Premature Infants

The data are overwhelming. Even the most reluctant of neonatologists have accepted the tremendous importance of human milk to all infants large and small.

Research in the science of nutrition for low-birth-weight (LBW) infants and micropremature infants has advanced tremendously as the technology to study the important questions has improved. Neonatologists meanwhile have spent the past decades studying the physiology of respiration. Their advances have contributed to the survival of smaller and smaller infants. The edge of viability is 24 weeks and a weight of 500 g; however, infants have survived under these values. One of the key points learned retrospectively about survival, generation after generation, has been the critical impact of fluid and nutrition. Although human milk has gained prominence in these studies, the early use of unsupplemented drip milk and some donor milks produced poor growth patterns. Drip milk is low in fat and, therefore, low in calories. The protein levels in donor milk from women late in lactation (i.e., beyond 6 to 8 months, when the levels have dropped) parallel a child’s decreased biologic needs with the addition of solid foods. These factors contributed to the abandonment of human milk until supplements were developed and studies of the milk of women who had delivered prematurely sparked new investigations.

This discussion highlights only the important issues; the reader is referred to reviews such as the exhaustive summary of human milk for the premature infant in the technical review of the optimal feeding of LBW infants for the World Health Organization (WHO) by Edmond and Bahl that was released in 2006. Policy statements from WHO, UNICEF, and other international and national organizations confirm the importance of providing a mother’s own milk to preterm and small-for-gestational-age (SGA) infants. Standard practice in neonatal units is to promote mother’s own milk as the food of choice for all LBW infants. Edmond and Bahl state that their review confirms this position worldwide. Nutritional Needs of the Preterm Infant by Tsang et al. is an international collaboration that involved many major premature infant centers in discussions to create unity out of a tremendous disparity of practice and various recipes for nutritional support in 1993. This collaboration also produced a consensus on individual nutrient requirements for infants of less than 1000-g birth weight, for 1000- to 1750-g infants, and for postdischarge management. In spite of these strong statements, however, neonatologists have not reached a consensus on the feeding of premature infants. The absolute standard for evaluating the nutritional outcome of preterm infants remains undefined. A strategy to minimize mobilization of endogenous nutrient stores is moving from a focus on intrauterine-based, short-term growth and nutrient retention rates to a system that considers long-term growth achievement. The optimal time to initiate oral feedings in the smallest and sickest preterm infants is under revision. Prolonged exclusive parenteral nutrition is being replaced with minimal amounts of oral feedings with parenteral nutrition to preserve and maintain intestinal function. As nutritional markers shift, a preterm infant’s own mother’s milk may well be recognized, even by the most skeptical clinicians, as the “gold standard” to prevent short-term morbidities and enhance long-term outcome. With this change comes the recognition that even fortified donor milk is superior to artificial feeds.

LBW has been defined by WHO as a weight at birth of less than 2500 g. The global incidence of LBW is 15.5%, which includes 20.6 million infants born each year, only 35% of which occur in developed countries. LBW infants form a heterogeneous group, some born early, some who are born at term but are SGA, and some both early and small. LBW infants account for 60% to 80% of all neonatal deaths and are at high risk for early growth retardation, infectious disease, developmental delay, and death in infancy and childhood.

A normal full-term infant can usually be breastfed with only minor adjustments, even without the support of medical expertise. When an infant cannot nurse directly at the breast, is providing mother’s milk appropriate? What is the overall prognosis for ever feeding at the breast or, perhaps, for survival itself? Parents are so awed by the medical staff of special and intensive care nurseries that they are often afraid to bring up the subject of breastfeeding. In addition, the nursery staff may be so busy balancing electrolytes and adjusting ventilators and monitors that they have not thought to ask what plans the mother might have had for feeding before the infant developed a problem ( Table 15-1 ).

The birth of an extremely LBW (ELBW) premature infant is a nutritional emergency. Even with parenteral nutrition from the first day, weight loss exceeds 10%, and it takes at least 10 days to regain birth weight. The long-term consequences of early nutrition have a great impact on neurodevelopment and may well reduce the risk for perinatal brain lesions. Fetal and postnatal events affect gut development.

Gastrointestinal Tract Development

The gastrointestinal (GI) tract is one of the first structures defined in the developing embryo. Gut length proceeds rapidly throughout fetal life and for the first years of life. The proton pump is present at 13 weeks of gestation. Intrinsic factor and pepsin are identifiable a few weeks later ( Figure 15-1 ). Even in ELBW premature infants, the gastric pH can be lowered to 4.0. Digestive enzymes are capable of intraluminal digestion of fat, protein, and carbohydrates. Although pancreatic lipase and bile salts are minimal in ELBW infants, the introduction of mother’s milk will stimulate maturation and also provide lipases and other digestive enzymes.

The ontogenic timetable showing structural and functional gastrointestinal development.

(Modified from Newell SJ: Enteral feeding of the micropremie, Clin Perinatol 27:221, 2000.)

The intestinal villi and cellular differentiation occur at about 10 to 12 weeks’ gestation and begin a complex interrelationship with developing epithelium and the mesoderm, according to Newell. Lactase and other carbohydrate enzymes begin to appear. Gut motility is believed to appear first as irregular GI activity at 23 weeks progressing to organized motility at approximately 28 weeks. Most studies of nutritive sucking and swallowing are done with artificial feeding with a bottle. Suckling at the breast, which begins with peristaltic motion of the tongue and continues down the esophagus, has been initiated by breastfeeding as early as 28 weeks or sooner.

Gastric emptying in premature infants is slow, generating the impression that feedings are not tolerated. Gastric emptying is enhanced by human milk and slowed by formula and increased osmolarity ( Box 15-1 ). Half emptying time with human milk is reported to be as rapid as 20 to 40 minutes. Ultrasound studies have assessed small volume feeds. Some premature infants show delayed antral distention after a nasogastric feeding with emptying that follows a curvilinear pattern after an initial rapid phase.

Maturation of the small intestinal motility, and hence tolerance of feeds, is enhanced by previous exposure of the gut to nutrition. Early feeding precipitates preferential maturation and thus a more mature response to feeds. Total gut transit time in premature infants varies from 1 to 5 days and is more rapid in those who have received food. In those younger than 28 weeks, it takes 3 days to pass meconium. Breast milk feedings, however, increase motility and stool passage.

When prematurity is complicated by intrauterine growth failure, the resultant cascade of events includes decreased splanchnic circulation and oligohydramnios, poor gut perfusion, decreased growth of the small intestine and pancreas culminating in a fetal echogenic gut, and poor intestinal motility resulting in poor tolerance to milk feeds. It is not uncommon for this to result in necrotizing enterocolitis (NEC). These events require careful consideration, including the choice to use mother’s milk, especially beginning with colostrum.

Although feeding regimens vary, evidence is strong and consistent that feeding mother’s own milk to preterm infants at any gestation is associated with a lower incidence of infections and NEC and improved neurodevelopmental outcome compared with the use of bovine milk products. The challenge is to increase the availability of mother’s milk ( Figure 15-2 ).

Strategies for beneficial effects of bioactive agents in human milk. Human milk contains bioactive agents with overlapping and synergic effects on intestinal development of neonates. MFGM, Milk fat globule membrane; PAF-AH, platelet-activating factor-acetylhydrolase.

(Modified from Goldman AS: Modulation of the gastrointestinal tract of infants by human milk. Interface and interactions. An evolutionary perspective, J Nutr 130:426S, 2000.)

GI Priming

When feedings are delayed in any newborn, luminal starvation results in epithelial cell atrophy. Lung injury may aggravate this because of multiorgan system dysfunction, increasing the risk for intestinal mucosal injury and associated barrier dysfunction. The ultimate injury would be the invasion of bacteria from the gut lumen. Initiating feeds is a delicate balance between insufficient feeds that fail to trigger gut maturation and excessive feeds that overwhelm the digestive capacity. Also, excessive feeds can result in bacterial overgrowth and injury to the brush border. When internal nutrients are absent, the intestinal size and weight are diminished; atrophy of the mucosa, delayed maturation of intestinal enzymes, and increased permeability and bacterial translocation may occur. Intestinal motilities, perfusion, and reactions to the usual GI tropic hormones are also affected by lack of nutrients. Trophic hormone levels in the plasma are significantly altered by starvation.

In the words of Lucas, “It is fundamentally unphysiological to deprive an infant of any gestation of enteral feeding since the deprivation would never normally occur at any stage.” This statement is based on the fact that a fetus normally makes sucking motions and swallows amniotic fluid from early gestation. This may even have a trophic effect on the gut. By the third trimester, a fetus is swallowing up to 150 mL/kg/day, which actually provides as much as 3 g/kg of protein per day. The secretion of GI hormones is believed to occur in response to the first postdelivery feedings. In animals, after only a few days of deprivation of enteral feeds, atrophic changes take place in the gut. In human infants who have never received enteral feedings, no gut peptide surges occur, not even those of the trophic hormones enteroglucagon, gastrin, and gastric inhibitory polypeptide. These hormones are believed to be key to the activation of the enteroinsular axis ( Box 15-2 ). Clinical trials of early priming in premature infants showed that infants primed in the first few days or first week had better feeding tolerance to advancing feeds and were weaned from parenteral nutrition promptly. It was also associated with lower serum alkaline phosphatase activity and significant stimulation of GI hormones such as gastrin. It also resulted in more mature intestinal motility patterns, greater absorption of Ca and P, increased lactase activity, increased bone mineral content (BMC), and reduced intestinal permeability. Tyson and Kennedy reviewed the studies of early priming and found shorter times to full feeding, fewer days when feedings were held, a shorter duration of hospitalization, and no increase in NEC. Many of the involved infants were actually at high risk for complications by virtue of their own morbidities, including mechanical ventilation, umbilical catheterization, and patent ductus arteriosus. Schanler recommended that ELBW infants who are ill be given small volumes, 10 to 20 mL/kg/day, in the first few days of life to continue for 3 to 7 days before advancing the feeds. Clinical stability is required before advancing the feeds. These volumes are compatible with the volume of mother’s milk of a mother of a premature infant ( Boxes 15-3 and 15-4 ). In a randomized trial of GI priming and the tube-feeding method, bolus feeding was found to be superior, the major outcome being time required to attain full oral feedings. GI priming was not associated with adverse effects. Feeding intolerance was less and the rate of weight gain was greater. The greater the amount of human milk fed, the lower the morbidity.

Although early enteral feedings are not universally accepted, a number of randomized controlled studies support the concept. Berseth reports that the response of the preterm infant’s intestine to entire feedings at different postnatal ages showed significantly more mature motor patterns of the gut as well as higher plasma concentrations of gastrin and gastric inhibitory peptide. From a management standpoint, early-fed infants were able to tolerate full oral feeds sooner, had fewer days of feeding intolerance, and required shorter hospital stays. Studies varied from infants who were fed at less than 24 hours of age at 1 mL/h to infants who were fed full feeds starting at days 2 to 7 compared with infants on usual delayed protocols. All showed an advantage to early feeds ( Table 15-2 and Box 15-5 ).

Requirements of ELBW infants begin with water, the first great need, followed by energy requirements of 120 kcal/kg/day to meet metabolic and growth rates. Protein is key because ELBW infants miss the last trimester, when protein and fat are stored. To stop catabolism and promote protein accretion, Brumberg and LaGamma recommend 3.5 to 4 g/kg/day of protein, presuming a daily loss of 1.1 to 1.5 g/kg of stored protein per day. Protein should start early either orally or by parenteral nutrition.

Human milk is the preferred feeding for all infants, including premature and sick newborns, with rare exception according to the American Academy of Pediatrics (AAP), WHO, and the Institute of Medicine.

Human milk is better than formula in early feeds in establishing enteral tolerance and discontinuation of parenteral nutrition, in long-term improved neurodevelopmental outcome, and in the psychological benefit to mothers. Human milk falls short after 4 to 6 weeks in the amount of protein, calcium, and phosphorus, a problem solvable with the use of a human milk fortifier. No substitute has been developed that replaces the many and varied advantages of human milk, however.

Many investigators have concluded that minimal enteral feedings with human milk can optimize growth, development, and progress for small premature infants, even if ventilator dependent. In most studies, the incidence of NEC has been similar with and without early feeds. The presence of an umbilical catheter has long been a contraindication to feeding because of the risk for NEC. When Davey et al. investigated this, the incidence of NEC was comparable in infants with and without umbilical catheters.

Other advantages of early feeds include lower serum direct and indirect bilirubin and less phototherapy. Benefits from early feeds were measurable with raw maternal milk, pasteurized premature milk, and even to some extent whey-dominant infant formula ( Figure 15-3 ).

Episodes of apnea and bradycardia before and after initiation of transpyloric tube feedings especially when limited to human milk.

(From Malcolm WF, Smith PB, Mears S, et al: Transpyloric tube feeding in very low birthweight infants with suspected gastroesophageal reflux: impact on apnea and bradycardia, J Perinatol 29:372, 2009.)

Low Birth Weight (LBW) Infants

All premature infants are not the same. Infants who are born weighing less than 2500 g are referred to as being low birth weight (LBW). If the infants are less than 37 weeks’ gestation, they are premature; if they are full term and LBW, they are SGA.

Very LBW (VLBW) refers to an infant weighing less than 1500 g. The probability of survival has changed dramatically in all weight ranges. With the availability of surfactant for respiratory distress, infants between 500 and 1000 g are surviving in greater numbers. The problems of nutrition, however, pose new challenges to the neonatologist. The feedings appropriate for a 2000-g premature infant vary only in volume and frequency from full-term infants in most cases. Feedings for VLBW infants must address the advantages and disadvantages of human milk at this point in their growth curve. The composition of mother’s milk varies in some constituents with the degree of prematurity, which is advantageous ( Box 15-6 ).

The advantages of human milk for LBW infants include the physiologic amino acid and fat profile, the digestibility and absorption of these proteins and fats, and the low renal solute load. The presence of active enzymes enhances maturation and supplements the enzyme activity of this underdeveloped gut. The antiinfective properties and living cells protect immature infants from infection and protect against NEC. The psychological benefit to the mother who can participate in her infant’s care by providing her milk is a less tangible but no less important advantage.

The disadvantages are the possible gaps in certain nutrients that have been estimated to be required for adequate growth, which include the volume of total protein and macrominerals, especially calcium and phosphorus. Much of the attention to the shortcomings has been based on work done using pooled milk samples collected from women whose infants are full term and many months old, resulting in the impression that mother’s milk is inadequate. The sources of the human milk and processing—freezing or pasteurizing—are significant to the question of nutritional adequacies. Many laboratory and clinical scientists have studied the questions posed here with new techniques and provided hundreds of reports regarding the nutrition and nurturance of LBW and VLBW infants. Only a fraction of the resources can be referenced here.

Optimal Growth for Premature Infants

Optimal growth for infants born prematurely is considered to be the growth curve they would have followed had they remained in utero ( Figure 15-4 and Tables 15-3 and 15-4 ). Achieving this goal utilizing the immature intestinal tract requires that the nutrients be digestible and absorbable and not impose a significant metabolic stress on the other immature organs, especially the kidney. Although human milk provides the ideal nutrients, it would require an inordinate nonphysiologic volume to achieve adequate amounts of some nutrients without calculated supplementation. To fill these growth needs, one can use an artificial or chemical formula or use human milk as a base, with all its advantages, and add the deficient nutrients to it.

Postnatal bone mineral content (BMC) in 33- to 35-week-old appropriate-for-gestational-age or preterm infants compared with intrauterine bone mineralization curve. Regression curve and 95th percentile confidence limits for regression for BMC of infants born at different gestational ages (30 to 42 weeks’ gestational age) represent intrauterine bone mineralization curve. Infants fed routine cow milk formula (solid triangles) had significantly lower BMC than infants fed standard formula supplemented with calcium and phosphorus (solid circles). In these infants, BMC was not different from intrauterine bone mineralization curve at 4 and 6 weeks’ postnatal age.

(From Steichen JJ, Gratton TL, Tsang RC: Osteopenia of prematurity: the cause and possible treatment, J Pediatr 96:528, 1980.)

Special Properties of Preterm Milk

The identification of special quantitative differences in nutrients in the milk of mothers who delivered prematurely created new interest in the use of human milk for premature infants (see Box 15-6 ). Many investigators have contributed to the pool of knowledge after the initial revelations in 1980 by Atkinson et al., who reported the nitrogen concentration of milk from mothers of premature infants to be greater than that of milk from mothers delivering at term.

Preterm milk is higher in protein content during the first months of lactation, containing between 1.8 and 2.4 g/dL. Preterm milk contains similar fat in quality and quantity, although Anderson et al. reported increased values for preterm milk over term milk. Lactose in preterm milk averages 5.96 g/dL and up to 6.95 g/dL at 28 days, whereas the values in term milk are 6.16 and 7.26 g/dL, respectively. Preterm milk has higher energy than term milk, 58 to 70 kcal/dL, compared with 48 to 64 kcal/dL in the first month postpartum ( Figure 15-5 ).

Protein content of human milk.

(Data from Butte NF, Garza C, Johnson CA, et al: Longitudinal changes in milk composition of mothers delivering preterm and term infants, Early Hum Dev 9:153, 1984; Gross SJ, David RJ, Bauman L, Tomarelli RM: Nutritional composition of milk produced by mothers delivering preterm, J Pediatr 96:641, 1980.)

The macronutrients calcium and phosphorus are slightly higher in preterm milk (14 to 16 mEq/L vs. 13 to 16 mEq/L calcium and 4.7 to 5.5 m/L vs. 4.0 to 5.1 m/L phosphorus). Neither term nor preterm milk has adequate calcium and phosphorus for the VLBW infant. Magnesium levels in preterm milk are 28 to 31 mg/L, dropping to 25 mg/L at 28 days, and term milk levels are 25 to 29 mg/L. Zinc levels are higher in preterm milk, beginning at 5.3 mg/L and dropping to 3.9 mg/L, whereas term milk begins at 5.4 mg/L and drops to 2.6 mg/L. Sodium levels in preterm milk are higher (26.6 mEq/L, dropping to 12.6 mEq/L), whereas term milk is 22.3 mEq/L, decreasing to 8.5 mEq/L at 28 days. Chloride has a similar average (preterm 31.6 mEq/L, decreasing to 16.8 mEq/L, and term 26.9 mEq/L, decreasing to 13.1 mEq/L).

Requirements for Growth in Premature Infants

The whey protein in human milk is an advantage for all infants but especially for premature infants. It includes the nine amino acids known to be essential to humans, as well as taurine, glycine, leucine, and cystine, which are considered essential for premature infants. Taurine is not present in cow milk and has to be manufactured and added to formula. The premature infant lacks the necessary enzymes for metabolism and has been noted to accumulate nonphysiologic levels of methionine, tyrosine, phenylalanine, blood urea, and ammonia. When fed formula, the protein requirement for LBW infants based on intrauterine accretion rates is 2.5 g/100 kcal or 325 mg/kg of body weight per day. The metabolizable energy requirement is 109 kcal/kg/day. Further study has led to the recommendation of 3.2 to 4 g/kg/day because VLBW infants’ protein requirements have to be considered in combination with energy intake. If energy intake is deficient, protein synthesis can be depressed and protein retention reduced. Greater protein intake is risky if energy intake is limited. LBW infants fed mother’s milk exclusively for 2 weeks have been found to have low protein. This has led to the need to supplement human milk when the infant has reached full tolerated volumes (150 mL/kg/day). Protein content of human milk on average is 1.09 g/dL, whereas fortified human milk is 2.2 g/dL. Fortified milk can achieve 3 to 3.5 g/kg/day; however, in some cases 4 g/kg/day may be necessary. Although formula has more protein, it is not well absorbed.

A diurnal variation in the creamatocrits (see Chapter 21 ) of expressed breast milk of mothers delivering prematurely was demonstrated in 23 mothers by Lubetsky et al. The creamatocrit was significantly higher in the evening—7.2% ± 2.0% compared with first morning samples, 5.4% ± 1.2% ( p < 0.001)—regardless of gestational age or birth weight.

Fat content of mother’s milk is not affected by fetal growth of the infant. Fifty-six lactating women of newborns (26 SGA and 30 AGA [appropriate-for-gestational-age]) had their creamatocrits measured on the third day postpartum and again at 7 and 14 days. Other parameters (maternal age, body mass index, gestational age, weight gain, or parity) were similar except for birthweight for gestational age (SGA or AGA). Fat content of the milk was not affected by fetal growth status.

The requirement for fat is based on the essential fatty acid proportion as 3% of total caloric intake. Human milk has high levels of linoleic acid (9% of lipids) and adequately meets this requirement. Human milk fat is more readily absorbed in the presence of milk lipase and other enzymes in human milk. It is reported that infants less than 1500 g absorb 90% of human milk fat and 68% of cow milk formula fats. This phenomenon is due to the fact that human milk has a very special fat globule containing another protein coat and inner lipid core (see Chapter 4 ). The pattern of fatty acids (i.e., high in palmitic 16.0, oleic 18:1, linoleic 18:2 omega-6, and linolenic 18:3 omega-3), their distribution on the triglyceride molecule, and the presence of bile salt-stimulated lipase characterize the lipid system in human milk. The presence of lipase in human milk facilitates the fat digestion and absorption. Lipase is heatable, is reduced in activity in donor milk, and does not exist in formula. So, although formula has higher levels of fat, it is not as well absorbed or metabolized.

Fat digestion is efficient in LBW infants who receive their own mother’s milk fresh and untreated. Fat absorption is decreased by calcium supplementation, however, and by sterilizing the milk. If human milk is supplemented with lipids, it will change the vitamin E/polyunsaturated fatty acid (PUFA) ratio. Vitamin E may need to be added to keep the vitamin E/PUFA ratio greater than 0.6 (human milk vitamin E/PUFA is 0.9 normally).

Special attributes of human milk for VLBW infants have been confirmed as investigators inspect the value of adding nutrients to formulas specifically for these infants. In a study of omega-3 fatty acids on retinal function using electroretinograms, human milk was associated with the best function, followed by formula supplemented with omega-3 fatty acids. This supports the concept that omega-3 fatty acids are essential to retinal development.

Although human milk contains 250 mg Ca and 140 mg/L P in ready absorbable form, preterm and term milk do not contain sufficient calcium and phosphorus for bone accretion in LBW infants. Rickets has developed in LBW infants who are not supplemented because the requirement for bone growth at this point in the growth curve is high. Calcium and phosphorus fetal accretion increases steadily during the last trimester of pregnancy. Magnesium accretion is unchanged in that period.

Mineral accretion is a complex phenomenon dependent on a number of variables beyond simple levels of calcium, phosphorus, magnesium, and vitamin D. Absorption and retention are altered by the quantities of other minerals and other nutrients, including fat, protein, and carbohydrate. Although the calcium/phosphorus ratio in human milk is more physiologic than that of cow milk, the low levels of phosphorus may lead to loss of calcium in the urine if not supplemented.

Even with optimal vitamin D and magnesium, the amount of calcium absorbed from preterm milk is not enough to meet intrauterine accretion rates without supplementation. Because human milk phosphorus levels are low, even with high intestinal absorption and high renal tubular reabsorption, compared with the needs of the premature infant, supplementation is necessary to avoid depletion or deficiency. Intrauterine accretion rates for calcium and phosphorus were achieved when Schanler and Abrams fed human milk supplemented with calcium gluconate and glycerophosphate to VLBW infants. In their study, supplementation with magnesium was not included. The authors concluded that greater intakes of calcium and phosphorus and not improved bioavailability were responsible for the improved net retention. Premature infants who receive only unfortified human milk never achieve intrauterine retention rates of Ca and P.

Vitamin D requirements in this period of high skeletal development depend on maternal vitamin D status because significant correlation exists between maternal serum and preterm infant cord serum 25-hydroxyvitamin D values. Recommendations for vitamin D have changed dramatically. No longer are maternal stores considered adequate. Work by Wagner et al. has demonstrated that average women, even with a healthy lifestyle, have low vitamin D levels and thus their infants are relatively deficient at birth, especially infants born prematurely. The milk was also low in vitamin D. The recommended daily dose of vitamin D for mothers is 1000 units. Obtaining vitamin D blood levels is simple and should be checked early in pregnancy and the dose adjusted. Because infants are no longer exposed to sunlight, dietary sources are crucial. LBW infants quickly become dependent on exogenous vitamin D because fetal storage is minimal. The recommended dietary allowance of 400 units of vitamin D appears to be appropriate for all LBW infants, regardless of feedings, as well as for term infants. The 2014 AAP Committee on Nutrition recommends 125 to 333 USP units of vitamin D for infants less than 1000 g and the same for infants more than 1000 g, varying the absolute value by the actual weight—larger infants receive the larger dose.

Other vitamin needs of LBW infants depend on body stores, intestinal absorption, bioavailability of the vitamin, and rates of utilization and excretion. Little information suggests that major differences exist in absorption between term and LBW infants, although fat-soluble vitamins depend on bile acids for absorption. (See Chapter 9 for vitamin requirements.) It is recommended that LBW infants receive daily vitamin supplements to address the increased need and borderline levels provided in the volume of human milk they can reasonably consume ( Box 15-7 ).

Box 15-7

Vitamin Supplements for Low-Birth-Weight Infants Fed Human Milk

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  Vitamin B ₁₂ : Only if mother’s diet deficient

  
  
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  Folic acid: Human milk usually adequate

  
  
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  Thiamin (B ₁ ): Borderline

  
  
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  Riboflavin (B ₂ ): Borderline

  
  
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  Vitamin B ₆ : Human milk usually adequate

  
  
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  Niacin: Human milk usually adequate

  
  
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  Vitamin A: 1000-1500 IU/day

  
  
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  Vitamin C: If infant receives supplementary protein up to 60 mg/day

  
  
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  Vitamin D: 400 IU/day

  
  
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  Vitamin K: All infants should receive 0.5-1 mg at birth; recommended 5 mg/kg/day; human milk borderline

  
  
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  Vitamin E: 25 IU/day for first month; 5 IU/day after first month; human milk adequate

IU, International units.

The mineral supplementation required for LBW infants fed human milk is based on intrauterine accretion rates, which may not actually be achieved ( Table 15-5 ). Not all premature infants fed human milk develop rickets, which occurs infrequently in infants greater than 1500 g. VLBW infants do need supplementation, and cases of rickets are well documented in the literature for this group. Supplements are usually not necessary while an infant is receiving fortified human milk or formula and when an infant reaches 40 weeks’ postconceptional age. Hypophosphatemia is a sensitive biochemical indicator of low bone mineralization in VLBW infants fed human milk. Tsang et al. recommend weekly measurements of serum phosphorus for the first month and biweekly until 2000 g or 40 weeks’ gestation. A level less than 4 mg/dL phosphorus should be followed by X-ray films of the wrists for osteopenia and rickets. Supplementation should be based on an infant’s needs. Calcium levels should also be obtained weekly to evaluate levels greater than 11 mg/dL for too much calcium or too little phosphorus. Supplements of calcium and phosphorus are incorporated in available human milk supplements derived from formula ( Table 15-6 ). Now such supplementation is available from human milk products: Prolact CR, product of Prolacta ( Figure 15-6 and Box 15-8 ) and Medolac ( Box 15-9 ).

Table 15-5

Required Calcium (Ca), Phosphorus (P), and Magnesium (Mg) Intake to Meet Fetal Accretion Rate at 27 and 30 Weeks ^∗

	27 Weeks			30 Weeks
	Ca	P	Mg	Ca	P	Mg
Accretion (mg/kg/day)	121	72	3.37	123	72	3.17
Retention (% intake)	50	89	59	50	89	59
Intake (mg/kg/day)	242	81	5.70	246	81	5.37

 

From Steichen JJ, Krug-Wispe SK, Tsang RC: Breastfeeding the low birth weight preterm infant, Clin Perinatol 14:131, 1987.

* Assuming a weight of 1000 g and 1250 g, respectively, in an infant fed human milk.

Table 15-6

Weight Gain (g/day) Supported by Intake of 180 mL Human Milk per Kilogram at Selected Body Weights

	Weight Gain (g/day)
	800	1000	1500	2000
Calcium	4	5	6.7	8.4
Phosphorus	4	5	6.8	8.7
Nitrogen	10	12	16	21
Sodium	5	7	11	15
Magnesium	12	15	22	28
Chloride	22	30	48	68
Potassium	21	33	49	66

 

Data from Forbes GB: Nutritional adequacy of human breast milk for premature infants. In Lebenthal E, editor: Textbook of gastroenterology and nutrition in infants, New York, 1981, Raven, pp 321–329.

Prolact CR®.

(Reproduced with permission from Prolacta Bioscience®.)

Box 15-8

Prolact CR® 10 mL Human Milk Caloric Fortifier (Human, Pasteurized)

Product Description

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  Prolact CR is pasteurized human milk cream derived from human milk. It is composed of 25% fat and provides 2.5 Cal/mL. It contains no added minerals.

  
  
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  Store at: − 20° C or colder until ready to thaw for preparation and use.

  
  
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  Available frozen in 30 mL bottles containing 10 mL of product (four bottles per package).

Intended Use

Prolact CR is intended for use with mom’s own breast milk or donor human milk to achieve a 20 Cal/fl oz feeding solution.

Directions for Thawing

Under no circumstances should the product be defrosted or warmed in a microwave.

Remove bottle from the freezer and label with date and time. Thaw product using any of the following methods:

• 1.
  

  Refrigeration: (2° C to 8° C) Place unopened bottle in refrigerator. Once thawed, must be administered within 24 hours. Do not refreeze, keep refrigerated.

  
  
• 2.
  

  Rapid Thawing: Place bottle under lukewarm running water, or place in a water bath. Do not submerge top of bottle. Warm only until product is thawed. Continued warming, or exposure to high temperatures, could result in undesirable changes to the product. Wipe outside of bottle with appropriate disinfectant to reduce the risk of contamination. Once thawed, keep refrigerated, do not refreeze. Product must be administered within 24 hours of thawing.

Ingredients

Human milk cream and human milk ultrafiltration permeate.

Preparation Instructions

Always maintain aseptic technique when preparing and handling human milk products. **DO NOT ADD WATER**

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  Thaw mom’s own or donor milk according to hospital policy.

  
  
• 2.
  

  Measure caloric content of mom’s own or donor milk.

  
  
  
  
  
  
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    If using a commercial human milk analyzer, follow the manufacturer’s instructions.

    
    
  • b.
    

    If using a creamatocrit, ensure the milk is room temperature and follow the manufacturer’s instructions.

  
  
  
  
• 3.
  

  Thaw Prolact CR according to “Directions for Thawing.” Swirl gently prior to each aliquot.

  
  
• 4.
  

  Based on the measured caloric content of mom’s own or donor milk, follow the instructions in table below to formulate 100 mL of human milk plus Prolact CR.

  
  
  
  

  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  

  Cal/oz (equivalent to)	Cal/100 mL	Mom’s own or donor milk volume	+ Add to milk
  19-20	64-67.9	98 mL milk	2 mL Prolact CR
  18-18.9	61-63.9	96 mL milk	4 mL Prolact CR
  17-17.9	57-60.9	94 mL milk	6 mL Prolact CR
  16-16.9	54-56.9	93 mL milk	7 mL Prolact CR
  15-15.9	51-53.9	91 mL milk	9 mL Prolact CR
  14-14.9	47-50.9	90 mL milk	10 mL Prolact CR

   
  
  
  
  
• 5.
  

  Swirl gently to mix.

  
  
• 6.
  

  Once completed, the product is ready for use, OR

  
  
• 7.
  

  Store bottle in refrigerator (2° C to 8° C). Use within 24 hours after thawing Prolact CR.

For More Information

Visit us at www.prolacta.com or call 1(888) PROLACT

#1 for Customer Service

Manufactured by:

Prolacta Bioscience, Inc.

City of Industry, CA 91746

Reproduced with permission from Prolacta Bioscience®.

Box 15-9

Medolac® Offers Commercially Sterile, Shelf-Life-Stable Human Donor Milk as Easy-to-Use as Formula

May 4, 2015—Medolac® Laboratories, an Oregon-based human milk nutritionals start-up, announced the launch of Donormilk.com, the first direct-to-consumer offering of human milk. Medolac’s Co-op Donor Milk human milk is commercially sterile, safe, tested, homogenized, and can be stored at room temperature making it easier for home use. In addition, Medolac human donor milk is less expensive and safer than donor milk bought from online classifieds and other milk banks where testing, safety, and nutritional content cannot always be verified. This new product will make it possible for more babies to receive 100% human milk protein instead of bovine or soy protein formula.

From Medolac http://www.medolac.com/press-releases.html , with permission.

Trace minerals in general appear in physiologic amounts in human milk and are more bioavailable from human milk than artificial feedings. The minimum daily requirements for LBW infants are based on daily accretion rates as calculated from third-trimester data and calculated obligatory losses.

Zinc is known to be readily available in human milk, although zinc deficiency syndromes from hyperalimentation are well known in the literature and in neonatal intensive care units (NICUs). Zinc requirements (1000 to 3000 mg/kg/day) are probably met by a mother’s own milk, but pooled milk levels are lower because zinc levels drop from term birth through 6 months, and donor milk will need supplementation.

Copper accretion requires 59 mg/kg/day, and absorption is thought to be 50% to 70%. Copper levels also decline in milk from term to 6 months postpartum. It is recommended that VLBW infants receive an additional 30 to 40 mg/day or 120 to 150 mg/kg/day of copper for the first 3 months.

Manganese represents an apparent deficiency because the minimum daily requirement is calculated to be 7 ng/kg/day. The provision in human milk is 0.35 ng/mL, or 0.5 mg/kg/day, but no information is available recommending supplementation.

The selenium suggested requirement is 1.5 to 2.5 mg/kg/day (1 mg minimum). Human milk provides 1 to 2 mg/dL and is stable throughout lactation, so no supplementation has been recommended.

Iodine levels in human milk are sufficient to meet daily requirements in LBW infants.

Chromium requirements are calculated to be 1.0 to 2.0 mg/kg/day based on an accretion rate of 0.1 to 0.2 mg/kg/day and only 10% absorption. Levels in human milk are reported to be 0.03 mg/dL, which, with 150-mL/kg/day intake, would supply 0.045 mg/kg/day. Supplementation is not usually provided, and absorption in human milk is probably greater than 10%.

Molybdenum levels in human milk are believed sufficient to meet LBW accretion rates (1 mg/kg/day).

Iron requirements are a complex issue, and intrauterine accretion rates are not appropriate values on which to base requirements. Iron stores partially enlarged by hemoglobin breakdown in early life will eventually be used up if no iron is provided. Providing iron, however, interferes with the immunologic properties of human milk, especially the bacteriostatic properties of lactoferrin in the gut.

The recommendations for iron supplementation for infants receiving human milk (either own mother’s or donor milk, which are similar in iron) are based on age and weight of the infant. Supplementation should begin at 2 to 3 months or when birth weight has doubled. For birth weight less than 1000 g, infants should receive 4 mg elemental iron/kg/day; infants weighing 1000 to 1500 g should receive 3 mg/kg/day.

It is necessary also to ensure adequate vitamin C and vitamin E supplementation (4 to 5 mg/day), even though human milk normally contains 5 mg/dL vitamin C and 0.25 mg/dL vitamin E. Vitamin C levels in mother’s milk can be increased by dietary increases. However, vitamin C is affected by pasteurization.

GI Characteristics of Premature Infants

The anatomic differentiation of the intestinal tract begins before 20 weeks’ gestation, but the functional development is limited before 26 weeks. Different parts of the fetal gut develop at different times so that some nutrients are better tolerated than others ( Tables 15-7 and 15-8 ). The present concentration of digestive enzymes determines the rate of digestion and absorption, along with the maturity of membrane carriers. (See Chapter 7 for the impact of human milk on gut maturation.) The presence of active enzymes in the gut improves the digestion and absorption of human milk. As noted earlier, the gastric emptying time in preterm infants when given human milk is biphasic, with an initial fast phase in which 50% has left the stomach in the first 20 to 25 minutes. After 1 hour, 25 mL of human milk has left the stomach. In contrast, the formula feeding follows a linear pattern, with half emptying in 51 minutes and a total of 19 mL in 1 hour.

Table 15-8

Digestion and Absorption in Human Fetus and Neonate

Factors	First Detectable (Weeks of Gestation)	Term Neonate (% of Adult)
Protein
H + (hydrogen ion)	At birth	< 30
Pepsin	16	< 10
Trypsinogen	20	10-60
Chymotrypsinogen	20	10-60
Procarboxypeptidase	20	10-60
Enterokinase	26	10
Peptidases (brush border and cytosol)	< 15	> 100
Amino acid transport	?	> 100
Macromolecular absorption	?	> 100
Fat
Lingual lipase	30	> 100
Pancreatic lipase	20	5-10
Pancreatic colipase	?	?
Bile acids	22	50
Medium-chain triglyceride uptake	?	100
Long-chain triglyceride uptake	?	10-90
Carbohydrate
α-Amylases
Pancreatic	22	0
Salivary	16	10
Lactase	10	> 100
Sucrase-isomaltase	10	100
Glucoamylase	10	50-100
Monosaccharide absorption	11-19	> 100 (?)

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