Koletzko B, Poindexter B, Uauy R (eds): Nutritional Care of Preterm Infants: Scientific Basis and Practical Guidelines. World Rev Nutr Diet. Basel, Karger, 2014, vol 110, pp 215–227 (DOI: 10.1159/000358470)
Human Milk and Human Milk Fortifiers Ekhard E. Ziegler Department of Pediatrics, University of Iowa, Iowa City, Iowa, USA Reviewed by Richard Ehrenkranz, Yale University School of Medicine, New Haven, Conn., USA; Karen Simmer, University of Western Australia, Crawley, WA, Australia
Abstract Human milk contains numerous immune-protective components that protect the premature infant from sepsis and necrotizing enterocolitis. Because of these protective effects, human milk is the feeding of choice for the premature infant. However, human milk does not provide adequate amounts of most nutrients for premature infants and must therefore be supplemented (fortified) with nutrients. Commercially available fortifiers provide energy and most nutrients in adequate amounts. The exception is protein, which is present in expressed milk in highly variable amounts and which is not provided in sufficient amounts by most fortifiers. Some liquid fortifiers are higher in protein content © 2014 S. Karger AG, Basel than powder fortifiers and provide adequate amounts of protein.
Human milk has the dual functions of supporting and complementing the preterm infant’s developing immune system, and of providing the nutrients needed for growth and development. Because of its immune-protective function, human milk is the feeding of choice for premature infants. As a source of nutrients, however, human milk is inadequate, necessitating nutrient supplementation (fortification) [1]. Nutrient intakes that fall short of requirements place the infant at risk of impaired neurodevelopment. The main challenge is to meet the high nutrient needs of premature infants in the face of highly variable human milk composition. Methods of nutrient fortification have improved over the years but have yet to reach a state where nutrient intakes are consistently adequate.
Many bioactive components have been identified in human milk. Table 1 provides a select listing of these components grouped into immune-protective and trophic components, hormones and immune cells. Their biological activity has been doc-
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Non-Nutritive Components of Human Milk
Table 1. Anti-infectious and other bioactive substances and cells in human milk
umented experimentally to varying degrees. Immune-protective components exert anti-bacterial, anti-viral and anti-inflammatory effects. The abundant oligosaccharides exert important anti-adhesive as well as prebiotic effects promoting a healthy microbiota and limiting gut inflammatory responses and growth of pathogenic bacteria. Clinical correlates associated with the use of human milk include lower rates of bacterial sepsis and necrotizing enterocolitis (NEC). These effects are attributed collectively to the bioactive components of human milk but cannot be linked to any one specific component. Other substances exert maturational, anti-inflammatory and trophic effects on the gastrointestinal tract. As with the immune components, the known clinical effects are attributed collectively to the trophic substances. Most likely it is the interplay of these multiple components that brings about beneficial clinical effects. For example, the protective effect against NEC is likely to be brought about by the synergy of gut maturational (trophic) effects with anti-infectious, anti-adhesive, anti-inflammatory as well as prebiotic effects.
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Ziegler Koletzko B, Poindexter B, Uauy R (eds): Nutritional Care of Preterm Infants: Scientific Basis and Practical Guidelines. World Rev Nutr Diet. Basel, Karger, 2014, vol 110, pp 215–227 (DOI: 10.1159/000358470)
Downloaded by: UCLA Biomedical Library 128.97.90.221 - 4/30/2014 12:14:46 PM
Anti-infectious compounds Immunoglobulins (predominantly sIgA) Lactoferrin Lysozyme Lactadherin Nucleotides Defensins Mucins Oligosaccharides Toll-like receptors Cytokines Substances with trophic effects Epidermal growth factor Transforming growth factor-α Transforming growth factor-β Lactoferrin Trefoil factors Insulin-like growth factor (IGF)-I and -II Nerve growth factor Hormones Pituitary hormones Thyroid hormones Steroid hormones Cells Neutrophils Macrophages T-lymphocytes
Protective Effects of Human Milk Protection against sepsis and NEC are the main reasons why human milk is fed to preterm infants. The protection of preterm infants against sepsis is widely appreciated and has been well documented over the years [2–8]. A recent study has shown that the protective effect of human milk against sepsis is strongly dose-dependent [9]. It is of interest that these findings point to the gastrointestinal tract as the portal of entry for bacteria causing late-onset sepsis. This is consistent with the notion that trophic factors in human milk play an important role in sepsis prevention by advancing maturation of the immature gastrointestinal tract. Protection by human milk against NEC in dose-dependent fashion was first documented by Schanler et al. [4, 5]. It was confirmed subsequently by Sisk et al. [8] and most recently by Meinzen-Derr et al. [10] who demonstrated a strong and dose-dependent protective effect in a large cohort of extremely low birth weight infants. For each 100 ml/kg increase of human milk intake during the first 2 weeks of life, the risk of NEC or death after 2 weeks was decreased by a factor of 0.87. Trophic Effects of Human Milk Trophic components of human milk enhance and facilitate maturation of the immature gastrointestinal tract. Clinical correlates of maturational effects pertain mostly to motility of the gastrointestinal tract. Human milk leads to smaller gastric residuals (often referred to as improved ‘tolerance’) which are indicative of more rapid gastric emptying and which enable more rapid feeding advancement [5, 11, 12]. Improved gut motility reduces the propensity to abdominal distension [5]. Human milk decreases intestinal permeability [13, 14]. As indicated earlier, the maturational effects of human milk are thought to be key contributors to the protection it affords against sepsis and NEC.
Nutrient requirements of preterm infants are defined as intakes that enable the infant to grow at the same rate and with the same body composition (except for water) as the fetus. Requirements for most nutrients have been derived from accretion rates of protein, fat and minerals derived from analysis of fetal body composition at various stages of gestation. In addition, empirical methods have been employed to define requirements including those for nutrients such as vitamins [15]. As shown in table 2, requirements for protein and energy show a clear dependence on body weight, such that protein needs are highest in the least mature and smallest infants and decrease with increasing body weight, whereas energy needs increase with increasing body weight due to increasing energy deposition in the form of fat. Estimates of needs for major minerals, electrolytes and some trace minerals derived from fetal body composition are summarized in table 3. Required intakes of most nutrients are presumed
Human Milk and Human Milk Fortifiers Koletzko B, Poindexter B, Uauy R (eds): Nutritional Care of Preterm Infants: Scientific Basis and Practical Guidelines. World Rev Nutr Diet. Basel, Karger, 2014, vol 110, pp 215–227 (DOI: 10.1159/000358470)
217
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Nutrient Requirements of Preterm Infants
Table 2. Requirements for protein and energy; best estimates by factorial and empirical methods Body weight, g
Weight gain of fetus, g/kg/day Protein, g/kg/day Energy, kcal/kg/day Protein/energy, g/100 kcal
500–1,000
1,000–1,500
1,500–2,200
2,200–3,000
19.0 4.0 106 3.8
17.4 3.9 115 3.4
16.4 3.7 123 3.0
13.4 3.4 130 2.6
Energy, kcal Protein, g Ca, mg P, mg Mg, mg Na, mmol K, mmol Cl, mmol Fe, mg Zn, mg Cu, µg
Required per kg/day
Required per 100 kcal
Human milk per 100 kcal
Fortified human milk per 100 kcal
108 4.0 184 126 6.9 3.3 2.4 2.8 2.0 1.5 120
3.8 170 116 6.4 3.0 2.2 2.6 1.85 1.4 111
1.8 37 21 4.8 1.8 1.9 2.4 0.13 0.54 56
2.75 156 94 6.6 2.4 2.6 2.9 1.9 1.5 102
to decrease with increasing body weight since growth rates per unit of body mass decrease with advancing postnatal age. Requirements for iron have been established empirically. They are dictated mainly by high needs for the expanding hemoglobin pool. However, for most micronutrients, requirements are known only approximately. This explains the wide variation in micronutrients provided by human milk fortifiers. The consequences of intakes falling short of requirements vary from nutrient to nutrient. For the great majority of nutrients, small shortfalls are inconsequential, especially if they are temporary. Energy intakes below requirements mean that less energy is going into storage without an effect on growth of lean body mass as long as intake remains at least 90–100 kcal/kg/day. With protein, however, any shortfall is prone to affect growth, and, since growth and neurocognitive development are so closely linked [16], inadequate protein intake carries the risk of neurocognitive impairment. This is why special attention must be paid to the protein supply in early life and why intakes below requirements must be avoided.
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Ziegler Koletzko B, Poindexter B, Uauy R (eds): Nutritional Care of Preterm Infants: Scientific Basis and Practical Guidelines. World Rev Nutr Diet. Basel, Karger, 2014, vol 110, pp 215–227 (DOI: 10.1159/000358470)
Downloaded by: UCLA Biomedical Library 128.97.90.221 - 4/30/2014 12:14:46 PM
Table 3. Nutrient requirements of infants weighing
Human Milk and Human Milk Fortifiers Ekhard E. Ziegler Department of Pediatrics, University of Iowa, Iowa City, Iowa, USA Reviewed by Richard Ehrenkranz, Yale University School of Medicine, New Haven, Conn., USA; Karen Simmer, University of Western Australia, Crawley, WA, Australia
Abstract Human milk contains numerous immune-protective components that protect the premature infant from sepsis and necrotizing enterocolitis. Because of these protective effects, human milk is the feeding of choice for the premature infant. However, human milk does not provide adequate amounts of most nutrients for premature infants and must therefore be supplemented (fortified) with nutrients. Commercially available fortifiers provide energy and most nutrients in adequate amounts. The exception is protein, which is present in expressed milk in highly variable amounts and which is not provided in sufficient amounts by most fortifiers. Some liquid fortifiers are higher in protein content © 2014 S. Karger AG, Basel than powder fortifiers and provide adequate amounts of protein.
Human milk has the dual functions of supporting and complementing the preterm infant’s developing immune system, and of providing the nutrients needed for growth and development. Because of its immune-protective function, human milk is the feeding of choice for premature infants. As a source of nutrients, however, human milk is inadequate, necessitating nutrient supplementation (fortification) [1]. Nutrient intakes that fall short of requirements place the infant at risk of impaired neurodevelopment. The main challenge is to meet the high nutrient needs of premature infants in the face of highly variable human milk composition. Methods of nutrient fortification have improved over the years but have yet to reach a state where nutrient intakes are consistently adequate.
Many bioactive components have been identified in human milk. Table 1 provides a select listing of these components grouped into immune-protective and trophic components, hormones and immune cells. Their biological activity has been doc-
Downloaded by: UCLA Biomedical Library 128.97.90.221 - 4/30/2014 12:14:46 PM
Non-Nutritive Components of Human Milk
Table 1. Anti-infectious and other bioactive substances and cells in human milk
umented experimentally to varying degrees. Immune-protective components exert anti-bacterial, anti-viral and anti-inflammatory effects. The abundant oligosaccharides exert important anti-adhesive as well as prebiotic effects promoting a healthy microbiota and limiting gut inflammatory responses and growth of pathogenic bacteria. Clinical correlates associated with the use of human milk include lower rates of bacterial sepsis and necrotizing enterocolitis (NEC). These effects are attributed collectively to the bioactive components of human milk but cannot be linked to any one specific component. Other substances exert maturational, anti-inflammatory and trophic effects on the gastrointestinal tract. As with the immune components, the known clinical effects are attributed collectively to the trophic substances. Most likely it is the interplay of these multiple components that brings about beneficial clinical effects. For example, the protective effect against NEC is likely to be brought about by the synergy of gut maturational (trophic) effects with anti-infectious, anti-adhesive, anti-inflammatory as well as prebiotic effects.
216
Ziegler Koletzko B, Poindexter B, Uauy R (eds): Nutritional Care of Preterm Infants: Scientific Basis and Practical Guidelines. World Rev Nutr Diet. Basel, Karger, 2014, vol 110, pp 215–227 (DOI: 10.1159/000358470)
Downloaded by: UCLA Biomedical Library 128.97.90.221 - 4/30/2014 12:14:46 PM
Anti-infectious compounds Immunoglobulins (predominantly sIgA) Lactoferrin Lysozyme Lactadherin Nucleotides Defensins Mucins Oligosaccharides Toll-like receptors Cytokines Substances with trophic effects Epidermal growth factor Transforming growth factor-α Transforming growth factor-β Lactoferrin Trefoil factors Insulin-like growth factor (IGF)-I and -II Nerve growth factor Hormones Pituitary hormones Thyroid hormones Steroid hormones Cells Neutrophils Macrophages T-lymphocytes
Protective Effects of Human Milk Protection against sepsis and NEC are the main reasons why human milk is fed to preterm infants. The protection of preterm infants against sepsis is widely appreciated and has been well documented over the years [2–8]. A recent study has shown that the protective effect of human milk against sepsis is strongly dose-dependent [9]. It is of interest that these findings point to the gastrointestinal tract as the portal of entry for bacteria causing late-onset sepsis. This is consistent with the notion that trophic factors in human milk play an important role in sepsis prevention by advancing maturation of the immature gastrointestinal tract. Protection by human milk against NEC in dose-dependent fashion was first documented by Schanler et al. [4, 5]. It was confirmed subsequently by Sisk et al. [8] and most recently by Meinzen-Derr et al. [10] who demonstrated a strong and dose-dependent protective effect in a large cohort of extremely low birth weight infants. For each 100 ml/kg increase of human milk intake during the first 2 weeks of life, the risk of NEC or death after 2 weeks was decreased by a factor of 0.87. Trophic Effects of Human Milk Trophic components of human milk enhance and facilitate maturation of the immature gastrointestinal tract. Clinical correlates of maturational effects pertain mostly to motility of the gastrointestinal tract. Human milk leads to smaller gastric residuals (often referred to as improved ‘tolerance’) which are indicative of more rapid gastric emptying and which enable more rapid feeding advancement [5, 11, 12]. Improved gut motility reduces the propensity to abdominal distension [5]. Human milk decreases intestinal permeability [13, 14]. As indicated earlier, the maturational effects of human milk are thought to be key contributors to the protection it affords against sepsis and NEC.
Nutrient requirements of preterm infants are defined as intakes that enable the infant to grow at the same rate and with the same body composition (except for water) as the fetus. Requirements for most nutrients have been derived from accretion rates of protein, fat and minerals derived from analysis of fetal body composition at various stages of gestation. In addition, empirical methods have been employed to define requirements including those for nutrients such as vitamins [15]. As shown in table 2, requirements for protein and energy show a clear dependence on body weight, such that protein needs are highest in the least mature and smallest infants and decrease with increasing body weight, whereas energy needs increase with increasing body weight due to increasing energy deposition in the form of fat. Estimates of needs for major minerals, electrolytes and some trace minerals derived from fetal body composition are summarized in table 3. Required intakes of most nutrients are presumed
Human Milk and Human Milk Fortifiers Koletzko B, Poindexter B, Uauy R (eds): Nutritional Care of Preterm Infants: Scientific Basis and Practical Guidelines. World Rev Nutr Diet. Basel, Karger, 2014, vol 110, pp 215–227 (DOI: 10.1159/000358470)
217
Downloaded by: UCLA Biomedical Library 128.97.90.221 - 4/30/2014 12:14:46 PM
Nutrient Requirements of Preterm Infants
Table 2. Requirements for protein and energy; best estimates by factorial and empirical methods Body weight, g
Weight gain of fetus, g/kg/day Protein, g/kg/day Energy, kcal/kg/day Protein/energy, g/100 kcal
500–1,000
1,000–1,500
1,500–2,200
2,200–3,000
19.0 4.0 106 3.8
17.4 3.9 115 3.4
16.4 3.7 123 3.0
13.4 3.4 130 2.6
Energy, kcal Protein, g Ca, mg P, mg Mg, mg Na, mmol K, mmol Cl, mmol Fe, mg Zn, mg Cu, µg
Required per kg/day
Required per 100 kcal
Human milk per 100 kcal
Fortified human milk per 100 kcal
108 4.0 184 126 6.9 3.3 2.4 2.8 2.0 1.5 120
3.8 170 116 6.4 3.0 2.2 2.6 1.85 1.4 111
1.8 37 21 4.8 1.8 1.9 2.4 0.13 0.54 56
2.75 156 94 6.6 2.4 2.6 2.9 1.9 1.5 102
to decrease with increasing body weight since growth rates per unit of body mass decrease with advancing postnatal age. Requirements for iron have been established empirically. They are dictated mainly by high needs for the expanding hemoglobin pool. However, for most micronutrients, requirements are known only approximately. This explains the wide variation in micronutrients provided by human milk fortifiers. The consequences of intakes falling short of requirements vary from nutrient to nutrient. For the great majority of nutrients, small shortfalls are inconsequential, especially if they are temporary. Energy intakes below requirements mean that less energy is going into storage without an effect on growth of lean body mass as long as intake remains at least 90–100 kcal/kg/day. With protein, however, any shortfall is prone to affect growth, and, since growth and neurocognitive development are so closely linked [16], inadequate protein intake carries the risk of neurocognitive impairment. This is why special attention must be paid to the protein supply in early life and why intakes below requirements must be avoided.
218
Ziegler Koletzko B, Poindexter B, Uauy R (eds): Nutritional Care of Preterm Infants: Scientific Basis and Practical Guidelines. World Rev Nutr Diet. Basel, Karger, 2014, vol 110, pp 215–227 (DOI: 10.1159/000358470)
Downloaded by: UCLA Biomedical Library 128.97.90.221 - 4/30/2014 12:14:46 PM
Table 3. Nutrient requirements of infants weighing
