Enteral Nutrition*

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17. Enteral Nutrition *
Marianne Sollosy Anderson, Linda Lee Wood, Jacqueline A. Keller and William W. Hay Jr.
Advances in perinatal care have decreased morbidity and mortality for many infants, 80 but the provision of adequate and optimal nutrition to support term and preterm infants in the neonatal intensive care unit continues to be a difficult, though important, challenge. Recent research in neonatal nutrition has provided some evidence-based guidance for clinicians, resulting in the adoption of earlier, more substantial parenteral and enteral strategies for nutrition of newborn infants, particularly those born very preterm. Other research has emphasized the importance of early enteral feeding for the best support of gastrointestinal development, somatic growth, metabolic homeostasis, prevention of infection, and future health. Together, such research has demonstrated that immediate parenteral support and early enteral feedings are fundamental and not optional in neonatal management.
This chapter provides an overview of the physiology of fetal and neonatal nutrition and growth, gastrointestinal anatomic and functional development, and the fundamentals of neonatal nutritional requirements. More specific detail about the assessment and monitoring of growth, feeding strategies and techniques, and the possible complications of enterally feeding at-risk infants is included. The ongoing nutritional needs of infants recovering from complications of preterm birth and other disorders also are presented, as well as the elements of providing for those needs after hospital discharge.


Fetal Growth

Fetal growth is regulated by complex genetic, nutritional, endocrine, environmental, and epigenetic factors. 15,42,117 Genetic potential alone has a relatively minor impact. 64,65 Maternal factors such as prepregnancy weight and weight gain during pregnancy directly correlate with fetal size. 1,13,62,114 The quality of the maternal diet (protein, energy, vitamins, minerals) also directly affects fetal growth. 94 In general, however, a large maternal reserve of nutrients is available to the fetus, and in most circumstances, changes in maternal diet do not limit fetal growth.
The growth and function of the placenta strongly determine fetal growth by providing oxygen and essential nutrients. 21,57,58,97 Critical fetal anabolic hormones, such as the insulin-like growth factors (IGF)–I/II and insulin, are regulated by circulating concentrations of nutrients and are themselves regulators of fetal nutrient uptake and metabolism. Apancreatic infants, who have no circulating insulin, are among the most severely growth restricted of all newborns (Figure 17-1); infants of diabetic mothers, who respond to increased maternal-fetal glucose delivery with increased insulin secretion, are among the largest (Figure 17-2). Thyroid hormone also contributes to fetal growth by regulation of oxidative metabolism. Infants with other endocrine deficiencies, such as those resulting from anencephaly, panhypopituitarism, or hypothyroidism, are near normal in age-specific size at birth, indicating a complex interplay between the fundamentally required supply of nutrients to the fetus and the supporting roles of the fetal endocrine milieu that regulates intrauterine growth.
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(Courtesy Newborn Service, University of Colorado Hospital, Denver, Colo [WW Hay, Jr].)

Gastrointestinal Development

Enteral feeding continues to support gastrointestinal development that begins in early fetal life. The fetal gut is anatomically complete by 20 to 22 weeks after conception; functional development of the gastrointestinal system begins in utero and continues into infancy (Table 17-1). In utero, the fetal intestine is exposed to nutrients and growth factors from the mother, placenta, amniotic fluid, and the fetal tissues. The fetal gut is in communication with the external amniotic fluid environment by 7 weeks post-conception, and early development and functional priming are supplied by growth factors, enzymes, immunoglobulins, and hormones present in that fluid. 87 Fetal swallowing can be observed as early as 11 weeks’ gestation. 29 The components of the amniotic fluid, including carbohydrates and amino acids, change during development, as does the volume of amniotic fluid ingested, varying from a few milliliters per day to more than 450 mL per day, or 20% of fetal weight, late in gestation. 10 Amniotic fluid contains growth factors that promote gut cell differentiation. Such growth factors and nutrients in the amniotic fluid stimulate production of enteric hormones that act locally to promote further gut development. The timing of the appearance of gastrointestinal hormones, polypeptides, neurotransmitters, and digestive enzymes in the fetus is variable, but most are present in the gastrointestinal tract by the end of the first trimester of pregnancy. Nutrient transport systems are in place by 14 weeks for amino acids, 18 weeks for glucose, and 24 weeks for fatty acids.
TABLE 17-1 Development of the Human Gastrointestinal Tract: First Appearance of Developmental Markers
Data from Lebenthal E: The impact of development of the gut on infant nutrition, Pediatric Ann 16:211, 1987; Montgomery RK, Mulberg AE, Grand RJ: Development of the human gastrointestinal tract: twenty years of progress, Gastroenterology 116:702, 1999.
Developmental Marker Weeks of Gestation
Gastrulation 3
Gut tube formed, early differentiation of foregut, midgut, and hindgut 4
Gut lumen in continuity with amniotic cavity 7
Growth of intestines into umbilical cord 7
Intestinal villus formation 9
Intestines into abdominal cavity 10
Δ glucosidase, dipeptidase, lactase enzymes 10
Glucose transporters 10
Liver lobules, bile metabolism 11
Swallowing 11
Parietal cells, pancreatic islets, bile secretion 12
Stomach fundus, body, pylorus, greater and lesser curvature 14
Gastric glands 14
Intestinal crypts, elongation of intestinal villi 14
Intestinal lymph nodes 14
Differentiation of pancreatic endocrine and exocrine tissue 14
Active transport of amino acids 14
Sucking movements 19
Superficial esophageal glands 20
Gastric motility and secretion 20
Fatty acid absorption 24
Coordination of suck and swallow 33-36
After birth, the gastrointestinal system must further adapt for enteral digestion, absorption, mucosal growth and differentiation, and peristalsis. Some gastrointestinal functions are “switched on” at birth (e.g., decrease in intestinal permeability, increase in mucosal lactase activity), regardless of the length of gestation. Others, however, are intrinsically “programmed” to occur at a certain post-conceptual age (e.g., the onset of peristalsis at 28 to 30 weeks and the coordination of suck, swallow, and breathing at 33 to 36 weeks). Environmental influences, including colonization of the gut by bacteria and the introduction of nutrients into the gut, also affect postnatal gastrointestinal and immunologic development. 2,18,77
Infants born before term have both anatomic and functional limits to the digestion and tolerance of enteral feedings. Neurologic maturation is important not only for coordination of sucking, swallowing, and breathing during feeding but also for gastrointestinal motility. Peristalsis in the esophagus is immature and bidirectional in the preterm infant, with forward movement of food to the stomach developing only near term. 56 Abnormal esophageal peristalsis and transient relaxations of the lower esophageal sphincter muscle likely contribute to the common problem of gastroesophageal reflux seen in preterm infants. Enteral feeding promotes the ongoing maturation and development of the gastrointestinal system in both the term and preterm infant. 17 Once enteral feedings are established, gastric emptying rate seems to be similar in term and preterm infants. 89,113
Intestinal motor activity in the preterm infant is immature and disorganized compared with that in term infants, with term infants having distinct fasting phases of gastrointestinal quiescence, nonmigrating motor activity, and migrating motor complexes. After feeding, term infants show a dramatic increase in the intensity of motor activity that is not observed in preterm infants. A measure of gastrointestinal motility is provided by the passage of stool within 24 hours of birth in more than 95% of full-term infants; however, the more preterm the infant, the greater the delay in passing the first stool. Coordinated, mature gastrointestinal motility and peristalsis with feeding develop in the preterm infant between 33 weeks and term.
Protein digestion and absorption are remarkably efficient in the preterm infant despite the fact that enterokinase, a rate-limiting enzyme in the activation of pancreatic proteases, has only 20% of activity found in the term newborn and 10% of adult activity. In the newborn, protein digestion is aided by the activity of brush border and cytosolic peptidases. Carbohydrate absorption is limited by a relative deficiency of lactase, which splits lactose into glucose and galactose. Lactase in the infant of less than 34 weeks’ gestation is present at only about 30% of the activity found in the normal term infant, although lactose intolerance is rare in these infants, particularly when they are fed human milk. Preterm infants malabsorb 10% to 30% of dietary fat because of a small bile acid pool size and relative lack of pancreatic lipase. 78 Some compensation is provided by lingual and gastric lipases, as well as the lipase present in human milk. Despite relative deficiencies in many enzymes important in nutrient processing, the preterm infant usually can digest and absorb complex nutrient mixtures such as human milk quite effectively.

Postnatal Growth of Preterm Infants

After birth, usual nutritional regimens, even when provided more aggressively, fail to produce growth rates in preterm infants that mimic normal rates of intrauterine growth, the accepted goal of nutrition for the preterm infant. 27,32,96 A variety of complications contribute to this growth failure, but the primary problem is that most preterm infants are fed less protein and calories immediately after birth than are needed to support normal fetal rates of protein accretion and body growth. In addition, the preterm infant is exposed to environmental factors that increase energy expenditure, including low relative humidity and radiant and convective heat losses, as well as energy-consuming demands of breathing, resistance to gravity, and the processes of digestion, absorption, and synthesis of nutrients into body structure. Stress-induced hormones that are catabolic in sick infants, particularly corticosteroids and catecholamines, limit the production and action of anabolic growth factors, particularly insulin and IGFs, further preventing normal rates of growth and weight gain at rates comparable to those of healthier infants of the same gestational age. Overall, however, even in sick or physiologically unstable infants, the principal factor causing postnatal growth failure is delayed and inadequate intake of protein and energy. 32
After birth, all infants lose excess extracellular salt and water. Term infants usually lose 5% to 8% of birth weight by the third day of life. In extremely-low-birth-weight (ELBW, <1000 g birth weight) preterm infants, normal diuresis and fluid management strategies to limit fluid overload over the first 10 to 14 days of life usually produce a net loss of body weight. Such infants may lose 8% to 15% of birth weight. Further weight loss and failure to gain weight are exacerbated by inadequate nutritional support, particularly of protein and energy. Deficits accumulated daily during early neonatal life may take weeks to months to replenish. Accurate measurement of body length can be helpful in the early newborn period. More recent methodologies to assess the neonate include (1) dual x-ray absorptiometry (DXA), and (2) air displacement plethysmography, which partitions new tissue accrual into water, fat, and lean body mass components, thus helping define needs for additional specific nutrients (protein, lipids, carbohydrates) for body growth (even during the early postnatal period of fluctuating water weight). Early provision of both adequate calories and protein to sustain optimal nutrition is difficult without the addition of parenteral nutrition for preterm infants and sick infants of all gestational ages (see Chapter 16).

Assessment of Growth and Nutritional Status

The generally accepted goal of postnatal nutrition for preterm infants is to achieve and maintain the normal rate of intrauterine growth (Figure 17-3). Unfortunately, there is no clear standard for normal fetal growth. Many growth curves have been developed from anthropometric measurements taken at birth in populations of infants born at different gestational ages. 3,32 Because preterm birth is not a normal outcome, cross-sectional anthropometric measurements obtained at birth do not accurately describe normal growth parameters for any given gestational age. Growth curves based on serial ultrasound measurements of fetuses who were born at term in healthy condition and with normal measurements provide continuous, rather than cross-sectional, data that correlate better with the expected fetal growth rate of a particular fetus or newborn (Figure 17-4). 16,36For the average, appropriately grown, preterm infant, expected weight gain is approximately 15 to 20 g/kg/day.
We lack good methods to assess nutritional adequacy over time in very small infants. Rates of change in anthropometric measurements provide some retrospective information, but they do not tell us what an infant needs to maintain a normal growth rate (Box 17-1; Figure 17-5). Too often, growth charts simply document the failure to provide adequate nutrition during the previous days to weeks. Indirect calorimetry offers some advantage, but instruments that are clinically practical and sufficiently accurate to quantify nutrient metabolism in tiny infants are not yet available. Similarly, application of stable isotope methodology to measure utilization and oxidation rates of individual nutrients remains confined to large medical centers with expensive and sophisticated mass spectrometry facilities. Evaluation of an individual infant’s immediate nutrient requirements and responses to the administration of different mixtures and amounts of nutrients remains an elusive but still necessary goal.
BOX 17-1

1. Weight is subject to large variations based on fluctuations in fluid balance (e.g., presence or absence of edema, congestive heart failure, renal failure) and attached equipment (e.g., intravenous lines and boards, endotracheal tubes). Infant weight should be measured daily as follows:
a. Use the same scale and weigh infant naked or using supportive weighing method as possible. Supportive weighing, or swaddled weights, help ensure an infant’s physiologic and behavioral stability during the weighing procedure. 61 Remove “attached” equipment if possible, or weigh similar items separately and subtract from total weight. Swaddled weights are equal to the naked weight after the weight of the diaper and blanket are subtracted. Unswaddled weights still can be used to improve accuracy for very small infants or if swaddling puts the infant at risk or interferes with the infant’s care needs. In-bed scales are useful for extremely-low-birth-weight infants or infants who become unstable with handling. An electronic scale that averages several measurements reduces movement artifact and may be useful for active infants.
b. Reference standards for the weights of nursery equipment (e.g., diapers, intravenous boards, tubing, endotracheal tubes) should be available for nursery use.
c. Weigh the infant at the same time daily, preferably before a feeding.
d. Record the infant’s weight, the time of weight measurement, and the scale used on the chart. Energy (calories) and fluid intake should be recorded on the same chart. This information combined with biochemical parameters (e.g., serum electrolytes, hemoglobin, albumin) and the physical examination provides the best overview of the infant’s nutritional status. Daily weight should be plotted on the appropriate preterm or term growth chart. Weekly review of the infant’s weight change provides useful information on trends in overall growth or weight loss that may be overlooked in the daily charting.
2. Crown-heel length and head circumference are measured and recorded on admission and at least weekly thereafter. Accurate length measurements are difficult to obtain without special equipment such as a length board, but accuracy can be improved by repeated measurements and use of the tonic-neck reflex to straighten the hip and knee. Increase in head circumference is used as an indicator of brain growth.
a. To measure the crown-heel length, place the infant supine on a firm surface with the knees extended and the ankles flexed 90 degrees. Measure the length from the top of the head (crown) to the bottom of the heel.
b. Head circumference is obtained using a paper or soft tape measure. Record the largest measurement obtained with the tape placed over the frontal, parietal, and occipital prominences.
3. The ponderal index (or weight-length index; see Figure 17-5) is used to assess “quality” of growth. The index is calculated as the weight in grams multiplied by 100, divided by the cube of the length in centimeters. True organ growth and tissue accretion are accompanied by increases in both weight and length and can be evaluated partly using the ponderal index.
4. Biochemical monitoring of the growing infant may include periodic measurement of serum electrolytes, calcium, phosphorus, alkaline phosphatase, total protein, albumin, and hemoglobin. These data can be used to help prevent specific deficiencies in the diet, such as hyponatremia in preterm infants with excessive renal solute losses or hypophosphatemia with increased alkaline phosphatase as seen in rickets and osteopenia.
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(From Lubchenco L, Hansman C, Boyd E: Intrauterine growth in length and head circumference as estimated from live birth at gestational ages from 26 to 42 weeks. Reproduced with permission from Pediatrics 37:403, 1966, copyright by the American Academy of Pediatrics.)


Nutritional requirements should be considered in general categories: energy (or calories), protein, carbohydrate, fats, minerals and solutes, and vitamins. Water requirements and limits also must be considered when designing nutrition support strategies. The source, complexity, and constituents of these nutrients are important, as well as the route of administration. Box 17-2 on p. 405 lists commonly used nutritional conversion factors and formulas. See Chapter 16 for parenteral nutrition and Chapter 18 for breast feeding.
BOX 17-2

1 kcal = 4.184 kJ
Gross energy (kcal/g)
Protein = 5.65
Carbohydrate = 3.95
Fat = 9.25
Metabolizable energy (kcal/g)
Protein = 4
Carbohydrate = 4
Fat = 9
Total protein (g/dL) = total nitrogen (g/dL) × 6.25
1 International unit vitamin A = 0.3 retinol equivalent
= 0.3 mcg retinol
= 1.8 mcg beta-carotene
400 International units vitamin D = 10 mcg vitamin D
1 International unit vitamin E = 1 mg dl-α-tocopherol
1 mEq Na = 1 mmol Na = 23 mg Na
1 mEq K = 1 mmol K = 39 mg K
1 mEq Cl = 1 mmol Cl = 35 mg Cl
2 mEq Ca = 1 mmol Ca = 40 mg Ca
1 mmol P = 31 mg P
Osmolarity (mOsm/L) = Osmolality (mOsm/kg H 2O) × kg H 2O/L solution
Renal solute load (mOsm/dL) = [Protein (g/dL)] × 4 + [Na + K + Cl (mEq/dL)]
Potential renal solute load (mOsm/dL) = [Protein (g/dL)] × 5.7 + [Na + K + Cl (mEq/dL)] + [P (mg/dL)/31]


Negative energy balance is frequent in preterm infants because they have limited energy stores, high energy expenditures, and low intake. Energy requirements are determined by an infant’s total energy expenditure, energy excretion, and energy stored in new tissue as growth. Total energy expenditure can be subdivided into contributions of basal metabolic rate, activity, thermoregulation, and the energy costs of digestion and metabolism. Energy excretion is composed of fecal and urinary losses, as well as heat lost by radiation and evaporation. Nursing infants in thermoneutral, humidified incubators, starting at admission to the NICU, can substantially decrease energy expenditure in preterm infants. Estimates of energy requirements for growing preterm infants are shown in Table 17-2 on p. 406. The large range of these estimates reflects the variability of infant activity and environmental conditions. Therefore it is essential to adjust nutrient delivery to individual requirements. For example, if an infant is particularly active and showing poor growth, nutrient delivery should be adjusted upward accordingly.
TABLE 17-2 Estimated Daily Energy Requirement (kcal/kg) for Preterm Infants
Modified from American Academy of Pediatrics, Committee on Nutrition: Nutrition needs of low-birthweight infants, Pediatrics 112:622, 1988; Committee on Nutrition of the Preterm Infant, European Society of Pediatric Gastroenterology and Nutrition: Nutrition and feeding of the preterm infant, Oxford, UK, 1987, Blackwell.
European Society of Gastroenterology and Nutrition
Factor American Academy of Pediatrics Average Range
Energy expenditure
Resting metabolic rate 50 52.5 45-60
Activity 15 7.5 5-10
Cold stress 10 7.5 5-10
Energy cost of digestion 8 17.5 10-25
Energy stored 25 25 20-30
Energy excreted 12 20 10-30
Total requirements 120 130 95-165
Caloric requirements for the healthy term infant average 110 kcal/kg/day, much lower than the energy requirements of preterm infants. Increased energy requirements can be anticipated during sepsis, acute and chronic respiratory illness, and recovery from surgery (Figure 17-6). Daily caloric intake should be calculated for each infant growing or recovering from illness in the neonatal intensive care unit. A useful approach for calculating caloric intake is shown in Box 17-3 on p. 407.
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(Modified from Thureen P, Hay WW Jr: Conditions requiring special nutritional management. In Tsang RC, Lucas A, Uauy R, et al, editors: Nutritional needs of the preterm infant, Baltimore, 1993, Williams & Wilkins.)
BOX 17-3

Conversion Factors

20 kcal/oz = 0.67 kcal/mL
24 kcal/oz = 0.80 kcal/mL
1 kcal = 1 calorie
1 oz = 30 mL


1. Add total daily feeding intake (in mL)
2. Divide total intake (mL) by the infant’s weight (kg)
This equals enteral intake in mL/kg/day
3. Multiply mL/kg/day intake by kcal per ounce of feeding
4. Multiply by 1 oz/30 mL
This equals enteral intake in kcal/kg/day.


Protein accretion is critical for normal growth. The amount and type of protein necessary for optimal growth in preterm infants have been difficult to establish. Metabolic balance studies support a need for higher protein intakes in the growing preterm infant than in the term infant. Throughout the normal period of breast feeding, the concentration of protein in human milk decreases; however, the preterm infant’s need for protein continues to be much higher than the term infant. Mature human milk provides adequate protein to meet the recommended goals of 2 to 2.5 g/kg/day for term infants, but it is inadequate to meet the goals of 3.5 to 4 g/kg/day for preterm infants. 74 In one study, preterm infants receiving both protein and energy supplementation during enteral feedings (to as much as 3.6 g/kg/day protein and 149 kcal/kg/day energy) had increased gains only in length and head circumference in relation to increased protein intake. In the same study, extra energy increased primarily weight and triceps skinfold thickness, demonstrating the need for protein to grow bone, brain, and lean body mass, whereas excess energy leads primarily to increased fat deposition (Figure 17-7). 59,60 These benefits unique to protein and energy have since been supported by a Cochrane Review of the literature. 68
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(From Kashyap S, Schulze KF, Forsyth M, et al: Growth nutrient retention and metabolic response in low-birth-weight infants fed varying intakes of protein and energy, J Pediatr 113:713, 1988; Kennaugh JM, Hay WW, Jr: Nutrition of the fetus and newborn, West J Med 147:435, 1987.)
Although infants with growth failure may be at higher neurodevelopmental risk, 40 it has been difficult to establish long-term benefits to developmental outcome with particular feeding strategies. Studies of preterm infants maintained on diets fortified with protein and energy have shown improved neurodevelopmental test scores in early life. Neurodevelopmental outcome appears to be even better when human milk is supplemented with protein and energy. 75,76 More recent studies have shown such benefits extended into adolescence when previously preterm infants had increased brain size, caudate nucleus volume, and intelligence quotient (IQ) in direct relation to their protein and energy intake during their postnatal period. 51,54
Human milk from an infant’s own mother is unique and the preferred source of protein for that newborn. Human milk contains whey-predominant protein (whey:casein ratio of 70-80: 30-20), whereas cow’s milk has a whey:casein ratio of 18:82. Whey protein is particularly rich in essential and conditionally essential amino acids. Milk expressed from mothers of preterm infants is somewhat higher in protein than milk from mothers of term infants. Nonetheless, fortification of preterm maternal milk with protein (as well as calcium, phosphorus, sodium, potassium, and lipid) usually is necessary to promote growth rates approximating those of normal human fetuses, particularly in the very-low-birth-weight (VLBW) preterm infant. 99 Given the multiple benefits of mother’s milk feeding for preterm infants, including provision of antimicrobial factors and improved feeding tolerance, mother’s milk feeding with protein and energy supplementation, (e.g., with Enfamil® Human Milk Fortifier produced by Mead Johnson Nutritionals or Similac® Human Milk Fortifier produced by Abbott Nutrition) is highly recommended (see Table 17-3 on p. 408). A human milk–based fortifier, ProlactPlus HMF™ (Prolacta Bioscience, Monrovia, Calif.), is also available.
TABLE 17-3 Composition of Preterm Human Milk and Human Milk Fortifiers
This table lists the major constituents; refer to product inserts for a complete listing of vitamins, minerals, and trace elements.
MCT, Medium-chain triglyceride.
*Data from Klein CJ, editor: Nutrient requirements for preterm infant formulas, J Nutr 132:1395S, 2002.
Mead Johnson Nutritionals, Evansville, Indiana.
Ross Products Division, Abbott Nutrition, Columbus, Ohio.
Human Milk Fortifiers (per 4 Packets)
Mature Preterm Human Milk (28 Days, Approximate per 100 mL*) Enfamil® Human Milk Fortifier Similac® Human Milk Fortifier
Energy (kcal) 67-75 14 14
Amount (g) 1.3-1.8 1.1 1
Source Human milk Milk protein isolate and whey protein isolate hydrolysate Nonfat milk and whey protein concentrate
Whey:casein ratio 70-80:20-30 60:40 60:40
Amount (g) 3-3.9 1 0.36
Source Triglycerides MCT oil (70%)Soy oil (30%) MCT oil
Amount (g) 6-11 <0.4 1.8
Source Lactose and glucose Mineral salts and corn syrup solids Corn syrup solids
Calcium (mg) 25 90 117
Phosphorus (mg) 13 50 67
Sodium (mEq)) 0.9 ± 0.2 0.7 0.7
Potassium (mEq) 1.2 ± 0.3 0.7 1.6
Chloride (mEq) 1.5 ± 0.2 0.4 1.1
Iron (mg) 0.2 1.44 0.35
Zinc (mg) 0.3 0.72 1
Magnesium (mg) 3 1 7
Potential renal solute load (mOsm/100 mL) 12.6 9.7 11.2
Osmolality (mOsm/kg water) 290 +35 (above human milk when mixed) +90 (above human milk when mixed)
An average protein intake of 3.5 g/kg/day is recommended for most preterm infants born before 30 weeks’ gestation. Protein requirements are higher (4.0 g/kg/day) in ELBW infants (i.e., <27 weeks’ gestation and <1000 g). Growth should be monitored and supplementation provided expectantly. Term infants in general do not require protein or energy supplementation unless their dietary fluid is restricted because of illness (e.g., congestive heart failure).
The amino acid profile in the newborn diet is as important as the amount of protein provided. Growth rate of lean body mass is determined directly by the intake of the essential amino acids. Conditionally, or developmentally, essential amino acids (those that are uniquely required in larger amounts at certain developmental stages and cannot be synthesized at sufficient rates for requirements [e.g., cysteine, taurine, histidine, arginine, lysine]) also are important to the infant, especially if preterm. Normal growth, energy metabolism, and immune function depend on appropriate availability of these amino acids. Particularly in the rapidly growing infant, growth requirements may not be met by the relatively limited intake of essential amino acids common with most current nutritional regimens or by the limited biosynthesis of conditionally essential amino acids.


Human neonates are unique among neonatal mammals in having a relatively high white fat content of 16% to 18% of body weight at term. The term infant also has stores of brown fat, which is necessary for neonatal thermogenesis. In utero fat deposition occurs predominantly during the last 12 to 14 weeks of gestation. Thus infants born preterm are deficient in fat stores, both for use as energy and for thermogenesis. Dietary fats are important to sustain growth, provide essential fatty acids, and promote the absorption of fat-soluble vitamins. Newborn infants absorb fat less efficiently than older children. Preterm infants demonstrate even greater deficiencies in fat digestion and metabolism. Pancreatic lipase and bile acids are less available for fat digestion and absorption. Lingual and gastric lipases, present in newborn secretions, compensate for deficient pancreatic lipase, as does mammary gland lipase if the infant is receiving breast milk. Current recommendations for dietary fat consist of provision of 40% to 52% of total calories (4.4 to 5.7 g/100 kcal). Long-chain polyunsaturated fatty acids (LC-PUFAs) are essential for normal growth and development, particularly of the retina and brain. LC-PUFA supplementation, therefore, has been a topic of much discussion and research in recent years. Of particular interest are the n-3 and n-6 essential fatty acids, alpha-linolenic acid (ALA) and linoleic acid (LA), and their metabolites, docosahexaenoic acid (DHA) and arachidonic acid (ARA), respectively. 52 Both term and preterm human milk contain considerable quantities of linolenic acid. The preterm infant can synthesize DHA from its precursor linolenic acid, but whether the synthesized amount is sufficient remains uncertain. Human milk also contains preformed LC-PUFAs. In an effort to make formula more like the gold-standard human milk, manufacturers in the United States have added DHA and ARA to both term and preterm infant formulas.
LC-PUFA supplementation is thought to be safe for both term and preterm infants. 34,37,53,67 The evidence for long-term benefit, however, particularly for term infants, is mixed. 39,107 The inconsistent conclusions among studies have been recently reviewed. 48 For preterm infants, in whom PUFAs are particularly important for growth and brain and visual development and who have not had the opportunity for late gestation accumulation of fats, there may be benefit and little risk with supplementation. 39,66,102 Areas of ongoing research include (1) maternal supplementation of n-3 long-chain polyunsaturated fats to promote fetal growth and improve the length of gestation, (2) exploration of the effects of LC-PUFAs on preventing necrotizing enterocolitis, and (3) the relationship of neonatal fat composition to the development of atherosclerosis in later life.
Medium-chain triglycerides (MCTs) do not require bile salts for absorption and can be directly absorbed into the portal venous circulation. This offers theoretical advantages for the preterm infant, although there is little evidence that inclusion of MCTs improves growth of the healthy preterm infant. MCTs do improve fat absorption and energy intake in infants with hepatic dysfunction or short bowel syndromes.
Some fats (e.g., essential fatty acids) are essential for normal infant growth. All fatty acids provide a concentrated source of energy. The polyunsaturated n-3 fatty acids are important components of cell membranes, particularly significant for the developing nervous system. There is no place for “fat restriction” in the nutritional support of preterm or term infants within the guidelines just mentioned.


Carbohydrate reserves begin to accumulate as glycogen in the developing fetus as early as the start of the second trimester. Most of this glycogen (as much as 90% of total body glycogen in term infants) serves local cellular needs in different organs, whereas hepatic glycogen specifically provides glucose for other glucose-dependent tissues, primarily the brain. Immediately after birth, with cessation of glucose supply from the placenta, the neonate must use stored glycogen for energy. The newborn can exhaust the supply of stored glucose from the liver within 12 hours of birth under severely stressful conditions (e.g., hypoxia, hypotension, increased catecholamine and glucagon release) if food or IV glucose is not provided. The normal glucose utilization rate in the term newborn is 4 to 6 mg/kg/min. The brain accounts for most of the glucose use, especially in preterm and asymmetrically growth-restricted infants, who have a larger-than-normal brain:body-weight ratio.
The predominant carbohydrate in human milk is lactose, a disaccharide composed of glucose and galactose. Glucose has a central role in energy metabolism. Galactose provides 50% of the calories derived from lactose; its major metabolic role is in energy storage, because the newborn liver readily incorporates galactose from the portal circulation into hepatic glycogen.
Provision of 40% to 50% of total caloric intake as carbohydrate (12 to 14 g/kg/day) prevents accumulation of ketone bodies and other adverse metabolic effects (e.g., hypoglycemia) in the newborn. This amount of carbohydrate generally is supplied as lactose in human milk or commercial formulas. If there are signs of lactose intolerance, such as frequent loose stools, abdominal distention or apparent cramping, or positive stool reducing substances (Clinitest), then a portion of the carbohydrate may be given as sucrose or glucose polymers. Glucose polymers have the added advantage of keeping formula osmolality low. Lactose-free infant formulas are commercially available (Table 17-4). Use of such non-lactose products should be reserved for those rare infants with clinically proven lactose intolerance.
TABLE 17-4 Comparative Nutritional Composition of Term Infant Feedings per 100 kcal
This table lists the major constituents; refer to product inserts for a complete listing of vitamins, minerals, and trace elements.
ARA, Arachidonic acid; DHA, docosahexaenoic acid.
*Data from Klein CJ, editor: Nutrient requirements for preterm infant formulas, J Nutr 132:1395S, 2002; and Tsang RC, Uauy R, Koletzko B, et al, editors: Nutrition of the preterm infant: scientific basis and practical guidelines, ed 2, Cincinnati, 2005, Digital Educational Publishing.
Mead Johnson Nutritionals, Evansville, Ind.
Abbott Nutrition, Columbus, Ohio
Cow’s Milk–Based
Lactose Free Soy Protein–Based
Mature Human Milk (28 Days) * Enfamil® Lipil® with Iron Similac® Advance® with Iron Enfamil® Lactofree® Lipil® Similac® Sensitive® with Iron Enfamil® ProSobee® Lipil® Similac® Isomil® Advance®
Nutrient density (kcal/oz) 20 20 20 20 20 20 20
Energy (kcal) 98-110 100 100 100 100 100 100
Amount (g) 1.8 2.1 2.07 2.1 2.14 2.5 2.45
% Total calories 7 8.5 8 8.5 9 10 10
Source Human milk Reduced minerals; whey and nonfat milk Nonfat milk and whey protein concentrate Milk protein isolate Milk protein isolate Soy protein isolate Soy protein isolate and l-Methionine
Amount (g) 4.3-4.9 5.3 5.4 5.3 5.4 5.3 5.46
% Total calories 50 48 49 48 49 48 49
Source Triglycerides
Palm olein
Soy oil
Coconut oil
High oleic vegetable oil
Single cell oil products (DHA and ARA)
High oleic safflower oil
Soy oil
Coconut oil
Single cell oil products (DHA and ARA)
Palm olein
Soy oil
Coconut oil
High oleic vegetable oil
Single cell oil products (DHA and ARA)
High oleic safflower oil
Soy oil
Coconut oil
Palm olein
Soy oil
Coconut oil
High oleic vegetable oil
Single cell oil products (DHA and ARA)
High oleic safflower oil
Soy oil
Coconut oil
Single cell oil products (DHA and ARA)
Linoleic acid (mg) 440-1500 860 1000 860 1000 860 1000
Amount (g) 10-11 10.9 10.8 10.9 10.7 10.6 10.3
% Total calories 40-44 44 43 44 43 42 41
Source Lactose and glucose Lactose Lactose Corn syrup solids Corn maltodextrin and sucrose Corn syrup solids Corn syrup and sucrose
Calcium (mg) 39-45 78 78 82 84 105 (5.2) 105 (5.2)
Phosphorus (mg) 18-24 43 42 46 56 69 75
Ca:P ratio 1.9-2.1 1.8 1.8 1.5 1.5 1.5 1.4
Sodium (mg [mEq]) 18-26 [0.8-1.1] 27 [1.2] 24 [1] 30 [1.3] 30 [1.3] 36 [1.6] 44 [1.9]
Potassium (mg [mEq]) 60-80 [1.5-2] 108 [2.8] 105 [2.7] 110 [2.8] 107 [2.7] 120 [3.1] 108 [2.8]
Chloride (mg [mEq]) 55-63 [1.6-1.8] 63 [1.8] 65 [1.8] 67 [1.9] 65 [1.8] 80 [2.3] 62 [1.8]
Iron (mg) 0.05-0.75 1.8 1.8 1.8 1.8 1.8 1.8
Zinc (mg) 0.2-0.3 1 0.75 1 0.75 1.2 0.75
Magnesium (mg) 4.5-5 8 6 8 6 11 7.5
Vitamin A (international units) 110-320 300 300 300 300 300 300
Vitamin D (international units) 3-3.2 60 60 60 60 60 60
Vitamin E (international units) 0.3-0.6 2 1.5 2 3 2 1.5
Vitamin K (mcg) 0.3 8 8 8 8 8 11
Vitamin C—ascorbic acid (mg) 5.6-6 12 9 12 9 12 9
Vitamin B 1—thiamine (mcg) 29-31 80 100 80 100 80 60
Vitamin B 2—riboflavin (mcg) 49-51 140 150 140 150 90 90
Vitamin B 6 (mcg) 10-46 60 60 60 60 60 60
Folic acid (mcg) 2.5-18 16 15 16 15 16 15
Potential renal solute load (mOsm) 14 19.4 18.7 20 19.9 23.9 22.8
Osmolality (mOsm/kg water) 290-305 300 300 200 200 200 200


Vitamins are organic substances that are present in trace amounts in natural food sources and are essential to normal metabolism. Lack of vitamins in the diet produces well-recognized deficiency states in adults. The biologic roles of many vitamins are not completely understood in preterm infants, and recognition of clinical deficiency states often is difficult. 98 Certain vitamins have received close attention in neonatology, in particular vitamin C for its role in enhancing iron absorption from the gastrointestinal tract, vitamin K for prevention of hemorrhagic disease of the newborn, 4 vitamin D for the prevention of rickets, 103,116 and vitamins A and E as antioxidants. 49 Vitamin A supplementation has been shown in some studies to decrease chronic lung disease in ELBW infants. 112
Because vitamins have a central role in many metabolic processes, signs of vitamin deficiency can be nonspecific, such as lethargy, irritability, and poor growth. Table 17-5 is a summary of the recommended vitamin intake for enterally fed infants. For comparison, the average vitamin content of term human milk and commercial infant formulas is included in Table 17-4. 110 Routine supplementation of vitamins above the recommended doses is not advised because of possible toxicity and lack of clearly demonstrated benefits. For example, although supplementing vitamin D at 1000 international units/day has not been shown to result in full repletion, 25 there is no evidence that supplementation above the recommended dose prevents osteopenia in preterm infants.
TABLE 17-5 Recommended Enteral Mineral and Vitamin Intake for Infants
Data from Klein CJ, editor: Nutrient requirements for preterm infant formulas, J Nutr 132:1395S, 2002; Reidel BD, Greene HL: Vitamins. In Hay WW Jr, editor: Neonatal nutrition and metabolism, St Louis, 1991, Mosby.
RE, Retinol equivalents.
Term (per 100 kcal) Preterm (per 100 kcal)
Calcium (mg) 50-140 123-185
Phosphorus (mg) 20-70 82-109
Ca:P ratio by weight 1-2:1 1.7-2:1
mg 25-50 39-63
mEq 1.1-2.2 1.7-2.7
mg 60-160 60-160
mEq 1.5-4.1 1.5-4.1
mg 50-160 60-160
mEq 1.4-4.6 1.7-4.6
Iron (mg) 0.2-1.65 1.7-3
Zinc (mg) 0.4-1 1.1-1.5
Magnesium (mg) 4-17 6.8-17
Vitamin A (mcg RE) 61-152 204-380
(international units) 203-506 679-1265
Vitamin D (international units) 40-100 75-270
Vitamin E (international units) 0.5-? 2-8
Vitamin K (mcg RE) 1-25 4-25
Vitamin C—ascorbic acid (mg) 6-15 8.3-37
Vitamin B 1—thiamine (mg) 30-200 30-250
Vitamin B 2—riboflavin (mg) 80-300 80-620
Vitamin B 6—pyridoxine (mg) 30-130 30-250
Folate (mcg) 11-40 30-45

Minerals and Trace Elements

The content of minerals in human milk is the gold standard for mineral requirements in term infants. Mineral requirements for the preterm infant have been estimated from in utero accretion rates. Preterm infants are relatively lacking in some important minerals (e.g., iron, calcium, zinc), because their accumulation occurs mostly in the third trimester. Published recommendations for selected daily intakes in healthy, enterally fed preterm infants are shown in Tables 17-5 and 17-6 and discussed in detail in Reference 63

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