WWK Koo, NV Raju, MA Tan-Laxa

The knowledge and practice of infant nutrition is continually evolving in the quest to meet the goal of maintaining the best possible physical and developmental outcome for the infant. Although many gaps still exist in our knowledge, nonetheless, many aspects that are reasonably well understood frequently are not applied in clinical practice or applied inappropriately i.e., "too little too late" or "too much too quickly". The former often occurs when the infant is considered to be "too sick" or "too immature" to tolerate nutritional support. The latter often occurs when there is unreasonable expectation of dramatic reversal of prior prolonged periods of inadequate nutritional support. This review aims to combine the science and "art" of enteral and parenteral nutrition so that no infant is too sick or too immature to receive nutrition support, thus allowing the infant to gain maximum benefit with minimal adverse effects.

Enteral Nutrition (EN)

I. Term Infants

A. Human milk

Human milk is undoubtedly the most important nutrient for the infant and breast-feeding should be strongly encouraged throughout infancy.^1-4 Numerous advantages of breast-feeding have been documented for the mother-infant dyad, family and society. These include health, nutritional, immunologic, developmental, social, economic and environmental benefits.^1-7

The successful management of breast-feeding begins during pregnancy. Prenatal care should include discussions of feeding plans and breast care. Postnatally, breast-feeding should begin as soon as possible after delivery usually within the first hour, unless medically contraindicated. In general, newborns should be nursed 8-12 times every 24 hours until satiety, usually 10-15 minutes on each breast, or whenever the baby shows signs of hunger such as increased alertness or activity, mouthing or rooting. Crying is probably a late indicator of hunger. In the early weeks after birth, non-demanding babies should be aroused to feed if four hours has elapsed since the last nursing. Thereafter, most infants can successfully demand feed and tolerate eight feeds or less per day.^2-10

Human milk composition is highly complex and contains enzymes, hormones, growth and immunologic factors, in addition to the classic nutrients. It exhibits extensive quantitative and qualitative variability depending on various maternal factors such as immunologic exposure,^11-12 diet,^13-15 nutrient supplement,^14,16-17 geographic region^18-19 and even smoking.²⁰ Its composition varies greatly from antepartum period²¹ to after extended periods of lactation for six months or more.^15,19,21-24 It also may exhibit diurnal variability,²⁵ and differences may exist between breasts²⁶ and during a feeding.^26-27 The duration of pregnancy also may influence human milk composition at least during the early weeks after onset of lactation.^28-32 Many components of human milk can be present in its free form, in a complexed or chelated form, or "packaged" in various physical or chemical forms.^{2,7,11,12,14,33-34}

The composition of colostrum also differs from the milk secreted once lactation is established. Compared to mature milk, it is generally produced in lower volumes but also contains numerous nutrients, hormones, immunologic and growth factors. It has higher content of protein specifically immunoglobulins, and electrolytes but lower fat content.^{2,7,11,29,33-35}

In mature human milk, the lipid fraction is quantitatively the most variable among the energy-yielding constituents. The total fat content of a 24 hour sample of milk may vary among individuals from <2 g/dL to >5 g/dL.³⁶ Its content may be doubled at the end of a feed.^26-27 However, the average fat content of milk secreted on day seven of lactation for a particular woman was found to be predictive of the amount in later lactation.³⁷ The fatty acid content of the milk also may vary with the maternal diet.¹⁵ Longitudinal studies of adequately nourished mothers in developed countries over 12 months of lactation show milk lipid concentration and energy density are highly correlated with maternal percent of ideal weight, whereas this relationship was less striking for protein and lactose. The mean energy density and macro-nutrient content varied by <10% during the first year despite a 40% decrease in the volume of milk secreted and consumed by the end of one year.²² Other reports of longitudinal changes in human milk composition over at least six months of lactation show that the content of many nutrients including protein, chloride and calcium remained stable or decreased by <15%, whereas sodium and potassium decreased by >20%.²¹ Phosphorus was stable²¹ or decreased by about 27%.²³ Lactose and glucose were stable or increased by <10%^21,22 and ionized calcium increased by about 15%.²¹ Variability in human milk vitamins^14,16-17 electrolytes,^21,29 trace minerals,^24,27 fatty acids¹⁵ and immunologic factors^11-12 also have been reported.

Most well nourished women breast feeding single infants produce 700-900 ml per 24 hours^21-22,34,38 although an average milk yield of >1100 mL per 24 hours has been reported.38 Mothers breast feeding twins can produce >2100 mL of milk per 24 hours.³⁸ Good maternal nutritional status may be associated with higher milk production, ²² and whereas, smoking lowers milk production.²⁰

Growth pattern of exclusively breast fed infants differs somewhat from the widely used growth charts based on predominantly formula fed Caucasian infants. In general, breast fed infants from affluent populations grow at a comparable rate to formula fed infants during first two to three months; whereas, length and head circumference gain is comparable but weight gain is significantly slower in breast fed infants between three to 12 months.^39-40 This was a result of lower energy intake in the breast fed cohort from self regulational. The milk production remains adeqate to meet the energy requirement of healthy infants based on the measurement of individual total daily energy expenditure and energy deposition derived from total body fat and fat free mass gian.⁴² The slower weight gain was not associated with any adverse functional outcomes with regard to motor development, activity, or morbidity.⁴³ More appropriate growth charts are being generated for breast fed infants.^39,40

For healthy breast-fed infants, no supplements (water, glucose water, formula and so forth) are needed during the first six months.^4,5,7,44 However, in the exclusively breast fed infant, vitamin D supplement at 400 IU/day is safe and avoids the concern for vitamin D insufficiency from lack of sunlight exposure associated with cultural practices or living at high latitudes.^5,45 It is important to be aware that vitamins B1 and B12 deficiency have been reported in breast fed infants of strict vegetarian mothers^5,13 and appropriate counseling and management are needed.

Despite the support for breast-feeding, a recent survey reported 59.4% of women in the USA were breast-feeding either exclusively or in combination with formula feeding at the time of hospital discharge, only 21.6% of mothers were nursing at 6 months; and many of these were supplementing with formula.⁴⁶ Numerous obstacles to successful breast-feeding are reported. However, higher education of the mother and society's acceptance and support may be the best means to t crease the rate and duration of breast-feeding.^1,4,47-48

There are several specific contraindications to breast-feeding, for example, the infant with galactosemia, the infant whose mother uses certain illicit drugs such as cocaine, heroin, amphetamine and phencyclidine, has highly infectious maternal illness such as untreated active tuberculosis, and in developed countries, mothers with the human immunodeficiency virus (HIV) infection.^4,49 The World Health Organization (WHO) has recommended that mothers residing in areas where infectious disease and malnutrition are an important cause of mortality early in life should be advised to breast feed their infants regardless of the mother's HIV serologic status.⁵⁰ There are only a few therapeutic medications when taken by the mother result in absolute contraindication to breast-feeding. These include radioactive isotopes, antimetabolites and cancer chemotherapy agents. Resources are available to determine the advisability of breast-feeding with specific maternal medications.^51-52

Transmission of environmental or industrial pollutants^53-54 and adverse dietary components⁵⁵ through the breast milk is well known. Occasionally these situations may lead to adverse clinical consequences.^53,56 It is advisable to be vigilant to this possibility.

Other situations normally not a contraindication to breast feeding include multiple birth, breast-milk jaundice, diarrhea, and hemorrhagic disease of newborn. Most women can successfully breast feed twins.^2,7,38 Both infants may be fed simultaneously or sequentially. Additional counseling and support are usually needed to initiate and maintain successful breast-feeding for multiple births. True breast milk jaundice generally does not occur until the milk flow is established at 4-5 days and frequent breast feeding actually lowers serum bilirubin.⁵⁷ Discontinuation of human milk and feeding with infant formula for 2-3 days, while maintaining the mother's milk supply with a manual or mechanical pump, is probably the easiest method for the diagnosis and treatment of breast milk jaundice. Other approaches include continuing breast-feeding with or without phototherapy⁵⁸ may necessitate an overall greater number of tests and monitoring. Diarrhea is often wrongly diagnosed in the breast fed infant by health workers unaware of the wide range of normal stool frequency and fluidity in healthy breast fed infants, particularly in the first weeks. There is no reason to stop, even temporarily, breast feeding of an infant who has diarrhea^2,59 particularly in developing countries, since breast milk substitutes when prepared inappropriately or under suboptimal hygienic situations is frequently the cause of diarrhea in the first place. Transient vitamin K deficiency with hemorrhagic manifestations is rarely observed in full term infants. Vitamin K levels in breast milk depend on maternal intake in the last stage of pregnancy.¹⁷ However, this is easily preventable by the standard practice of intramuscular or oral administration of vitamin K to the infant at birth.^2,16

Failure to thrive and hypernatremia are generally a manifestation of unsuccessful breast feeding primarily associated with the lack of post hospital discharge support in women who never previously breast fed.^60-61 The infant appears fretful or lethargic but also may be contented. This problem is largely avoidable through counseling of mothers, good support system and proper follow-up.

B. Infant formula

The development of substitutes for human milk has become an integral part of the history of pediatrics since many women for various reasons could not breast feed their infants. In many developed countries and increasingly in developing countries, most mothers do not exclusively breast feed their infants beyond 6 months.⁴⁶ Thus safe and efficacious human milk substitutes must be available for infants who are not being breast fed.

Human milk is the standard with which all infant formulas are compared. However, infant formulas are unable to mimic the natural variability in the nutrient composition and the numerous non nutritive components present in the human milk. Qualitative similarity between infant formulas and human milk is limited to few components, for example, lactose as the carbohydrate source in standard cow milk-based infant formula and human milk. Qualitative differences in the basic composition even for the same class of nutrients, for example, the protein and amino acid composition^5,62 and lipid class distribution and fatty acid composition⁶³ of human milk differ markedly from infant formulas. Similarity between these milks exists almost exclusively with respect to the overall quantity of nutrients after taking into account the difference in absorption and utilization between these forms of milk. Nevertheless, in affluent societies, formula fed infants may have physical growth exceeding of breast fed infants.^39-40 The neurodevelopmental advantage of human milk fed infants under these circumstances is not well defined since it is intimately related to socioeconomic and familial variables.^64-65 Some infant formulas are being fortified with additional components found in human milk, for example, nucleotides,⁶⁶ n3 and n6 long chain polyunsaturated fatty acids (LCP)^67-68 but definitive clinical benefits remain to be defined. It is possible that some of the putative benefits of the non-nutritive substances in human milk may be elicited from- and perhaps may be of lesser importance than- the metabolic and hormonal changes induced by process of enteral feeding.^69-72

In USA, the nutrient levels of the formula as required by the Infant Formula Act in 1980 with revisions in 1985⁷³ are listed in Table I.⁷⁴ These values were predominantly aimed to prevent the deficiency states, and as yet there are only relatively few recommendations for upper limits of the nutrients.⁷⁵

Infant formulas are available in three forms: ready to feed, concentrated liquid, or powder. The latter two preparations need to be reconstituted with boiled water. The utensils should be cleaned and terminally sterilized by soaking in commercially available mild antiseptic solution, by electric sterilizer, or by boiling for five minutes.^3,5 Tap water or commercially available bottled water is not free from contamination and should be boiled prior to reconstitution of infant formulas.

Commercially available formulas for use in term infants normally have an energy density of 67 kcal/dL. They have many similarities but also differ significantly from each other even for formulas made from same base source e.g., milk- or soy- protein isolate.⁷⁶ However, functional significance of the compositional differences among infant formulas in the same class is not fully understood.

Infant formulas are based on two major protein sources: cow milk and soy protein. Cow milk based formulas are either casein or whey predominant. In addition, casein or whey hydrolysate based preparations are being promoted as "hypoallergenic" formulas for infants. The lipid content is primarily provided as some combination of milk fat; palm, coconut, sunflower, corn and soy oils; with or without added lecithin. The carbohydrate source is normally lactose. However, some manufacturers have added maltodextrin or substituted lactose with corn syrup solid. Almost all nutrients are contained in formulas at higher concentrations than in human milk to compensate for the possible lower bioavailability of nutrients from infant formula. Details on the extensive manufacturing processes involved in the commercial production of infant formulas, rationale for the fortification of other nutrients, and detailed composition of infant formulas used for term infants have been reported.^74,76-77 The industry practice of overage is the fortification of certain nutrients particularly vitamins, to levels well above that specified on the label to compensate for the potential loss during processing or storage.⁷⁴ Thus some nutrients in infant formulas may be present well in excess of infant's need depending on the duration between manufacturing and consumption. The content label generally reflects the minimum content of nutrients for a specific product. Studies using lower nutrient contents in infant formulas are being done.⁷⁸

Soy proteins have low methionine content and all soy formulas are fortified with L-methionine. The fat blend in soy formulas are similar to milk based formulas. The carbohydrate source is sucrose with or without corn starch hydrolysate. Minerals and vitamins are added to soy formulas generally in amounts greater than milk based formulas to compensate for possible lower bioavailability. For example, calcium (Ca) and phosphorus (P) content are higher to compensate for their lower absorption from phytate content of soy. Taurine and carnitine also are added to soy formulas. Soy formula is indicated in galactosemia and documented lactose intolerance. It is also used if parents seek a vegetarian-based diet for term infants. There is no proven value of soy protein-based formulas in atopy and infantile colic. Despite the limited indications for the use of soy formulas, about 25% of the infants in USA receive these formulas.⁷⁹ Reports of decreased bone mineralization in infants fed older formulations of soy formula have been resolved with resuspension and adjustment of Ca and P content.^80-81

Protein hydrolysate formulas consist of free amino acids and peptides of varying length depending on the extent of hydrolysis. Fortification with amino acids is needed to compensate for those lost during the manufacturing processes. The fat blend frequently contains medium chain triglycerides to facilitate absorption of fat. Carbohydrate sources include various combinations of sucrose, tapioca starch, corn syrup solids and corn starch. They may be useful in preventing or delaying atopy since the more extensive the hydrolysis, the more reduced the antigenicity. Infants with documented cow milk protein-induced enteropathy or enterocolitis should be started on hydrolyzed protein or synthetic amino acids based formulas, as these infants are frequently sensitive to soy protein-based formulas.^82-83 However allergenic response to both casein-^83-84 and whey-based⁸⁴ formulas have been reported.

All standard infant formulas are designed to meet the nutrient needs of healthy infants at an intake of about 150 ml/kg/day. Infants fed iron fortified formulas do not require supplementation of any nutrients at least for the first six months after birth.^5,85 Newborn infants normally tolerate an intake of 30-60 mL/kg/day divided into about 8 feedings and gradually increasing the volume until full feeding is achieved within the first few days after birth. Thereafter the frequency of feeding would be similar to that of breast-fed infants and the volume of intake adjusted to infant's appetite. Most infants are satisfied with a daily intake of 750 to 1000 mL during the first six months.

Cow milk, skim milk, 1% or 2% fat milk, and evaporated milk formulas are nutritionally inadequate and can be associated with increased occult blood loss and are not recommended for use by infants.^5,86

Composition of formulas designed to meet unique nutritional needs e.g., inborn errors of metabolism may differ substantially from the composition of human milk, since infants requiring these formulas may not be able to tolerate one or more of the components present in human milk or infant formulas.⁵

II. Preterm infants

Low energy stores, immature gastrointestinal, hepatic, renal and neurobehavioral functions make the preterm infant more vulnerable to nutritional problems. These issues are further compounded by increased risk for respiratory illness, bronchopulmonary dysplasia (BPD), infection, or necrotizing enterocolitis (NEC) and therapies directed towards them. The potential nutritional problems and the importance of initiating early complete nutritional support for preterm infants are listed in the Table II.⁸⁷ Significant growth delay over short term (until hospital discharge)⁸⁸ and persistence into childhood⁸⁹ is well documented for small preterm infants. The extent of growth delay is inversely related to birth weight and gestational age of the infant. Nutrient intake during first few weeks also may be crucial to subsequent neurodevelopment.^90-91

The goals of nutritional support in preterm infant are aimed at achieving growth comparable to normal fetus until term and thereafter comparable to infants born at term.^5,92-94 It is assumed that the extent to which developmental outcome is influenced by nutritional support is also being optimized with initiation of early complete nutrition support.

Healthy enterally fed preterm infants with birth weight >1500 g generally grow adequately with human milk or regular formula although calcium and phosphorus obtained from these sources are lower than the in utero accretion^5,92-94 at least during the immediate postnatal period. However, there are no reported adverse long term sequelae for otherwise healthy preterm infants with birth weight >1500 g breast fed or taking regular infant formula ad libitum.

The major concerns with nutrition support of preterm infants therefore applies primarily to very low birth weight (VLBW, <1,500 g) infants and those with higher birth weights but complicated postnatal course having diseases and therapies that might interfere with nutrient delivery and utilization.

There is no specific dietary therapy for the prevention or treatment of specific illness such as respiratory distress syndrome, BPD, patent ductus arteriosus (PDA), and NEC that frequently complicate the clinical course of preterm infants. Nutritional support should take into account the pathophysiology of the underlying disease process and the implication of the therapies that might interfere with nutrient delivery, absorption and utilization. While undernutrition appears to play a role in causation of BPD and earlier studies suggesting there is greater work of breathing in infants with BPD, the greater need for energy intake remains controversial.⁹⁵ Selective supplements e.g., protein, lipid and/or glucose polymer, electrolytes and minerals are widely used in VLBW infants. However, selective nutrient supplementation is generally inappropriate since all VLBW infants have greater need for multiple nutrients.^92-94 Thus, protein supplementation without adequate energy intake and vice versa results in suboptimal growth. Increased energy intake alone can result in weight gain but unless there is adequate intake of other nutrients, the resultant weight gain constitutes only glycogen and fat. Furthermore, carbon dioxide associated with fat synthesis can increase work of respiration⁹⁶ with deleterious consequences. Qverfeeding, particularly excessive energy intake, can occur even in critically ill subjects.⁹⁷ Steroid therapy to minimize the mechanical ventilatory support in preterm infants is associated with glucose intolerance, negative nitrogen balance and growth delay.^98-100 Chronic diuretic use may cause electrolyte and acid base disturbances, growth delays and disturbed bone mineralization. ¹⁰¹ For preterm infants with specific dietary needs such as inborn errors of metabolism, the nutritional support is further complicated by the additional needs of preterm infants as stated above.

Thus, nutrition support for preterm infants differ from that for term infants primarily in the quantity of nutrients needed to achieve the stated goals, and how best to deliver the nutrients to these infants until full oral feeding is established. The key to successful nutritional support for all preterm infants is the early provision of an adequate and balanced nutrient intake. It is not a matter of the infant being too sick or too small to receive nutrition support but is a matter of how best to deliver it.

A. Human milk

VLBW infants also are recommended to receive their own mother's milk for the same reasons as that for term infants. However, despite the relatively enriched milk from mother's delivering preterm (preterm milk, PTM), at least during the first few weeks after delivery,^28-32 it is significantly deficient in energy, protein, sodium, calcium, phosphorus, zinc, copper and perhaps other essential nutrients to allow the growing VLBW infants to achieve the tissue accretion comparable to in utero rate.^5,92,94 The delivery of very large volumes (average of >250 mL/kg/ day) of human milk to compensate the relative lack of nutrients¹⁰² may be impractical in terms of consistent maternal milk production and tolerance by the VLBW infant. Commercial milk fortifiers are available in liquid or powder form and it is designed to raise the nutrient content of PTM to levels similar to the preterm infant formulas.⁹² This practice allows the use of lower volumes to meet the nutrient requirements to achieve an adequate growth rate, usually at an intake of 150 - 200 mL/kg/ day of appropriately fortified PTM. The fortifier can be added to human milk within several days after initiation of enteral feeding and continued at least until hospital discharge. Lyophilized human milk has been used as a fortifier on experimental basis.¹⁰³ Pooled human milk should not be used because of concerns with erratic and low concentration of nutrients and concerns with transmission of infectious illnesses. Elemental iron supplement at 2 to 4 mg/kg/day (maximum 15 mg/day) beginning at about 1 month (until 12 months) is advisable for the VLBW infant.^5,92-94 There is no documented need to supplement other vitamins, minerals or trace metals in vigorous VLBW infants tolerating full enteral feedings of appropriately fortified PTM, since the levels of nutrients are similar to that in preterm infant formulas which contain adequate amounts of minerals and trace metals and possibly an excess of some vitamins.^92,104

Until the infant is able to feed directly from the breast, the expressed mother's milk can be fed to the infant by various means as described in section C below. The mother should be encouraged to express her breasts as soon as possible, preferably within 24 hours after delivery. Breast milk can be expressed manually or with the aid of mechanical or electric pumps depending on mother's preference. Many small preterm infants also are acutely ill and extensive support from family and professionals including physician, nurse and lactation consultant is often needed to initiate and maintain successful lactation in the mother. Details of storage and transport of expressed milk are provided elsewhere.^5,87,105-106

B. Preterm infant formula (PTF)

Infant formulas specifically designed for VLBW infants have been commercially available for more than a decade, and are widely used in NICUs. PTFs have wide ranges of nutrient content which mirror the wide range of recommended daily nutrient requirements as shown in Table III. This situation reflects the incomplete knowledge and regional and philosophical differences in the approach to nutritional support of VLBW infants.^92-94

Regional and philosophical differences in nutrition support of VLBW infants are probably best reflected in the amount of vitamin D and Ca and P content in PTFs.¹⁰¹ In North America, PTF generally contain much higher Ca and P and lower vitamin D content while the reverse is true for most formulas in Europe. Both types of formulas appear to be well tolerated and each has scientific and theoretical rationale for their use. However detail direct comparison is difficult since variations exist in multiple nutrients among different formulations even within the same region.

Nevertheless, some generalizations can be made for the nutrient content of PTFs. The major difference between PTFs and standard formulas for term infant is the greater macro- and micro- nutrient content of PTFs to meet the greater demand for the catch up growth of the prematurely born infant. A number of qualitative differences exist for the PTFs compared to term infant formulas. The proportion of whey: casein content at 60:40 ratio is present in all PTFs. The fat blend contains long-chain and mediumchain triglycerides in approximate weight ratio of 1:1, and carbohydrates include both lactose and glucose polymers in approximate weight ratio of 1:1. All other nutrients are added in amounts to meet the recommended nutrient requirements of preterm infants when fed at > 150 mL/kg/day. Early studies on supplementation of longchain polyunsaturated fatty acids including arachidonic acid (20:4n6) and docosahexaenoic acid (22:6n3) on visual and neurodevelopment outcome show promise¹⁰⁷ although VLBW infants has been shown to be able to synthesize LCP from their 18C precursors. ¹⁰⁸ Additional fortification with nucleotides¹⁰⁹ arginine,¹¹⁰ and glutamine¹¹¹ have been proposed or used experimentally.¹¹²

PTFs are usually available at two caloric densities (67 or 81 kcal/dL). The latter preparation contains all nutrients at 20% higher concentration than the former. At an intake of 150 mL/kg/day, PTFs currently available in USA tend to provide most nutrients at the upper range of recommended intake whereas most PTFs in Europe tend to provide the mid- or lower- range of nutrient intake.⁹² Preliminary data suggest that the upper range of the current recommendations may provide some nutrients in excess of the needs of some preterm infants.¹⁰¹ In addition, hypercalcemia with and without documented hypervitaminosis D has been reported in infants given vitamin D supplement at 400 IU/day as vitamin D alone or as a part of multivitamin preparation while receiving PTF with high Ca and P or fortified PTM.^101,113 Thus, it is probably reasonable that only iron supplementation, as for those fed fortified PTM, is indicated in the thriving preterm infant receiving full enteral feedings of PTF with high Ca and P.

Soy protein-based formulas are not recommended for preterm infants with birth weights of <1800g.⁷⁹ The major drawback being the low mineral content and inadequate mineral absorption. The plasma levels of tyrosine, phenylalanine, tryptophan and cystine are lower and that of threonine is higher in these infants when compared to those fed on cow milk based preterm formulas.

Formulas containing highly modified macronutrients such as extremely hydrolyzed protein, high proportion of medium chain triglycerides, and glucose polymers as the sole source of carbohydrate, theoretically improves the absorption of these nutrients. However, all formulas with protein hydrolysate contain inadequate or imbalanced amounts of most nutrients to meet the needs of VLBW infants. VLBW infants receiving these formulas may have significantly higher plasma threonine, lower plasma tyrosine, phenylalanine, tryptophan and cystine, lower nitrogen absorption and retention, and lower phosphorus absorption compared to infants fed PTF.¹¹⁴ The use of commercially available protein hydrolysate formula even at an increased caloric density to resemble that provided by the PTFs still cannot meet the nutrient requirements recommended for these infants.

There is no nutritional advantage to the use of diluted human milk or formula. All undiluted PTF and fortified PTM are isotonic and are shown to be well tolerated in studies generated over the past ten years.¹⁰¹ Even in situations of decreased gut mucosal surface or enzyme activity, it is more appropriate to use small volumes of undiluted fortified PTM or PTF as tolerated with supplemental parenteral nutrition rather than the use of soy or hydrolyzed protein formulas.

C. Methods of enteral feeding

Enteral feeding can be initiated even during the periods of acute illness once the infant is hemodynamically stable. Mechanical ventilation, indwelling umbilical catheters, and medications such as inotropes and sedatives are not absolute contra-indications to enteral feeding. The choice of quantity, route, and schedule of feeding should be individualized on the basis of infant's gestation, birth weight, clinical status and tolerance to feeding. Trophic or minimal enteral feeds¹¹⁵ averaging <10 mL/kg/day even in infants with concomitant illness during first few days after birth are shown to enhance the circulating gastrointestinal hormones and potentially improve the growth and function of the gut.^{69-71,115-116} Feeding with undiluted human milk or PTF starting at 10-30 ml/kg/day with gradual increments of 10-30 ml/kg/day until full enteral feeding appears safe and is generally associated with minimal or absence of gastric residual or abdominal distension. Lower initial volume and smaller increments are more appropriate for very small infants and infants after prolonged periods of bowel rest e.g., post NEC, whereas higher initial amounts and increments are more appropriate in larger healthy preterm infants. Consistent growth is possible for VLBW infant fed appropriately fortified PTM or PTF at an intake of 150-200 mL/kg/ day. Fluid intake in VLBW infants may be increased due to increased insensible water losses but also may need to be lowered for example, in the presence symptomatic PDA.

In general, gavage feeds are indicated in infants with poor suck/swallow reflex or mild respiratory distress.^87,117-118 5 Fr catheter is often used as anchored indwelling catheter through nasogastric route to minimize occlusion of nares. 5 Fr or 8 Fr catheters can be used for intermittent gavage feeding or anchored indwelling oro-gastric catheters. Nasogastric tubes are better secured but they can increase the work of breathing in small preterm infants and may occlude the nares.^87,119 Correct tube placement minimizes the complication of the dislodgment of feeding tube and potential for aspiration. Polyvinylchloride catheters should be changed every 24 - 48 hours, whereas the silastic and polyurethane catheters are preferred if a feeding tube is to be left in situ for >72 hours.

The advantages of continuous gavage feeding delivered by constant rate infusion pump compare to bolus feeding include better tolerance and less gastric distension, lower energy expenditure, less airflow obstruction and less respiratory instability; the disadvantages being the potential for increased gastroesophageal reflux, risk of catheter dislodgment and aspiration. Bolus gavage feedings at q 1-3 hours are simple and less time consuming. Clinically stable and gestationally more mature preterm infants may tolerate bolus feeds at longer intervals. However bolus gavage feeds may be associated with more frequent episodes of abdominal distension, increase in gastroesophageal reflux and feeding intolerance. Transpyloric feeding has no convincing evidence to support its use in NICU. Gastrostomy tube (G-tube) placement is indicated in some infants with severe impairment of swallowing, esophageal obstruction, neurological handicap and failure to thrive. G-tube placement involves surgical procedure and is not free of complications.^87,120

All infants receiving gavage feeding should be monitored regularly for any gastric residuals, bilious aspirates, diarrhea, abdominal distension, bloody stools, respiratory distress, apnea and any signs of infection. If any of these are seen, the feedings should be stopped and appropriate management initiated to correct the problem.

Nursing the infants in the side or prone position with elevation of head of the bed, using smaller volumes but more frequent bolus feeds, increasing the duration of each feed or revert to continuous infusion may be helpful in improving the tolerance of the feeds.^87,117-118 To ensure the best delivery of fat when continuous infusion is used, the feeding syringe should be oriented with the tip upright, the syringe emptied completely after each use, and the shortest amount of tubing used.

Non-nutritive sucking while being gavage fed has been reported to accelerate sucking reflex, weight gain and decrease in the length of hospital stay.¹²¹ Gradual transition to oral feeding is dictated by the development of coordination of sucking, swallowing and breathing that frequently begins at 32-34 weeks of gestation. Experienced nurses are often the professionals who first note the ability of infants to begin oral feeding and with whom much of the "art" of feeding still exists.

D. Post Discharge Feeding and Monitoring

With the increasing practice of early hospital discharge, most preterm infants are still exhibiting marginal nutritional status and growth at the time of discharge. Some clinicians advocate continued use of fortified PTM and iron supplementation or PTF with iron as described above until the infant reaches 3 to 3.5 kg or at least until term corrected post menstrual age,⁸⁷ because of the relative low energy density and low concentration of most nutrients in human milk and regular infant formula.

Preliminary data indicate there may be short term benefit in weight gain and biochemical nutritional indices if VLBW infants continue to receive fortified milk.^122-124 However, the role of maturational status versus dietary effect on nutritional biochemical measurements remain unknown.^125-126 Thus, the practice of continue feeding with fortified PTM or PTF after hospital discharge remains controversial for a vigorous preterm infant feeding breast milk or standard iron fortified infant formula ad libitum. Iron and possibly standard commercial multivitamin supplement are needed for preterm infants fed human milk alone.

Post-discharge premature infant formulas with nutrient contents between PTF and term infant formula have been introduced both in Europe and the United States recently to support the catch up growth beyond term post menstrual age. This is based on the assumption that the nutrient requirement of preterm infants after hospital discharge may be less than that delivered from preterm infant formula but more than that provided by formulas intended for term infants. Studies on their clinical benefits are being actively pursued.

Solids can be introduced after 4 to 6 months corrected age and should follow the recommendations for term infants.

Monitoring of growth remains essential for all preterm infants after hospital discharge. This includes plotting the growth measurements after adjusting for prematurity on standard growth charts for term infants. Specific laboratory monitoring of growth and body composition, such as dual energy X-ray absorptiometry, remains investigational.

Parenteral Nutrition (PN)

PN is one of the major advances in neonatal medicine and can be used successfully for prolonged periods.^127-128 It is important to recognize that the technique of PN is deceptively simple and yet there are vast gaps in our knowledge on this mode of nutrition support and it is not entirely free of side effects. The earlier concept to individualize the PN solution for the needs of each child is a gross simplification on the extent of information needed for this purpose. Therefore, the most practical approach is the use of a few stock solutions with minimal manipulation of the nutrient content once the desired nutrient and fluid goal is achieved.⁸⁷ Successful PN is achieved only by rigorous attention to infant's needs, understanding the potential interference to nutrient delivery and utilization from underlying disease and its treatment, and constant monitoring with prevention or correction of potential side effects associated with PN therapy.

PN is indicated for infants who cannot or should not be fed, for example, major gastrointestinal tract anomalies or diseases that interfere with successful delivery, digestion, or absorption of enteral nutrients. In addition, any infant who is not expected to tolerate adequate amounts of enteral feeding for more than two to three days should receive PN support to minimize the adverse impact of obligatory nitrogen loss.^128-131 In general, the sicker and smaller the infant, the greater is the stress on the minimal nutritional reserve and the greater is the need for nutrition support. Thus PN should be initiated during first 24 hours after birth in these circumstances.

There is no place for dextrose electrolyte infusions for infants except during the few hours needed to prepare the PN infusate. Furthermore, it is critical to be aware that even at an infusion rate of 1 mL/hour, the volume infused is equivalent to 48 mL/kg/day for a small preterm infant weighing 500 g. This is equivalent to about one third of the daily fluid intake; thus a major source for the delivery of nutrients would be wasted with the use of dextrose electrolyte solution. Therefore, it is critical to maintain PN solution in infants with birth weight of <1000 g even at the minimum infusion rate. Enteral feeding should be initiated as soon as possible according to the clinical condition and increased as outlined earlier in this review. Early use of enteral nutrient support at whatever level the infant can tolerate is also critical to the successful weaning of the infant from PN.

There are many differences between PN and EN including the type and quantity of nutrients and the potential complications that are unique to PN. Nutrient requirements for PN are based on the data from enteral nutrient intake, mass balance studies, quantitative tissue measurements, e.g., bone mineral content, and functional and metabolic status of the infant. However, detailed information is lacking in all these aspects for each nutrient. In general, parenteral requirement for some nutrients may be 10 to 20% less than that for enteral nutrient (Table III) since PN eliminates the digestive and absorptive losses associated with enteral intake.

A. Nutrients

Qualitative difference in protein sources exists between PN and EN. Synthetic crystalline amino acids are normally used in PN compared to whole protein in human milk and infant formulas. Current preparations of amino acid solutions are based on the amino acid profiles of breast fed infants and human milk¹³² and are effectively utilized.^{129,131,133-137} Certain amino acids include taurine, cysteine, histidine and possibly arginine are considered as conditionally essential amino acids and are present in pediatric amino acid formulations. The addition of cysteine (40 mg/g of amino acid) also enhances the solubility of calcium and phosphorus. Preparations with other sources of nitrogen including dipeptides are being used experimentally.¹³⁸

The current amino acid preparations are well utilized as indicated by standard nitrogen balance studies^129,139 and by stable isotope studies.^{129,131,133-136} The protein gain is linearly related to protein intake extending over a range of net protein intakes from 2 to 4 g/kg/day.¹³⁹ Generally, a lower intake of 2-3 g/kg/day results in nitrogen retention comparable to that observed in enterally fed infants, although higher protein intakes of about 4 g/kg/day may be needed for the smallest preterm infants with gestational age <28 weeks.^{128-129,139-140} Metabolic complications with parenteral protein intake include hyperammonemia, acidosis and azotemia are less frequent with current amino acid preparations compared with older protein hydrolysate preparations. However, these complications still can occur with excessive intake particularly in the sick infant with hepatic and/or renal dysfunction.

Supplementation of specific amino acid for a particular reason, for example, adding glutamine up to 25% of total protein intake from PN to facilitate its role as the primary fuel for rapidly dividing cells is being studied.¹⁴¹ However, glutamine supplementation in animals even at < 10% of total protein intake is associated with increased extra fluid rather than gains in lean tissue mass¹⁴² and has potential neurotoxicity. ^143-144 The use of growth factors and hormones during nutrition support remains experimental.¹⁴⁵ The role of salvaged urea nitrogen for further metabolic interaction and its influence on protein requirement remains to be defined.¹⁴⁶

The energy requirement during PN is 10 - 20% lower than during EN. Consistent nitrogen accretion and weight gain can occur at an energy intake of about 70 kcal/kg/ day and a protein intake of about 2 g/kg/day, although small preterm infants often require greater energy and protein intake to achieve "in utero" rate of tissue accretion.^{128-129,139-140} With suboptimal energy intake, the endogenous protein is used as an energy source resulting in negative nitrogen balance whereas higher energy intake results in sparing of the endogenous protein from tissue catabolism and in the optimal utilization of the exogenous protein for lean tissue gain.^131,140 However, excess energy intake (>120-130 kcal/kg/day) is probably associated with increased fat deposition and possibly worsening of any underlying respiratory illness because of increased carbon dioxide release from fat synthesis.^96-97,140

Dextrose is the only freely available carbohydrate source for use in PN. The major drawback of its use is its hyperosmolarity and requires centrol venous access when used at a concentration of >12.5%. During periods of acute stress, e.g., sepsis or steroid therapy, infusion of dextrose at a much lower concentration of 3 to 5% may be needed to avoid hyperglycemia. Insulin has been used to treat persistent hyperglycemia¹⁴⁷ but caution is required to avoid hypoglycemia. Insulin administration does not improve overall nitrogen accretion and is associated with lactate accumulation and metabolic acidosis¹⁴⁸ thus routine use of insulin to enhance growth is not recommended. High glucose intake from PN results in increased carbon dioxide production as early as first few days after birth. When the glucose intake is >18 g/kg/day i.e., from an infusion of 15% dextrose at 120 mL/kg/day, the non-protein respiratory quotient was consistently >1.0 indicating fat synthesis and carbon dioxide release.⁹⁶ Addition of lipid optimizes nitrogen utilization without further increase in carbon dioxide production¹⁴⁹ and allows the use of lower dextrose load in PN. The use of PN potentially can provide two additional sources of gluconeogenic substrates, i.e., amino acids and fatty acids. Yet another potential benefit of PN is the inclusion of vitamins such as thiamine and trace elements such as chromium, both of which are critical to carbohydrate metabolism and may improve the tolerance to dextrose.

Lipid emulsions available in USA are from soy or a mixture of soy and safflower oil. They contain primarily triglycerides with linoleic and linolenic acids. Current commercial lipid emulsions are available in 10% and 20% concentrations. The 20% emulsion is more caloric dense without additional phospholipid content. Thus, the risk of hypercholesterolemia and hyperphospholipidemia is lower at the same infusion rate with the use of 20% versus 10% lipid emulsion.^150-151 Mixtures of long- and medium-chain triglyceride emulsions are available in Europe and have some theoretical advantages for metabolic utility. However, soy emulsions have been in use for more than 30 years and there is no definitive study to support the use of one preparation of lipid over another. In addition, none of the lipid preparations appear to maintain the normal intrauterine accumulation of very long chain polyunsaturated fatty acids of the n-3 and n-6 families in developing infant tissues.

Lipid emulsion can be given on the first day of PN at 0.5 to 1 g/kg/day and increased at 0.5 to 1 g/kg/day up to a maximum of 3 to 4 g/kg/day while maintaining serum triglyceride at <200 mg/dL. Smaller increments and lower total dose may be prudent for acutely ill or very small preterm infants.⁸⁷ In the presence of adequate energy intake, a minimum intake of 0.5 to 1 g of lipid/kg/day is necessary to avoid essential fatty acid deficiency.

Jaundice and sepsis are not absolute contraindications to the use of fat emulsions. Lipid emulsions can be continued if the serum bilirubin level is controlled with phototherapy. The dose probably should be in the range of 1-2 g/kg/day if the serum bilirubin is more than half of the exchange level, and at the normal dose if serum bilirubin is less than 50% of exchange level. Continuous infusion of lipids over 18-24 hours allows better tolerance and minimizes the complications associated with excess rate and volume of lipid administration.

Carnitine plays an essential role in the metabolism of long chain fatty acids, although there seems to be no convincing evidence of clinical benefit in preterm infants following addition of carnitine to their parenteral lipid infusions. However, a supplement of about 2.4 to 4.8 mg (15-30 μmol) L-carnitine/kg/day, i.e., comparable to the amount provided by human milk and enough to support in utero rates of tissue accretion, may be appropriate for preterm infants receiving parenteral lipid.¹⁵² High intakes of 48 mg (300 μmol) L-carnitine/kg/day may be associated with increased metabolic rate, decreased fat and protein accretion and prolong the time to regain birth weight in preterm infants.¹⁵³

Electrolytes and minerals are usually added to PN solutions as sodium and potassium salts of chloride, phosphate, or acetate. The latter may be used as a source of base.¹⁵⁴ Salts of amino acids are another source of anions. Magnesium (Mg) is provided as hydrated magnesium sulfate. Ca is usually provided as 10% Ca gluconate. Simultaneous addition of Ca and P will result in precipitation of minerals and the salts should be added sequentially. The specific procedures for predicting and maximizing the maintenance of Ca and P in PN solution are well known to pharmacists. The recommendation of higher amino acid intake and addition of cysteine further enhance the ability of current PN solutions to maintain high Ca and P content.¹⁰¹

Incomplete knowledge of micronutrient and vitamin requirement in infants and the limited commercial potential are reflected in the relatively few commercial preparations, although the requirement of increasing number of trace minerals is becoming better defined.^155,156 Trace elements are commercially available individually or in combination. It has been stated that only zinc (Zn) is needed for "short" term PN,¹⁵⁵ however, many institutions routinely add most of the currently recommended trace minerals (Table IV) regardless of the expected duration of PN. Parenteral iron (0.2 to 0.4 mg/kg/day) as iron dextran should be considered if PN is provided exclusively for two months during infancy or if iron deficiency develops.^155-157

There is no commercial parenteral multivitamin preparation that provides the amount of recommended daily intake for infants (Table V). The currently recommended daily intake of multivitamin preparation (MVI pediatric®, Astra Pharmaceutical Products, Inc., Westborough, MA) 2 mL/kg up to a complete 5 ml vial for infants weighing >3 kg⁵ may provide excess of some water soluble vitamins¹⁵⁸ and inadequate amounts of some fat soluble vitamins (e.g., vitamin A) especially for preterm infants.¹⁵⁹

Nutrient content of PN solution may need to be adjusted particularly in very small and sick infant. This may be necessary because of limited ability of these infants to tolerate large volume of PN fluid and large intake of glucose, lipid and protein, although the major constraint to the delivery of adequate amounts of parenteral nutrient is in situations where severe fluid restriction is needed. The latter requires greater concentration of nutrient infusate thus resulting in extremely high osmolarity, and possibly exceeding the limits of solubility of calcium and phosphorus salts. In contrast, in situations of high fluid requirement (>200 mL/kg/day) in preterm infants with low renal thresholds for many nutrients, a diluted infusate must be provided to prevent delivery of excessive nutrients particularly the dextrose load. In this situation, the limiting factor is the ability to provide a dilute solution without being significantly hypotonic. Some flexibility in manipulating the tolerance to the volume infused can be achieved by manipulating the environmental factors. For example, caring for the neonate under a radiant warmer results in greater insensible fluid loss, thus allows the delivery of a larger volume of PN.⁸⁷

B. Delivery

A stepwise increase in the macronutrients over the first 3-4 days of PN therapy is needed to allow better metabolic adaptations to parenteral nutrient load. PN may begin with a volume of intake between 80-120 mL/kg/day, protein intake of 1 g/kg/day, carbohydrate concentrations of 5-10% dextrose (providing about 7 mg glucose load/kg min at an intake of 100 mL of 10% dextrose/kg/day) and lipid intake of 0.5 - 1 g/kg/day. PN nutrients should be adjusted over first two to three days according to fluid goal and the appropriate concentrations of dextrose determined depending on whether the PN solution is delivered via peripheral or central catheter. Normally, adequate amounts of parenteral nutrients can be delivered in a total daily volume of 120-160 mL/kg/day.^87,128

The dextrose/amino acid solution and lipid emulsion can be provided separately and delivered together through a Y connector via the peripheral or central venous catheter, or umbilical venous or arterial catheters. Some institutions deliver PN as a Total Nutrient Admixture (TNA), i.e., mixing all nutrient components in the same container. The disadvantages of TNA are that stability of each component of TNA is not completely defined, it is impossible to determine whether there is a precipitation of nutrients in the admixture,¹⁶⁰ and standard 0.22u bacterial filter cannot be used with TNA solutions. Correct position of all central catheters including umbilical catheters must be confirmed before the infusion of PN solution.⁸⁷

C. Complications and monitoring

Many potential complications directly related to the use of PN (Table VI) may be minimized by continual assessment of the infant's clinical status, the effect on nutrient tolerance and utilization from underlying disease and its therapy, and by intermittent systematic laboratory studies.⁸⁷ It is theoretically possible that problems may occur during the preparation of PN solution from component nutrient. However, this is unlikely to occur if the preparation of PN is done by hospital pharmacist or commercial companies adhering strictly to the standard practice guidelines.¹⁶¹

Catheter related complications, in particular extravasation associated with peripheral infusion, are the most frequent complications in PN. Some institutions add 1 to 2 units of heparin per mL of PN solution to prolong catheter life, but meticulous attention to catheter insertion, confirmation of proper position and good catheter care, even electively changing peripheral catheter after 48 hours of infusion can minimize the risk of catheter related complications. Urokinase, 0.1N hydrochloric acid, 70% ethanol have been used to clear the central venous catheters of thrombus, chemical e.g., calcium phosphate, and lipid related occlusions, respectively.⁸⁷ However, unless the occlusions are detected early, removal of the catheter may be the only option to minimize further complications such as occlusion of the superior vena cava or sepsis.

Excesses and deficiencies of circulating levels of almost every electrolyte, mineral and trace mineral have been described. They usually are seen with excessive, imbalance or inadequate intakes. Excessive intake is usually relative to the infant's ability to tolerate the amount of nutrient delivered particularly during stress and certain treatment, for example, steroid therapy for the weaning of infants from ventilator. These situations are usually accompanied by decreased tolerance even to the "normal" amount of nutrient. If there is associated impairment of metabolic and excretory capacities as in liver dysfunction, the currently recommended intake of certain trace minerals, for example, copper and manganese, may be in excess of the infant's needs and potential toxicity may occur. ^155,162

The classic scenario of metabolic complication from imbalance intake is the administration of PN solution containing low or no phosphorus.¹⁰¹ This results in hypophosphotemia, phosphate deficiency and secondary hypercalcemia. Another possible scenario is the attempt to replace gastrointestinal fluid loss with an increase in PN solution. This results in the delivery of grossly imbalance and usually excessive amounts of many nutrients including protein and carbohydrates. Appropriate replacement fluids should be administered via a separate line piggyback onto the PN infusion line.

Deficiencies of micronutrients and vitamins are rarely reported except in situations where one or more components are inadvertently omitted from PN or provided in a relatively inadequate amount.^155,163 Inadequate replacement of gastrointestinal fistula losses, for example, Zn¹⁶⁴ and Mg¹⁶⁵ is frequently responsible for their deficiency.

Contamination with trace minerals may have positive and negative results. There are increasing information on the physiologic role of certain trace minerals such as boron, although their exact requirements remain ill defined. Thus contamination with some trace minerals theoretically may have undefined benefits. With increasing availability of highly purified nutrient components for PN and the limited number of trace minerals being added to the final solution, the potential exists for relative and absolute deficiencies of as yet undefined micronutrient(s) in subjects on prolonged PN.¹⁵⁵ Aluminum (Al) toxicity is a potential complication of long-term PN although the benefits of current PN solutions outweigh the potential risks of Al toxicity.¹⁶⁶

Hepatic^167-168 and skeletal^169-171 complications are inversely proportional to birth weight and gestational age and directly proportional to the duration of PN. The best means to minimize these complications is the introduction of enteral feeding at the earliest opportunity. Once the complications have occurred, continued maintenance of optimal nutritional status and use of enteral feeds whenever possible, are the cornerstones to the continued management of these complications. Specific management of PN related cholestasis also include restricting nutrients that require hepatic excretion, e.g., copper and manganese; and the use of cholecystokinin, ursodeoxycholic acid and conjugated bile acid analogue such as cholesarcosine, is being done on an experimental basis.^167-168

Another potential problem for infants received prolonged PN from birth is refusal to feed. Potentially this may be minimized with non-nutritive suction and early introduction of oral feeds.^121,172

Intestinal mucosal atrophy¹⁷³ and bacterial translocation¹⁷⁴ have been reported in association with total PN. The extent of changes appear to be greater in animals than humans, although it seems a prudent measure to maintain optimal nutritional status with PN and/or EN, in addition to initiation of enteral feeding at the earliest opportunity to minimize these potential complications.

Certain laboratory tests are necessary for the successful use of PN (Table VII). However, the frequency and the type of tests may need to be adjusted depending on the duration of PN and the amount of EN tolerated.⁸⁷ In general, regardless of the duration of PN, laboratory tests can be significantly fewer if PN is used as a supplement to EN.

Supplemental Foods

From the stand point of nutritional needs, physiological maturation, and immunologic safety, the provision of foods other than breast milk or infant formula before about 4 months of age is unnecessary.^2,5 Supplemental foods serve as introduction to a variety of food sources and as a transition to the family's cultural dietary habits. Nutritionally, they supply nutrients that may be limiting to the growth in the exclusive milk diet of rapidly growing infant. Recommendations and practices of feeding solid foods to infants are widely divergent. There is no best type or amount of solids that should be given to infants during transition period until complete weaning, and the order of introduction is not critical. Infants are highly adaptive and will thrive as long as the foods provide safe access to adequate and bioavailable nutrient, and the environmental and feeding practices do not burden the immature immune systems with pathogens.^2,175-179

The desire of mothers to see their infants gain weight rapidly, the ready availability of convenient forms of solid foods and the mistaken assumption that added solid foods help the infant sleep through the night are some reasons for the earlier introduction of solid foods. Introducing solid foods too early may interfere with breast feeding success and potential for the development of allergies from greater exposure of antigenic substances. In contrast, the markedly delayed introduction of solids may be associated with difficulties in its acceptance¹⁸⁰ as a "critical period of development" is thought to exist with respect to the introduction of solids.

The introduction of solid foods to infants should be based on the infant's development processes. By 4-5 months of age, the extrusion reflex of early infancy has disappeared and the ability to swallow non-liquid foods has become established. By 5-6 months of age, the infant will be able to indicate a desire for food by opening his mouth and leaning forward, and to indicate disinterest or satiety by leaning back and turning away.^2,5,177 Until the infant can react in this manner, feeding of solid food supplements may represent a form of forced feeding.

The process of introducing solid foods should be a gradual one. They are first introduced as single-ingredient foods and started one at a time at weekly intervals to permit the identification of food intolerance. Single-grain, precooked, partially hydrolyzed cereals - particularly rice, which contains no gluten - are usually well tolerated and is a good choice for the first supplemental food given to infant. Cereal can be started at about 1/4 of a teaspoon increasing to 1 tablespoon for 2-3 feedings/day. It is mixed with enough milk to make a very thin mixture to be given by spoon and thickened as tolerated. Cereals should not be added to bottles except for medically indicated reasons, e.g., gastroesophageal reflux.⁵ Dry infant cereal diluted 1:6 by weight with milk provides 108 kcal/dL. It also provides additional thiamin, riboflavin, niacin, iron, calcium and phosphorus. An average of two servings (1/2 oz or 15g per serving) of dry cereal between 4 to 6 months of age can provide about 1 mg elemental iron/kg and is equivalent to the daily iron requirement.^5,181 Even though the cereal might taste bland, salt or sugar should not be added as these do not offer any additional benefits. Honey should not be given to infants because of the risk for botulism.¹⁸³

At six months of age, two to three tablespoons of food a day are sufficient. At seven to nine months, one or two solid feedings a day can be given and to include an increased variety of fruits and vegetables starting as a puree and increasing in bulk and consistency appropriate with the infant's ability to chew and swallow. By nine to twelve months, the infant is gradually introduced to a variety of table food consistent with familial and cultural diets. Parents should be instructed that helping infants learn new flavors and textures takes time, and infants often need several feeding opportunities to learn to accept and enjoy some foods.¹⁸⁴ In addition, parents should be prepared for a mess when the infant attempts self-feeding.

Meats and egg are excellent sources of iron and protein although egg white may trigger an allergic reaction. These foods are usually introduced to the diet during later infancy to minimize the risk of adverse response.

Babies like trying to hold foods themselves when they are around eight or nine months old. This is a good time to start "teething biscuits". They soften easily upon sucking and chewing and are usually fortified with vitamins and iron.

Juices can be introduced as soon as the infant can drink from a cup. Juices provide carbohydrate and vitamin C, but it can increase stool frequency and even diarrhea when consumed in large volumes (>300 mL/day for an infant).^5,182 However, juices or milk in bottles used as pacifier predisposes to nursing-bottle caries and is therefore discouraged.^5,179

Homemade foods can satisfy the needs of all infants and is the personal preference of many families. They usually contain few or no additives and may be prepared in the amounts appropriate for the baby's needs by using a blender or food processor. Large amounts also can be prepared and frozen in ice cube trays. When prepared in large quantities from table food, they can be considerably less expensive than commercial food.

A large variety of commercially prepared baby food is available and convenient to use. Most commercially prepared baby foods in USA contain no added salt, although sugar or corn syrup is added to some preparations of dessert, fruit or cereal. Single ingredient infant foods contain fewer additives than junior foods, which are more likely to have fillers and thickeners of questionable value. Compared to homemade foods, they are relatively more expensive and an amount of food may be far in excess of what is needed with risk of spoilage on storage.

The combination of vitamins A, C, D for infants (with vitamin E and/or iron as optional ingredients) was originally designed to complement home prepared formulas.⁵ There is no need for supplemental vitamins and minerals for infants receiving appropriate mix of human milk or iron fortified infant formula and receiving an increasing variety of supplemental foods beginning at 4 to 6 months of age. Possible exceptions include a daily supplement of 400 IU vitamin D to prevent vitamin D deficiency^5,45 for the healthy breast-fed infant living in northern latitudes or have cultural restriction to sunlight exposure. In addition, appropriate counseling is needed on how to provide caloric dense foods at the time of weaning for most vegetarian groups. This is to insure that increased bulk of vegetarian diets does not interfere with adequate consumption of energy, protein and other nutrients, to maintain adequate nutritional status in these infants. Infants in families adhering to highly restricted vegetarian diets is vulnerable for nutrition deficiencies during the weaning period, and specific supplement of selected vitamins and minerals may be needed for these infants.^5,185

References

1. World Health Organization. Protecting, promoting and supporting breast-feeding: the special role of maternity services. Geneva, Switzerland: WHO 1989:13-8.

2. Akre J, editor. Infant Feeding: The Physiological Basis. Geneva, Switzerland: Bulletin of World Health Organization. 1989 Suppl to vol 67.

3. The American Academy of Pediatrics and the American College of Obstetricians and Gynecologists. Guidelines for Perinatal Care, 3rd edition. Washington, DC: ACOG, AAP, 1997:279-93.

4. Work group on breast feeding, American Academy of Pediatrics. Breastfeeding and the Use of Human Milk. Pediatrics 1997;100:1035-9.

5. Committee on Nutrition, American Academy of Pediatrics. Pediatric Nutrition Handbook, 4th edition. Elk Grove Village, Illinois: AAP, 1998.

6. Simopoulos AP, deOliveira JED, Desai ID, editors. Behavioral and metabolic aspects of breast feeding. World Rev Nutr Dietetics 1995:1-194.

7. Lawrence R, editor. Breast feeding: a guide for the medical profession, 3 rd edition. St Louis: Mosby company, 1995.

8. Righard L, Elade MO. Effect of delivery room routines on success of first breastfeed. Lancet 1990;336:1105-7.

9. Powers NG, Naylor AJ, Wester RA. Hospital policies: crucial to breastfeeding success. Semin Perinatol 1994;18:517-24.

10. De Carvalho M, Robertson S, Friedman A, et al. Effect of frequent breastfeeding on early milk production and infant weight gain. Pediatrics 1983;72:307-11.

11. Goldman AS, Garza C, Nichols BL, Goldblum RM. Immunologic factors in human milk during the first year of lactation. J Pediatr 1982;100:563-7.

12. May JT. Microbial contaminants and antimicrobial properties of human milk. Microbiol Sci 1988;5:42-6.

13. Specker BL, Black A, Allen L, Morrow F. Vitamin B12: low milk concentrations are related to low serum concentrations in vegetarian women and to methylmalonic aciduria in their infants. Am J Clin Nutr 1990;52:1073-6.

14. Ala-Houhala M, Koskinen T, Parviainen MT, Visakorpi JK. 25-hydroxyvitamin D and vitamin D in human milk; effects of supplementation and season. Am J Clin Nutr 1988;48:1057-60.

15. Makrides M, Simmer K, Neumann M, Gibson R. Changes in the polyunsaturated fatty acids of breast milk from mothers of full-term infants over 30 wk of lactation. Am J Clin Nutr 1995;61:1231-3.

16. Greer FR, Marshall SP, Foley AL, Suttie JW. Improving the vitamin K status of breastfeeding infants with maternal vitamin K supplements. Pediatrics 1997;99:88-92.

17. Gleason WA, Kerr GR. Questions about quinones in infant nutrition. J Pediatr Gastroenterol Nutr 1989;8:285-7.

18. Gebre-Medhin M,Vahlquist A, Hofvander Y, Uppsall L, Valquist B. Breast milk composition in Ethiopian and Swedish mothers: I, vitamin A and β-carotene. Am J Clin Nutr 1976;29:441-51.

19. Prentice A, Jarjou LMA, Cole T, Stirling DM, Dibba B, Fairweather-Tait S. Calcium requirements of lactating Gambian mothers: effects of a calcium supplement on breast milk calcium concentration, maternal bone mineral content, and urinary calcium excretion. Am J Clin Nutr 1995;62:58-67.

20. Hopkinson JM, Schanler RJ, Fraley JK, Garza C. Milk production by mothers of premature infants. Influence of cigarette smoking. Pediatrics 1992;90:934-8.

21. Allen JC, Keller RP, Archer P, Neville MC. Studies in human lactation: Milk composition and daily secretion rates of macronutrients in the first year of lactation. Am J Clin Nutr 1991;54:69-80.

22. Nommsen LA, Lovelady CA, Heinig MJ, Lonnerdal B, Dewey KG. Determinants of energy, protein, lipid, and lactose concentrations in human milk during the first 12 months of lactation: the DARLING study. Am J Clin Nutr 1991;53:457-65.

23. Greer FR, Tsang RC, Levin RS, Searcy JE, Wu R, Steichen JJ. Increasing serum calcium and magnesium concentrations in breast-fed infants: longitudinal studies of minerals in human milk and in sera of nursing mothers and their infants. J Pediatr 1982;100:59-64.

24. Vuori E, Kuitunen P. The concentrations of copper and zinc in human milk. A longitudinal study. Acta Paediatr Scand 1979;68:33-7.

25. Hytten FE. Clinical and chemical studies in human lactation. III. Diurnal variations in major constituents of milk. Br Med J 1954;1:179-82.

26. Hytten FE. Clinical and chemical studies in human lactation. II. Variation in major constituents during a feeding. Br Med J 1954;1:176-9.

27. Fransson GB, Lonnerdal B. Calcium and magnesium in human milk. J Pediatr 1982;101:504-8.

28. Gross SJ, Geller J, Tomarelli RM. Composition of breast milk from mothers of preterm infants. Pediatrics 1981;68:490-3.

29. Koo WWK, Gupta JM. Breast milk sodium. Arch Dis Child 1982;57:500-2.

30. Lemons JA, Moye L, Hall D, Simmons M. Differences in the composition of preterm and term human milk during early lactation. Pediatr Res 1982;15:113-7.

31. Anderson GH. The effect of prematurity on milk composition and its physiological basis. Fed Proc 1984;43:2438-42.

32. Schanler RJ. Human milk for preterm infants. Nutritional and immune factors. Sem Perinatol 1989;13:69-77.

33. Jensen RG. Handbook of milk composition. San Diego: Academic Press, 1995.

34. World Health Organization. The quantity and quality of breast milk. Report on the WHO Collaborative Study on Breast-feeding. Geneva, Switzerland, WHO 1985.

35. Ferlin MLS, Santoro JR, Jorge SM, Goncalves AL. Total nitrogen and electrolyte levels in colostrum and transition human milk. J Perinat Med 1986;14:251-7.

36. Hytten FE. Clinical and chemical studies in human lactation. V. Individual differences in composition of milk. Br Med J 1954;1:253-5.

37. Hytten FE. Clinical and chemical studies in human lactation. IV. Trends in milk composition during course of lactation. Br Med J 1954;1:249-53.

38. Hartmann PE, Prosser CG. Physiological basis of longitudinal changes in human milk yield and composition. Fed Proc 1984;43:2448-53.

39. World Health Organization working group on infant growth. An evaluation of infant growth. Geneva: Nutrition unit, World Health Organization, 1994.

40. Dewey KG. Cross-cultural patterns of growth and nutritional status of breast-fed infants. Am J Clin Nutr 1998;67:10-7.

41. Dewey KG, Heinig J, Nommsen LA, Lonnerdal B. Maternal versus infant factors related to breast milk intake and residual milk volume: The DARLING Study. Pediatrics 1991;87:829-37.

42. deBruin NC, Degenhert HJ, Gal S, Westerterp KR, Stiznen T, Visser HKA. Energy utilization and growth in breast fed and formula fed infants measured prospective during the first year of life. Am J Clin Nutr 1998;67:885-96.

43.Dewey KG, Heinig MJ, Nommsen LA, Lonnerdal B. Adequacy of energy intake among breast-fed infants in the DARLING study: relationships to growth velocity, morbidity and activity levels. J Pediatr 1991;119:538-47.

44. Goldberg NM, Adams E. Supplementary water for breastfed babies in a hot and dry climate - not really a necessity. Arch Dis Child 1983;58:73-4.

45. Koo WWK, Tsang RC: Building Better Bones: Calcium, Magnesium, Phosphorus, and Vitamin D. In: Tsang RC, Zlotkin SH, Nichols BL, Hansen JW, editors. Nutrition during infancy: principles and practice, 2nd edition. Cincinnati: Digital Educational Publishing Inc., 1997:175-207.

46. Ryan AS. The resurgence of breastfeeding in the United States. Pediatrics 1997;99(4). URL:http://www.pediatrics.org/cgi/content/full/99/4/e12.

47. Spisak S, Gross SS. Second follow-up report: the Surgeon General's workshop on breastfeeding and human lactation. Washington, DC: National center for education in maternal and child health, 1991.

48. Michaelson KF, Larsen PS, Thomsen BL, Samuelson G. The Copenhagen cohort study on infant nutrition and growth: breast-milk intake, human milk macronutrient content, and influencing factors. Am J Clin Nutr 1994;59:600-11.

49. 1997 Red Book: report of the committee on infectious diseases, 24th edition. Elk Grove Village, Illinois: AAP 1997.

50. World Health Organization. Consensus statement from the consultation on HIV transmission and breastfeeding. J Hum Lactation 1992;8:173-4.

51 .Committee on Drugs, American Academy of Pediatrics. The transfer of drugs and other chemicals into human milk. Pediatrics 1994;93:137-50.

52.Briggs G, Freeman R, Yaffe S. A reference guide to fetal and neonatal risk: drugs in pregnancy and lactation. 4th ed. Baltimore: Williams and Wilkins, 1994.

53. Miller RW. Pollutants in breast milk. J Pediatr 1977;90:510-1.

54.Assessment of health risks in infants associated with exposure to PCBs, PCDDs and PCDFs in breast milk. (Environmental Health Series 29). Copenhagen: World Health Organization 1988.

55. Hutchens TW, Henry JF, Yip T-T, et al. Origin of intact lactoferrin and its DNA-binding fragments found in the urine of human milk-fed preterm infants. Evaluation by stable isotopic enrichment. Pediatr Res 1991;29:243-50.

56. Machtinger S. Transfer of antigens via breast milk. In: Hamburger RN, editor. Food intolerance in infancy: allergology, immunology, and gastroenterology. New York: Raven Press, 1989:23-36.

57. De Carvalho M, Klaus MH, Merkatz RB. Frequency of breastfeeding and serum bilirubin concentration. Am J Dis Child 1982;136:737-8.

58.Provisional committee for quality improvement and subcommittee on hyperbilirubinemia, American Academy of Pediatrics. Practice parameter: management of hyperbilirubinemia in the healthy term newborn. Pediatrics 1994;94:558-65.

59. Provisional committee for quality improvement and subcommittee on acute gastroenteritis, American Academy of Pediatrics. Practice parameter: the management of acute gastroenteritis in young children. Pediatrics 1996;97:424-36.

60. Braveman P, Egerter S, Pearl M, et al. Problems associated with early discharge of newborn infants. Pediatrics. 1995;96:716-26.

61 .Cooper WO, Atherton HD, Kahana M, Kotagal UR. Increased incidence of severe breastfeeding malnutrition and hyernatremia in a metropolitan area. Pediatrics 1995;96:957-60.

62. Fomon SJ. Nutrition of normal infants: protein, 2nd edition. St Louis: Mosby, 1993:121-48.

63. Committee on Nutrition, European Society of Paediatric Gastroenterology and Nutrition. Comment on the content and composition of lipids in infant formulas. Acta Paediatr Scand 1991;80:887-96.

64. Temboury MC, Otero A, Polanco I, Arribas E. Influence of breast-feeding on the infant's intellectual development. J Pediatr Gastroenterol Nutr 1994;18:32-6.

65. Wang YS, Wu SY. The effect of exclusive breastfeeding on development and incidence of infection in infants. J Hum Lactation 1996;12:27-30.

66. Pickering LK, Granoff DM, Erickson JR et al. Modulation of the immune system by human milk and infant formula containing nucleotides. Pediatrics 1998;101:242-9.

67. Carlson SE, Ford AJ, Werkman SH, Peeples JM, Koo WWK. Visual acuity and fatty acid status of term infants fed human milk and formulas with and without docosahexaenoate and arachidonate from egg yolk lecithin. Pediatr Res 1996;39:882-8.

68. Auestad N, Montalto MB, Hall RT, et al. Visual acuity, erythrocyte fatty acid composition, and growth in term infants fed formulas with long chain polyunsaturated fatty acids for one year. Ross pediatric lipid study. Pediatr Res 1997;41:1-10.

69. Lucas A, Bloom S, Aynsley-Green A. Gut hormones and minimal enteral feeding. Acta Paediatr Scand 1986;75:719-23.

70. Shulman DI, Kanarek K. Gastrin, motilin, insulin, and insulin-like growth factor-I concentrations in very low-birth-weight infants receiving enteral or parenteral nutrition. JPEN 1993;17:130-3.

71. Colonna F, Pahor T, deVonderweid U, Tonini G, Radillo L. Serum insulin-like growth factor-I (IGF-I) and IGF binding protein-3 (IGFBP-3) in growing preterm infants on enteral nutrition. J Pediatr Endocr Metab 1996;9:483-9.

72. Schwarz SM, Heird W. Effects of feeding on the small intestinal mucosa of beagle pups during the first 5d of life. Am J Clin Nutr 1994;60:879-86.

73. Nutrient requirement for infant formulas, Final rule, Federal Register. 1985;50:45106-8:21 CFR 107.

74. Hansen JW, Boettcher JA. Human milk substitutes. In: Tsang RC, Zlotkin SH, Nichols BL, Hansen JW, editors. Nutrition during infancy: principles and practice, 2nd edition. Cincinnati: Digital Educational Publishing Inc., 1997:441-66.

75. Miller SA. Problems associated with the establishment of maximum nutrient limits in infant formula. J Nutr 1989;119(suppl): 1764-7.

76. Hansen JW. Nutrient composition of infant formulas. In: Nutrition during infancy. Tsang RC, Zlotkin SH, Nichols BL, Hansen JW, editors. Nutrition during infancy: principles and practice, 2nd edition. Cincinnati: Digital Educational Publishing Inc., 1997:467-85.

77. Proposed infant formula current good manufacturing practice regulations. 61 Federal register, July 9, 1996:36153-219, 21 CFR parts 106 and 107.

78. Hanning RM, Paes B, Atkinson SA. Protein metabolism and growth of term infants in response to a reduced-protein, 40:60 whey: casein formula with added tryptophan. Am J Clin Nutr 1992;56:1004-11.

79. Committee on Nutrition, American Academy of Pediatrics. Soy protein-based formulas. Recommendations for use in infant feeding. Pediatrics 1998;101:148-52.

80. Hillman LS. Bone mineral content in term infants fed human milk, cow milk-based formula, or soy-based formula. J Pediatr 1988;113:208-12.

81. Mimouni F, Campaigne B, Neylan M, Tsang RC. Bone mineralization in the first year of life in infants fed human milk, cow-milk formula, or soy-based formula. J Pediatr 1993;122:348-54.

82. Lake AM. Beyond hydrolysates: Use of L-amino acid formula in resistant dietary protein-induced intestinal disease in infants. J Pediatr 1997;131:658-60.

83. Vanderhoof JA, Murray ND, Kaufman SS, et al. Intolerance to protein hydrolysate in infant formulas: An underrecognized cause of gastrointestinal symptoms in infants. J Pediatr 1997;131:741-4.

84. De Boissieu D, Matarazzo P, Dupont C. Allergy to extensively hydrolyzed cow milk proteins in infants: Identification and treatment with an amino acid-based formula. J Pediatr 1997;131:744-7.

85. Committee on nutrition, American Academy of Pediatrics. Iron fortified formulas. Pediatrics 1989;84:1114-5.

86. Committee on nutrition, American Academy of Pediatrics. The use of whole cow's milk in infancy. Pediatrics 1992;89:1105-9.

87. Koo WWK, McLaughlin K, Saba M. Nutrition support for the preterm infant. In: The ASPEN. Nutrition Support Practice Manual. Washington DC: American Society for Parenteral and Enteral Nutrition 1998:26;1-16.

88. Hack M, Wright L, Shankaran S, et al. Very low birth weight outcomes of the National Institute of Child Health and Human Development Neonatal Network, November 1989 to October 1990. Am J Obstetr Gynecol 1995;172:457-64.

89. Hack M, Taylor HG, Klein N, Eiben R, Schatschneider C, Mercuri-Minich N. School age outcomes in children with birth weights under 750g. N Engl J Med 1994;331:753-9.

90. Lucas A, Morley R, Cole TJ, et al. Early diet in preterm babies and development status at 18 months. Lancet 1990;335:1477-81.

91. Lucas A, Morley R, Cole TJ, Gore SM. A randomised multicentre study of human milk versus formula and later development in preterm infants. Arch Dis Child 1994;70:F141-6.

92. Tsang RC, Lucas A, Uauy R, Zlotkin S, editors. Nutritional needs of the preterm infant: scientific basis and practical guidelines. Baltimore: Williams and Wilkins, 1993.

93. Committee on nutrition, American Academy of Pediatrics. Nutritional needs of low birth weight infants. Pediatrics 1985;75:976-86.

94. Committee on nutrition of the preterm infant, European Society of Paediatric Gastroenterology and Nutrition. Nutrition and feeding of preterm infants. Acta Paediatr Scand 1987;336(suppl):1-14.

95. Kalhan SC, Denne SC. Energy consumption in infants with bronchopulmonary dysplasia. J Pediatr 1990;116:662-4.

96. Jones MO, Pierro A, Hammond P, Nunn A, Lloyd DA. Glucose utilization in the surgical newborn infant receiving total parenteral nutrition. J Pediatr Surg 1993;28:1121-5.

97. Chwals WJ. Overfeeding the critically ill child: fact or fantasy? New Horizons 1994;2:147-55.

98. Van Goudoever JB, Wattimena JDL, Carnielli VP, Sulkers EJ, Degenhart HJ, Sauer PJJ. Effect of dexamethasone on protein metabolism in infants with bronchopulmonary dysplasia. J Pediatr 1994;124:112-8.

99. Weiler HA, Wang Z, Atkinson SA. Dexamethasone treatment impairs calcium regulation and reduces bone mineralization in infant pigs. Am J Clin Nutr 1995;61:805-11.

100. Papile LA, Tyson JE, Stoll BJ, et al. A multicenter trial of two dexamethasone regimans in ventilator dependent premature infants. N Engl J Med l998;16:1112-8.

101. Koo WWK, Tsang RC. Calcium, magnesium, phosphorus, and vitamin D. In: Tsang RC, Lucas A, Uauy R, Zlotkin S, editors. Nutritional needs of the preterm infant: scientific basis and practical guidelines. Baltimore: Williams & Wilkins, 1993:135-55.

102. Lewis MA, Smith BAM. High volume milk feeds for preterm infants. Arch Dis Child 1984;59:779-81.

103. Schanler RJ, Garza C. Improved mineral balance in very low birth weight infants fed fortified human milk. J Pediatr 1988; 122:452-6.

104. Friel JK, Andrews WL, Long DR, Herzberg G, Levy R. Thiamine, riboflavin, folate, and vitamin B12 status of infants with low birth weights receiving enteral nutrition. J Pediatr Gastroenterol Nutr 1996;22:289-95.

105. Hamosh M, Ellis LA, Pollock DR, Henderson TR, Hamosh P. Breastfeeding and the working mother: effect of time and temperature of short-term storage on proteolysis, lipolysis, and bacterial growth in milk. Pediatr 1996;97:492-8.

106. Jocson MAL, Mason EO, Schanler RJ. The effect of nutrient fortification and varying storage conditions on host defense properties of human milk. Pediatrics 1997;100:240-3.

107. Carlson SE, Werkman SH, Peeples JM, Wilson WM. Long-chain fatty acids and early visual and cognitive development of preterm infants. Eur J Clin Nutr 1994;48(suppl 2):S27-30.

108. Carnielli VP, Wattimena DJ, Luijendijk IH, Boerlage A, Degenhart HJ, Sauer PJ. The very low birth weight premature infant is capable of synthesizing arachidonic and docosahexaenoic acids from linoleic and linolenic acids. Pediatr Res 1996;40:169-74.

109. Martinez-Augustin O, Boza JJ, Del Pino JI, Lucena J, Martinez-Valverde A, Gil A. Dietary nucleotides might influence the humoral immune response against cow's milk proteins in preterm neonates. Biol Noenate 1997;71:215-23.

110. Zamora SA, Amin HJ, McMillan DD, et al. Plasma L-arginine concentrations in premature infants with necrotizing enterocolitis. J Pediatr 1997;131:226-32.

111. Neu J, Roig JC, Meetze WH, et al. Enteral glutamine supplementation for very low birth weight infants decreases morbidity. J Pediatr 1997;131:691-9.

112. Hamosh M. Should infant formulas be supplemented with bioactive components and conditionally essential nutrients present in human milk? J Nutr 1997;127:971S-4S.

113. Nako Y, Fukushima N, Tomomasa T, Nagashima K, Kuroume T. Hypervitaminosis D after prolonged feeding with a premature formula. Pediatrics 1993;92:862-4.

114. Rigo J, Senterre J. Metabolic balance studies and plasma amino acid concentrations in preterm infants fed experimental protein hydrolysate preterm formulas. Acta Paediatr 1994;Suppl 405:98-104.

115. Berseth CL. Minimal enteral feeding. Clin Perinatol 1995;22:195-205.

116. Berseth CL, Nordyke C. Enteral nutrients promote postnatal maturation of intestinal motor activity in preterm infants. Am J Physiol 1993;264:G1046-51.

117. Macagno F, Demarini S. Techniques of enteral feeding in the newborn. Acta Pediatr 1994;402:11-3.

118. Lemons PK, Lemons JA. Transition to breast/bottle feedings: the premature infant. J Am Coll Nutr 1996;15:126-35.

119. Blondeim O, Abbasi S, Fox WW, Bhutani VK. Effects of enteral gavage feeding rate on pulmonary functions of very low birth weight infants. J Pediatr 1993;133:751-5.

120. Georgeson KE. Laparoscopic versus open procedures for long-term enteral access. Nutr Clin Prac 1997;12:57-8.

121. Bernbaum JC, Pereira GR, Watkins JB, Peckham GJ. Nonnutritive sucking during gavage feeding enhances growth and maturation in premature infants. Pediatrics 1983;71:41-5.

122. Carlson SE, Peeples JM, Werkman SH, Koo WWK. Plasma retinol and retinol binding protein concentrations in premature infants fed preterm formula past hospital discharge. Eur J Clin Nutr 1995;49:134-6.

123. Rajaram S, Carlson SE, Koo WWK, Braselton WE. Plasma mineral concentrations in preterm infants fed a nutrient-enriched formula past hospital discharge. J Pediatr 1995;126:791-6.

124. Lucas A, Fewtrell MS, Morley R et al. Randomized outcome trial of human milk fortification and developmental outcome in preterm infants. Am J Clin Nutr 1996;64:142-51.

125. Koo WWK, Krug-Wispe S, Neylan M, et al. Effect of three levels of vitamin D intake in preterm infants receiving high mineral-containing milk. J Pediatr Gastroenerol Nutr 1995;21:182-9.

126. Koo WWK, Krug-Wispe S, Succop P, Tsang RC, Neylan M. Effect of different vitamin A intakes in very low birth weight infants. Am J Clin Nutr 1995;62:1216-20.

127. Howard L, Ament M, Fleming CR, Shike M, Steiger E. Current use and clinical outcome of home parenteral and enteral nutrition therapies in the United States. Gastroenterol 1995;109:355-65.

128. Heird WC, Gomez MR. Parenteral nutrition in low-birth-weight infants. Ann Rev Nutr 1996;16:471-99.

129. Mitton 8G. Amino acids and lipid in total parenteral nutrition for the newborn. J Pediatr Gastroenterol Nutr 1994;18:25-31.

130. Kalhan SC. Rates of urea synthesis in the human newborn: effect of matenal diabetes and small size for gestational age. Pediatr Research 1993;34:801-4.

131. Van Goudoever JB, Colen T, Wattimena JL, Huijmans JG, Carnielli VP, Sauer PJ. Immediate commencement of amino acid supplementation in preterm infants: effect on serum amino acid concentrations and protein kinetics on the first day of life. J Pediatr 1995;127:458-65.

132. Wu PY, Edwards N, Storm MC. Plasma amino acid patterns in normal term breast-fed infants. J Pediatr 1986;109:347-9.

133. Denne SC, Karn CA, Liu YM, Leitch CA, Liechty EA. Effect of enteral versus parenteral feeding on leucine kinetics and fuel utilization in premature newborns. Pediatr Res 1994;36:429-35.

134. Denne SC, Karn CA Ahlrichs JA, Dorotheo AR, Wang J, Liechty EA. Proteolysis and phenylalanine hydroxylation in response to parenteral nutrition in extremely premature and normal newborns. J Clin Invest 1996;97:746-54.

135. Battista MA, Price PT, Kalhan SC. Effect of parenteral amino acids on leucine and urea kinetics in preterm infants. J Pediatr 1996;128:130-4.

136. Clark SE, Karn CA, Ahlrichs JA, Wang J, Leitch CA, Leichty EA. Acute changes in leucine and phenylalanine kinetics produced by parenteral nutrition in premature infants. Pediatr Res 1997;41:568-74.

137. Helms RA, Mowatt-Larssen CA, Boehm KA, Christensen ML, Hughes MA, Fernances ET, Storm MC. Urinary nitrogen constituents in the postsurgical preterm neonate receiving parenteral nutrition. JPEN 1993;17:68-72.

138. Furst P, Stehle P. Are intravenous amino acid solutions unbalanced? New Horizons 1994;2:215-23.

139. Micheli JL, Schutz Y Protein. In, Nutritional Needs of the Preterm Infant: Scientific Basis and Practical Guidelines, Tsang RC, Lucas A, Uauy R, Zlotkin S, eds. Williams & Wilkins, Baltimore, MD 1993:29-46.

140. Heird WC. Amino acid and energy needs of pediatric patients receiving parenteral nutrition. Pediatr Clin N Amer 1995;42:765-89.

141. Lacey JM, Crouch JB, Benfell K, Ringer SA, Wilmore CK, Macguire D, Wilmore DW. The effects of glutamine-supplemented parenteral nutrition in premature infants. JPEN 1996;20:74-80.

142. House JD, Pencharz PB, Ball RO. Glutamine supplementation to total parenteral nutrition promotes extracellular fluid expansion in piglets. J Nutr 1994;124:395-405.

143. Kizer JS, Nemeroff CB, Youngblood WW. Neurotoxic amino acids and structurally related analogs. Pharm Rev 1978;29:301-18.

144. Murphy TH, Schnaar RL, Coyle JT. Immature cortical neurons are uniquely sensitive to glutamate toxicity by inhabition of cystine uptake. FASEB J 1990;4:1624-33.

145. Meyer NA, Miller MJ, Herndon DN. Nutrient support of the healing wound. New Horizons 1994;2:202-14.

146. Wheeler RA, Griffiths DM, Jackson AA. Urea kinetics in neonates receiving total parenteral nutrition. Arch Dis Child 1993;69:24-7.

147. Wilson DC, McClure G. Energy requirements in sick preterm babies. Acta Paediatrica 1994;405(suppl):60-4.

148. Poindexter BB, Karn CA, Denne SC. Exogenous insulin reduces proteolysis and protein synthesis in extremely low birth weight infants. J Pediatr 1998;132:948-53.

149. Van Aerde JE, Sauer PJ, Pencharz PB, Smith JM, Heim T, Swyer PR. Metabolic consequences of increasing energy intake by adding lipid to parenteral nutrition in full-term infants. Am J Clin Nutr 1994;59:659-62.

150. Innis SM. Fat. In, Nutritional Needs of the Preterm Infant: Scientific Basis and Practical Guidelines, Tsang RC, Lucas A, Uauy R, Zlotkin S, editors. Baltimore, MD: Williams & Wilkins 1993:65-86.

151. Goel R, Hamosh M, Stahl GE, Henderson TR, Spear ML, Hamosh P. Plasma lecithin: cholesterol acyltransferase and plasma lipolytic activity in preterm infants given total parenteral nutrition with 10% or 20% Intralipid. Acta Paediatr 1995;84:1060-4.

152. Larrson LE, Olegad R, Ljung A, Rubensson A, Cederblad G. Parenteral nutrition in preterm neonates with and without carnitine supplementation. Acta Anaesthesiol Scand 1990;34:501-5.

153. Sulkers EJ, Lafeber HN, Degenhart HJ, Przyrembel H, Schlotzer E, Sauer PJ. Effects of high carnitine supplementation on substrate utilization in low-birth-weight infants receiving total parenteral nutrition. Am J Clin Nutr 1990;52:889-94.

154.Peters O, Ryan S, Matthew L, Cheng K, Lunn J. Randomized controlled trial of acetate in neonates receiving parenteral nutrition. Arch Dis Child 1997;77:F12-5.

155. Greene HL, Hambridge KM, Schanler R, Tsang RC. Guidelines for the use of vitamins, trace elements, calcium, magnesium and phosphorus in infants and children receiving total parenteral nutrition. Am J Clin Nutr 1988;48:1324-1342 (Revised reprint December 1990).

156. Leung FY. Trace elements in parenteral micronutrition. Clin Biochem 1995;28:561-6.

157. Friel JK, Andrews WL, Hall MS, Rodway MS, Keith M, McCloy UC, Matthew JD, Long DR. Intravenous iron administration to very-low-birth-weight newborns receiving total and partial parenteral nutrition. JPEN 1995;19:114-8.

158. Moore MC, Greene HL, Phillips B, et al. Evaluation of a pediatric multiple vitamin preparation for total parenteral nutrition in infants and children. I. Blood levels of water-soluble vitamins. Pediatrics 1986;77:530-8.

159. Greene HL, Phillips BL, Granck L, et al. Persistently low blood retinol levels during and after parenteral feeding of very low birth weight infants: examination of losses into intravenous administration sets and a method of prevention by addition to a lipid emulsion. Pediatrics 1987;79:894-900.

160. Murphy S, Craig DQ, Murphy A. An investigation into the physical stability of a neonatal parenteral nutrition formulation. Acta Pediatr 1996;85:1483-6.

161. Deffenbaugh JH, editor. Quality assurance for pharmacy -prepared sterile product, ASHP technical assistance bulletin on practice standards of ASHP 1997-1998. Bethesda, MD: American society of health system pharmacists pp171-81.

162. Reynolds AP, Kiely E, Meadows N, et al. Manganese in long term pediatric parenteral nutrition. Arch Dis Child 1994;71:527-8.

163. La Selve P, Demolin P, Holzapfel L, Blanc PL, Teyssier G, Robert D. Shoshin beriberi: an unusual complication of prolonged parenteral nutrition. JPEN 1986;10:102-3.

164. Wolman SL, Anderson GH, Marliss EB, Jeejeebhoy KN. Zinc in total parenteral nutrition. Requirement and metabolic effects. Gastroenterol 1980;76:458-67.

165. Thoren L. Magnesium deficiency in gastrointestinal fluid loss. Acta Chir Scand 1963;306(suppl):1-65.

166. Koo WWK and Kaplan LA. Aluminum and bone disorders: with specific reference to aluminum contamination of infant nutrients. J Am Coll Nutr 1988;7:199-214.

167. Briones ER, Iber FL. Liver and biliary tract changes and injury associated with total parenteral nutrition: pathogenesis and prevention. J Am Coll Nutri 1995;14:219-28.

168. Teitelbaum DH. Parenteral nutrition-associated cholestasis. Cuff Opinion in Pediatr 1997;9:270-5.

169. Koo WWK. Parenteral nutrition-related bone disease. JPEN 1992;16:386-94.

170. Prestridge LL, Schanler RJ, Shulman RJ, Burns PA, Lame LL. Effect of parenteral calcium and phosphorus therapy on mineral retention and bone mineral. J Pediatr 1993;122:761-8.

171. Lipkin EW. A longitudinal study of calcium regulation in a nonhuman primate model of parenteral nutrition. Am J Clin Nutr 1998;67:246-54.

172. Schauster H, Dwyer J. Transition from tube feedings to feedings by mouth in children: preventing eating dysfunction. J Amer Dietet Assoc 1996;96:277-81.

173. Buchman AL, Moukarzel AA, Bhuta S, et al. Parenteral nutrition is associated with intestinal morphologyic and functional changes in humans. JPEN 1995;19:453-60.

174. Lipman TO. Bacterial translocation and enteral nutrition in humans: an outsider looks in. JPEN 1995;19:156-65.

175. Ballabriga A, Schmidt E. Actual trends of the diversification of infant feeding in industrialized countries in Europe. In: Weaning: Why, What and When? Ballabriga A, Rey J, eds. Nestle Nutrition Worship Series 1987;10:129-53.

176. King J, Ashworth A. Contemporary feeding practices in infancy and early childhood in developing countries. In: Infant and Child Nutrition Worldwide: issues and Perspectives. Falkner F, ed. CRC Press, Boca Raton, F1 1991:141-74.

177. Morris SE. Eating readiness cues: introducing supplemental foods. Ped Basics 1992;61:2-7.

178. Huffman SL, Martin LH. First feedings: optimal feeding of infants and toddlers. Nutr Res 1994;14:127-59.

179. Bartholmey SJ. Weaning - transition to the table. In: Tsang RC, Zlotkin SH, Nichols BL, Hansen JW, editors. Nutrition during infancy: principles and practice, 2nd edition. Cincinnati: Digital Educati6nal Publishing Inc., 1997:417-40.

180. Illingworth RS, Lister J. The critical or sensitive period, with special reference to certain feeding problems in infants and children. J Pediatr 1964;65:839-48.

181. Dewey KG, Cohen RJ, Rivera LL, Brown KH. Effects of age of introduction of complemaentary foods on iron status os breast fed infants in Honduras. Am J Clin Nutr 1998;67:878-84.

182. Lifshitz F. Weaning foods... the role of fruit juices in the diets of infants and children. J Am Coll Nutr 1996;15(5 Suppl):1S-3S.

183. Arnon SS, Midura TF, Damus K, Thompson B, Wood RM, Chin J. Honey and other environmental risk factors for infant botulism. J Pediatr 1979;94:331-6.

184. Sullivan SA, Birch LL. Infant dietary experience and acceptance of solid foods. Pediatrics 1994;93:271-7.

185. Truesdell DD, Acosta PB. Feeding the vegan infant and child. J Am Diet Assoc 1985;85:837-40.