Challenges of providing human milk to premature infants
Providing human milk to very premature infants presents a variety of challenges. To maximize milk supply, new mothers should begin frequent pumping shortly after delivery. Mothers whose babies are in the NICU should be encouraged to begin pumping within 6–12 hours of delivery and to pump 8 – 12 times per day, ensuring that they empty the breast each time. These interventions significantly increase the likelihood that a premature infant will receive his mother’s own milk.45
Perhaps the biggest concern in providing human milk to premature infants is growth. Term infants undergo rapid growth in the third trimester of pregnancy receiving nutrition through the placenta and swallowed amniotic fluid with no need to expend calories for temperature regulation or gas exchange. Premature infants miss out on much or all of the third trimester and thus have higher nutritional requirements on a per kilogram basis than term infants. Human milk evolved/was designed to nourish the term infant who can tolerate large fluid volumes, whereas premature infants are less tolerant of high fluid volumes.
For these reasons, human milk is generally fortified for premature infants with birth weight less than 1500 grams. Human milk fortifier powders were developed from bovine milk to supplement key nutrients with particular emphasis on protein, calcium, phosphorus, and vitamin D. Fortification of human milk leads to improved growth in weight,46 length and head circumference47 however improvements in bone mineralization and neurodevelopmental outcomes are unclear.47 Recent studies suggest that higher protein intake is beneficial for premature infants.48 There is large variation in the energy and protein content of human milk (between mothers, over time in a given mother, and between foremilk and hindmilk).49Protein content decreases over time of lactation and is likely to be much lower in donor human milk than milk from mothers delivering prematurely. Current NICU practices are often based on the clearly misleading assumption that human milk has approximately 0.67 kcal/ml with stable protein content. “Assumed” protein intake from standard fortification is significantly lower than actual protein intake.50These observations have led to clinical trials of “individualized” fortification, that is, adjusting the amount of added protein based on actual measurements of milk samples51 or based on metabolic parameters indicative of protein accretion in the neonate (e.g. blood urea nitrogen).52 Both methods led to increased protein intake and improved growth. A recent trial of a human milk fortifier with higher protein content demonstrated increased growth and fewer infants with weight below the 10th per centile.53
Use of commercial human milk fortifiers, however, is not without complications as demonstrated by the observation of a marked increase in metabolic acidosis associated with the introduction of a new fortifier.54Human milk fortifiers have also been associated with increased markers of oxidative stress compared to unfortified human milk and to infant formula.55 In addition, bacterial contamination56 of powdered infant formulas and associated sepsis57 has been well documented, resulting in more than 100 cases of neonatal Cronobacter (Enterobacter sakazakii) infections leading to high mortality rates. This association has led to calls for “powder-free” NICUs and the development of new liquid human milk fortifiers. Unfortunately, one of the challenges of liquid fortifiers is displacement of the volume of mother’s own milk, so that the infant receives less total volume of human milk. Table 1 provides a comparison of the nutrient content and volume of human milk displaced by the liquid formulations of several commercial human milk fortifiers available in North America. Note that the use of the bovine liquid fortifiers means that 17–50% of the volume ingested is formula. The table also demonstrates the significant variation in macro and micronutrients among these products.
Table 1
Nutrient content of commonly used human milk fortifiers in North America
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Pasteurized donor human milk for premature infants
There are significant challenges in providing donor human milk for all premature infants whose mothers are unable to provide an adequate supply of their own milk: nutrition, safety, supply, and immune protection. First, most donor human milk is provided by women who have delivered at term and have weaned their own infant but continue to pump and donate their milk in later lactation. As noted in Figure 1, this milk from mothers of term infants, several months after delivery is low in protein, fat, and many bioactive molecules compared to preterm milk provided in the first few weeks after delivery. A second challenge of providing donor milk is to minimize the potential to transmit infectious agents. For this reason, milk banks have rigid standards for screening and testing potential donors, for pasteurization, and for testing milk prior to distribution.58, 59 Pasteurization is highly effective at decreasing the risk of transmission of HIV, CMV, Hepatitis B and Hepatitis C. The costs involved in establishing and maintaining a milk bank are considerable, however the feasibility of providing pasteurized donor milk in developing countries has been demonstrated.60 Unpasteurized donor milk has been advocated for premature infants in areas where religious beliefs preclude the use of milk from unknown donors.61, 62Further, “mother-to-mother milksharing” through internet-based communities is a rapidly growing practice in more than 50 countries, 63 but health officials recommend against this practice due to safety risks, including lack of pasteurization, uncertain storage and shipping processes, and uncertain medication and substance use in the donor.64
Unfortunately, while pasteurization safeguards against transmission of infectious agents, it also has detrimental effects on the bioactive components of human milk. The currently recommended Holder pasteurization method (62.5 degrees C for 30 minutes) results in significant decreases in sIgA, lactoferrin, lysozyme, insulin-like growth factors, hepatocyte growth factor, water-soluble vitamins, bile salt-stimulated lipase, lipoprotein lipase, and anti-oxidant activity but does not decrease oligosaccharides, long-chain polyunsaturated fatty acids, gangliosides, lactose, fat-soluble vitamins, or epidermal growth factor.65–69 Holder pasteurization increases some medium chain saturated fatty acids, decreases some cytokines (TNFα, IFNγ, IL1β, and IL10), and increases others (IL8).70 High temperature short-time pasteurization (72–75 degrees C for 15–16 seconds) has been demonstrated to eliminate bacteria and many viruses71, 72 with less protein loss (including maintenance of bile salt stimulating lipase, lactoferrin, and some IgAs),73 less severe loss of antioxidant activity, but greater loss of antimicrobial activity.66, 74 In resource-poor countries, flash-heat treatment (temperature above 56 degress C for 6 min 15 seconds) does not alter milk antibacterial activity against E. coli and S. aureus, only minimally decreases lactoferrin antibacterial activity, but significantly diminishes lysozyme antibacterial activity.75 Further research to determine the optimal pasteurization method to minimize risk and maximize bioactivity has great potential benefit for premature infants.
A fundamental concern is that the supply of donor human milk is currently limited. There are 11 milk banks in the U.S. and Canada that form the Human Milk Banking Association of North America (HMBANA, www.hmbana.org). In 2011 HMBANA milk banks distributed more than 2 million ounces of donor milk (a five fold increase from the year 2000), and the International Breast Milk Project (www.breastmilkproject.org) has distributed more than 280,000 ounces of donor milk to infants in South Africa since its founding in 2006, but such distributions represent only a fraction of the potential demand. The scarcity of this precious resource raises questions about how to increase the supply and equitably allocate human milk.76
Go to:
An “all human” diet for premature infants
The development of a human milk fortifier formulated by concentrating pasteurized donor human milk and then adding vitamins and minerals has created the possibility of providing an “all-human diet” to premature infants. Various caloric densities of this fortifier allow for individual adjustment based on growth or blood urea nitrogen. A small study demonstrated a decrease in both moderate and severe NEC in small premature infants (birth weight < 1250 g) receiving the “all-human diet.”77 Unfortunately this study was not adequately powered to study NEC as an outcome and the comparison group received formula if mother’s milk supply was not adequate whereas the “all-human” infants received donor human milk in such a situation (i.e the increase in NEC in the comparison group could be related to either the powdered bovine human milk fortifier or the premature infant formula). This study underscores the fundamental question of whether components of human milk are protective against NEC or components of bovine milk somehow induce NEC. These two possibilities are, of course, not mutually exclusive. The cost of providing a fortifier made from donor human milk is significant. A recent cost-benefit analysis suggested that the savings in NEC prevention outweigh the costs of the “all-human” strategy, however this analysis was based on assumptions generated from the clinical trial described above and may therefore overestimate the protective effect of this approach.78 The ethical issues of marketing human milk for profit have recently been reviewed.76
Go to:
Improving breastfeeding rates for premature infants
Premature labor and delivery are highly stressful to parents. Education regarding the importance and value of
Challenges of providing human milk to premature infants
Providing human milk to very premature infants presents a variety of challenges. To maximize milk supply, new mothers should begin frequent pumping shortly after delivery. Mothers whose babies are in the NICU should be encouraged to begin pumping within 6–12 hours of delivery and to pump 8 – 12 times per day, ensuring that they empty the breast each time. These interventions significantly increase the likelihood that a premature infant will receive his mother’s own milk.45
Perhaps the biggest concern in providing human milk to premature infants is growth. Term infants undergo rapid growth in the third trimester of pregnancy receiving nutrition through the placenta and swallowed amniotic fluid with no need to expend calories for temperature regulation or gas exchange. Premature infants miss out on much or all of the third trimester and thus have higher nutritional requirements on a per kilogram basis than term infants. Human milk evolved/was designed to nourish the term infant who can tolerate large fluid volumes, whereas premature infants are less tolerant of high fluid volumes.
For these reasons, human milk is generally fortified for premature infants with birth weight less than 1500 grams. Human milk fortifier powders were developed from bovine milk to supplement key nutrients with particular emphasis on protein, calcium, phosphorus, and vitamin D. Fortification of human milk leads to improved growth in weight,46 length and head circumference47 however improvements in bone mineralization and neurodevelopmental outcomes are unclear.47 Recent studies suggest that higher protein intake is beneficial for premature infants.48 There is large variation in the energy and protein content of human milk (between mothers, over time in a given mother, and between foremilk and hindmilk).49Protein content decreases over time of lactation and is likely to be much lower in donor human milk than milk from mothers delivering prematurely. Current NICU practices are often based on the clearly misleading assumption that human milk has approximately 0.67 kcal/ml with stable protein content. “Assumed” protein intake from standard fortification is significantly lower than actual protein intake.50These observations have led to clinical trials of “individualized” fortification, that is, adjusting the amount of added protein based on actual measurements of milk samples51 or based on metabolic parameters indicative of protein accretion in the neonate (e.g. blood urea nitrogen).52 Both methods led to increased protein intake and improved growth. A recent trial of a human milk fortifier with higher protein content demonstrated increased growth and fewer infants with weight below the 10th per centile.53
Use of commercial human milk fortifiers, however, is not without complications as demonstrated by the observation of a marked increase in metabolic acidosis associated with the introduction of a new fortifier.54Human milk fortifiers have also been associated with increased markers of oxidative stress compared to unfortified human milk and to infant formula.55 In addition, bacterial contamination56 of powdered infant formulas and associated sepsis57 has been well documented, resulting in more than 100 cases of neonatal Cronobacter (Enterobacter sakazakii) infections leading to high mortality rates. This association has led to calls for “powder-free” NICUs and the development of new liquid human milk fortifiers. Unfortunately, one of the challenges of liquid fortifiers is displacement of the volume of mother’s own milk, so that the infant receives less total volume of human milk. Table 1 provides a comparison of the nutrient content and volume of human milk displaced by the liquid formulations of several commercial human milk fortifiers available in North America. Note that the use of the bovine liquid fortifiers means that 17–50% of the volume ingested is formula. The table also demonstrates the significant variation in macro and micronutrients among these products.
Table 1
Nutrient content of commonly used human milk fortifiers in North America
Go to:
Pasteurized donor human milk for premature infants
There are significant challenges in providing donor human milk for all premature infants whose mothers are unable to provide an adequate supply of their own milk: nutrition, safety, supply, and immune protection. First, most donor human milk is provided by women who have delivered at term and have weaned their own infant but continue to pump and donate their milk in later lactation. As noted in Figure 1, this milk from mothers of term infants, several months after delivery is low in protein, fat, and many bioactive molecules compared to preterm milk provided in the first few weeks after delivery. A second challenge of providing donor milk is to minimize the potential to transmit infectious agents. For this reason, milk banks have rigid standards for screening and testing potential donors, for pasteurization, and for testing milk prior to distribution.58, 59 Pasteurization is highly effective at decreasing the risk of transmission of HIV, CMV, Hepatitis B and Hepatitis C. The costs involved in establishing and maintaining a milk bank are considerable, however the feasibility of providing pasteurized donor milk in developing countries has been demonstrated.60 Unpasteurized donor milk has been advocated for premature infants in areas where religious beliefs preclude the use of milk from unknown donors.61, 62Further, “mother-to-mother milksharing” through internet-based communities is a rapidly growing practice in more than 50 countries, 63 but health officials recommend against this practice due to safety risks, including lack of pasteurization, uncertain storage and shipping processes, and uncertain medication and substance use in the donor.64
Unfortunately, while pasteurization safeguards against transmission of infectious agents, it also has detrimental effects on the bioactive components of human milk. The currently recommended Holder pasteurization method (62.5 degrees C for 30 minutes) results in significant decreases in sIgA, lactoferrin, lysozyme, insulin-like growth factors, hepatocyte growth factor, water-soluble vitamins, bile salt-stimulated lipase, lipoprotein lipase, and anti-oxidant activity but does not decrease oligosaccharides, long-chain polyunsaturated fatty acids, gangliosides, lactose, fat-soluble vitamins, or epidermal growth factor.65–69 Holder pasteurization increases some medium chain saturated fatty acids, decreases some cytokines (TNFα, IFNγ, IL1β, and IL10), and increases others (IL8).70 High temperature short-time pasteurization (72–75 degrees C for 15–16 seconds) has been demonstrated to eliminate bacteria and many viruses71, 72 with less protein loss (including maintenance of bile salt stimulating lipase, lactoferrin, and some IgAs),73 less severe loss of antioxidant activity, but greater loss of antimicrobial activity.66, 74 In resource-poor countries, flash-heat treatment (temperature above 56 degress C for 6 min 15 seconds) does not alter milk antibacterial activity against E. coli and S. aureus, only minimally decreases lactoferrin antibacterial activity, but significantly diminishes lysozyme antibacterial activity.75 Further research to determine the optimal pasteurization method to minimize risk and maximize bioactivity has great potential benefit for premature infants.
A fundamental concern is that the supply of donor human milk is currently limited. There are 11 milk banks in the U.S. and Canada that form the Human Milk Banking Association of North America (HMBANA, www.hmbana.org). In 2011 HMBANA milk banks distributed more than 2 million ounces of donor milk (a five fold increase from the year 2000), and the International Breast Milk Project (www.breastmilkproject.org) has distributed more than 280,000 ounces of donor milk to infants in South Africa since its founding in 2006, but such distributions represent only a fraction of the potential demand. The scarcity of this precious resource raises questions about how to increase the supply and equitably allocate human milk.76
Go to:
An “all human” diet for premature infants
The development of a human milk fortifier formulated by concentrating pasteurized donor human milk and then adding vitamins and minerals has created the possibility of providing an “all-human diet” to premature infants. Various caloric densities of this fortifier allow for individual adjustment based on growth or blood urea nitrogen. A small study demonstrated a decrease in both moderate and severe NEC in small premature infants (birth weight < 1250 g) receiving the “all-human diet.”77 Unfortunately this study was not adequately powered to study NEC as an outcome and the comparison group received formula if mother’s milk supply was not adequate whereas the “all-human” infants received donor human milk in such a situation (i.e the increase in NEC in the comparison group could be related to either the powdered bovine human milk fortifier or the premature infant formula). This study underscores the fundamental question of whether components of human milk are protective against NEC or components of bovine milk somehow induce NEC. These two possibilities are, of course, not mutually exclusive. The cost of providing a fortifier made from donor human milk is significant. A recent cost-benefit analysis suggested that the savings in NEC prevention outweigh the costs of the “all-human” strategy, however this analysis was based on assumptions generated from the clinical trial described above and may therefore overestimate the protective effect of this approach.78 The ethical issues of marketing human milk for profit have recently been reviewed.76
Go to:
Improving breastfeeding rates for premature infants
Premature labor and delivery are highly stressful to parents. Education regarding the importance and value of
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