LB, Rudolph AJ. et al: Retrolental fibroplasia: Efficacy of vitamin E in a double-blind clinical study of preterm infants. N Engl J Med 1981; 305(23): 1365-137 1.
CALCULATED DAILY RATES OF ACCUMULATION OF VARIOUS SUBSTANCES BY THE FETUS AT DIFFERENT PERIODS OF GESTATION5
ESTIMATE OF CALORIC EXPENDITURE DURING THE NEONATAL PERIOD14