Premature infants are at risk for growth failure, developmental delays, necrotizing enterocolitis, and late-onset sepsis. Human milk from women delivering prematurely has more protein and higher levels of bioactive molecules. Human milk must be fortified for premature infants to achieve adequate growth. Mother’s own milk improves growth and neurodevelopment, decreases the risk of necrotizing enterocolitis and late-onset sepsis, and should be the primary enteral diet for premature infants. Donor milk is a resource for premature infants whose mothers are unable to provide an adequate supply of milk. Challenges include the need for pasteurization, nutritional and biochemical deficiencies, and limited supply.
Key points
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Fortified mother’s own milk is the optimal diet for the premature infant to maximize growth, development, and protection against necrotizing enterocolitis and infection.
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Fortified pasteurized human donor milk is recommended by the American Academy of Pediatrics Section on Breastfeeding as the preferred alternative for premature infants whose mothers are unable to provide a sufficient volume of their own milk.
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Pasteurized donor human milk does not provide the same nutrient or biologically active molecules as unpasteurized own mother’s milk.
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Careful attention to establishing and maintaining milk production in women delivering preterm has significant benefits.
In the United States, approximately 12% of infants are born preterm (<37 weeks gestation). This is a very heterogeneous population with widely diverse nutritional requirements and highly different stages of immunocompetence. A 2.5-kg neonate born at 34 weeks gestation differs from a 500-g neonate born at 24 weeks gestation in essentially every physiologic aspect of the gastrointestinal system and the innate and adaptive immune systems. Consequently, the current body of knowledge about nutrition and host defense of premature infants has many gaps. Studies performed on larger, older premature infants may not be applicable to the extremely low birth weight infants (<1000 g) that now survive routinely.
Amniotic fluid, “premature” human milk, and “term” human milk
Amniotic fluid contains amino acids, proteins, vitamins, minerals, hormones, and growth factors. Although the concentration of these nutrients is much lower than that found in human milk, the large volumes of amniotic fluid swallowed in utero (up to 1 liter a day late in gestation, considerably more than the newborn consumes after birth) have a significant impact on growth and maturation of both the fetus and the fetal intestine. Animal studies and limited human observations suggest that swallowed amniotic fluid accounts for about 15% of fetal growth.
Milk from women who deliver prematurely differs from that of women who deliver at term. Preterm milk is initially higher in protein, fat, free amino acids, and sodium, but over the first few weeks following delivery these levels decrease ( Fig. 1 A). The mineral content (including trace minerals) of preterm milk is similar to that of term milk, with the following exceptions: Calcium is significantly lower in preterm milk than term milk and does not seem to increase over time, whereas copper and zinc content are both higher in preterm milk than term milk and decrease over the time of lactation.
Lactose is the major carbohydrate in human milk. This disaccharide is an important energy source, is relatively low in colostrum, and increases over time with more dramatic increases in preterm milk (see Fig. 1 A). Complex oligosaccharides are the second most abundant carbohydrate in human milk. These human milk oligosaccharides (HMOs) are not digestible by host glycosidases and yet are produced in large amounts with highly variable structures by the mother. HMOs seem to have 3 important functions: Prebiotic (stimulation of commensal bacteria containing the bacterial glycosidases to deconstruct and consume the HMOs), decoy (structural similarity to the glycans on enterocytes allows HMOs to competitively bind to pathogens), and provision of fucose and sialic acid, which seem to be important in host defense and neurodevelopment, respectively. Preterm milk is highly variable in HMO content with differences between populations and significant variability over time in content of fucosylated HMOs in individual mothers delivering preterm. Glycosaminoglycans also seem to act as decoys, providing binding sites for pathogenic bacteria to prevent adherence to the enterocyte. Premature milk is richer in glycosaminoglycans than term milk.
Bioactive molecules in human milk are important components of the innate immune system. Differences in cytokines, growth factors, and lactoferrin between preterm and term milk are most dramatic in colostrum and early milk and mostly resolve by 4 weeks after delivery (see Fig. 1 B). Leptin is produced by mammary glands, secreted into human milk, and may be important in post-natal growth. Human milk leptin does not seem to differ between preterm and term milk. Bile salt-stimulated lipase activity is similar in term and preterm milk, whereas lipoprotein lipase activity is higher in term milk.
Amniotic fluid, “premature” human milk, and “term” human milk
Amniotic fluid contains amino acids, proteins, vitamins, minerals, hormones, and growth factors. Although the concentration of these nutrients is much lower than that found in human milk, the large volumes of amniotic fluid swallowed in utero (up to 1 liter a day late in gestation, considerably more than the newborn consumes after birth) have a significant impact on growth and maturation of both the fetus and the fetal intestine. Animal studies and limited human observations suggest that swallowed amniotic fluid accounts for about 15% of fetal growth.
Milk from women who deliver prematurely differs from that of women who deliver at term. Preterm milk is initially higher in protein, fat, free amino acids, and sodium, but over the first few weeks following delivery these levels decrease ( Fig. 1 A). The mineral content (including trace minerals) of preterm milk is similar to that of term milk, with the following exceptions: Calcium is significantly lower in preterm milk than term milk and does not seem to increase over time, whereas copper and zinc content are both higher in preterm milk than term milk and decrease over the time of lactation.
Lactose is the major carbohydrate in human milk. This disaccharide is an important energy source, is relatively low in colostrum, and increases over time with more dramatic increases in preterm milk (see Fig. 1 A). Complex oligosaccharides are the second most abundant carbohydrate in human milk. These human milk oligosaccharides (HMOs) are not digestible by host glycosidases and yet are produced in large amounts with highly variable structures by the mother. HMOs seem to have 3 important functions: Prebiotic (stimulation of commensal bacteria containing the bacterial glycosidases to deconstruct and consume the HMOs), decoy (structural similarity to the glycans on enterocytes allows HMOs to competitively bind to pathogens), and provision of fucose and sialic acid, which seem to be important in host defense and neurodevelopment, respectively. Preterm milk is highly variable in HMO content with differences between populations and significant variability over time in content of fucosylated HMOs in individual mothers delivering preterm. Glycosaminoglycans also seem to act as decoys, providing binding sites for pathogenic bacteria to prevent adherence to the enterocyte. Premature milk is richer in glycosaminoglycans than term milk.
Bioactive molecules in human milk are important components of the innate immune system. Differences in cytokines, growth factors, and lactoferrin between preterm and term milk are most dramatic in colostrum and early milk and mostly resolve by 4 weeks after delivery (see Fig. 1 B). Leptin is produced by mammary glands, secreted into human milk, and may be important in post-natal growth. Human milk leptin does not seem to differ between preterm and term milk. Bile salt-stimulated lipase activity is similar in term and preterm milk, whereas lipoprotein lipase activity is higher in term milk.
Benefits of human milk for premature infants
The most recent policy statement from the Section on Breastfeeding of the American Academy of Pediatrics represents a significant shift from previous statements in its recommendation that all preterm infants should receive human milk, with pasteurized donor milk rather than premature infant formula the preferred alternative if a mother is unable to provide an adequate volume. The current recommendation is based on an impressive array of benefits that human milk provides to this highly vulnerable population, including decreased rates of late-onset sepsis, necrotizing enterocolitis (NEC), and retinopathy of prematurity, fewer re-hospitalizations in the first year of life, and improved neurodevelopmental outcomes. In addition, premature infants who receive human milk have lower rates of metabolic syndrome, lower blood pressure and low-density lipoprotein levels, and less insulin and leptin resistance when they reach adolescence, compared with premature infants receiving formula.
Among these benefits, perhaps the most compelling benefit of human milk feeding is the observed decrease in NEC, given its high prevalence (5%–10% of all infants with birth weight <1500 g), high case fatality, and long-term morbidity owing to complications like strictures, cholestasis, short-bowel syndrome, and poor growth and neurodevelopment. For many of these outcomes, there seems to be a dose response effect of human milk feeding. For instance, a dose of mother’s own milk of more than 50 mL/kg per day decreases the risk of late-onset sepsis and NEC compared with less than 50 mL/kg per day, and for each 10 mL/kg per day increase in human milk in the diet there is a 5% reduction in hospital readmission rate. The mechanisms by which human milk protects the premature infant against NEC are likely multifactorial. Human milk secretory immunoglobulin A, lactoferrin, lysozyme, bile salt-stimulating lipase, growth factors, and HMOs all provide protective benefits that could potentially contribute to reduction in NEC. In a multicenter, randomized clinical trial, bovine lactoferrin treatment decreased late-onset sepsis but not NEC in premature infants. Recombinant human lactoferrin trials are currently in progress in premature infants ( clinicaltrials.gov NCT00854633). In animal models, epidermal growth factor and pooled HMOs prevent NEC, but these have not yet been tested in premature infants.
Microbial colonization is thought to play an important role in risk of NEC. Breastfeeding is one of many factors that influence the composition of the intestinal microbiota in term infants ; limited studies suggest that diet may have less of an effect on the composition of the intestinal microbiota in the premature infant than other factors (such as antibiotic administration). New bioinformatic tools to correlate the extensive array of fecal metabolites and the fecal microbiota offer great promise in understanding the factors that influence the microbiota of the premature infant. Studies to date suggest that the metabolites differing between human milk-fed and formula-fed infants that are most closely associated with shaping the microbiota include sugars and fatty acids. Whether and how these metabolites differ functionally in the extremely premature infant is unknown.
Other potential benefits of human milk to premature infants have been studied with mixed results. There do not seem to be consistent benefits of human milk in premature infants in relation to feeding tolerance, time to full enteral feeding, or allergic/atopic outcomes. Providing human milk has been postulated to decrease parental anxiety, and increase skin-to-skin contact and parent–infant bonding, but data to support these hypotheses are limited. The provision of human colostrum in the form of oral care for intubated premature infants has been proposed as a method of stimulating the oropharyngeal-associated lymphatic tissue and altering the oral microbiota, but data to support this intervention are lacking.
Studies of the benefits of human milk in premature infants to date have predominantly compared mother’s own milk with premature infant formula. Whether pasteurized donor human milk (which generally is provided by women who delivered at term) provides similar or superior protection is unclear. In premature infants receiving only mother’s own milk or pasteurized donor human milk (no formula), increasing amounts of mother’s own milk correlate with better weight gain and less NEC. A meta-analysis in 2007 concluded that formula feeding was associated with both increased short-term growth and increased incidence of NEC compared with donor human milk feeding (relative risk, 2.5; 95% confidence interval [CI], 1.2–5.1), number needed to harm 33 (95% CI, 17–100) with no differences in long-term growth or neurodevelopment. However, of the 8 studies included in the meta-analysis, 7 were published before 1990, during which time nutritional comparisons were limited. For example, several of the reviewed studies did not include formulas designed for premature infants and none included nutrient-enriched donor milk. One study, initiated in 1982, followed a cohort of premature infants who received either premature infant formula or unfortified donor human milk with the latter group showing decreased blood pressure and improved lipoprotein profiles as adolescents. In the single included study published since 1990, infants whose mothers were unable to provide sufficient milk for their extremely premature infants (<30 weeks’ gestation) were randomly assigned to receive supplementation with either premature infant formula or nutrient-enriched donor human milk; donor human milk led to slower weight gain, but did not decrease episodes of sepsis, or retinopathy of prematurity, length of hospital stay, or mortality compared with supplementation with premature infant formula. The incidence of NEC was decreased in the donor human milk group by almost half compared with the formula group, but this did not attain significance owing to the small sample size. It is noteworthy in this study that, despite increased supplementation in the donor milk group, 20% of the infants were changed to formula because of poor growth. A more recent comparison of mother’s own milk with pasteurized human donor milk demonstrated improved growth and less NEC with the former.
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 neonatal intensive care unit (NICU) should be encouraged to begin pumping within 6 to 12 hours of delivery and to pump 8 to 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.
Perhaps the greatest 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 weights of less than 1500 g. 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, length, and head circumference ; however, improvements in bone mineralization and neurodevelopmental outcomes are unclear. Recent studies suggest that higher protein intake is beneficial for premature infants. 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). Protein 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. These observations have led to clinical trials of “individualized” fortification, that is, adjusting the amount of added protein based on actual measurements of milk samples or based on metabolic parameters indicative of protein accretion in the neonate (eg, blood urea nitrogen). 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 percentile.
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. Human milk fortifiers have also been associated with increased markers of oxidative stress compared with unfortified human milk and with infant formula. In addition, bacterial contamination of powdered infant formulas and associated sepsis 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. Note that the use of the bovine liquid fortifiers means that 17% to 50% of the volume ingested is formula. The table also demonstrates the significant variation in macro- and micronutrients among these products.
| Enfamil Human Milk Fortifier Acidified Liquid (4 Vials = 20 mL) Add to 100 mL EBM | Similac Special Care 30 Cal/oz (50 mL) Add to 50 mL EBM | Prolact +4 H 2 MF (20 mL) a Add to 80 mL EBM | Similac Human Milk Fortifier (4 Packets = 3.6 g) Add to 100 mL EBM | Enfamil Human Milk Fortifier (4 Packets = 2.8 g) Add to 100 mL EBM) | |
|---|---|---|---|---|---|
| Formulation | Liquid | Liquid | Liquid | Powder | Powder |
| Protein source | Bovine | Bovine | Human | Bovine | Bovine |
| Calories | 30 | 50 | 28 | 14 | 14 |
| Protein (g) | 2.2 | 1.5 | 1.2 | 1.0 | 1.1 |
| Fat (g) | 2.3 | 3.3 | 1.8 | 0.36 | 1 |
| Carbohydrate (g) | <1.2 | 3.9 | 1.8 | 1.8 | <0.4 |
| Vitamin A (IU) | 1160 | 625 | 61 | 620 | 950 |
| Vitamin D (IU) | 188 | 75 | 26 | 120 | 150 |
| Vitamin E (IU) | 5.6 | 2.0 | 0.4 | 3.2 | 4.6 |
| Vitamin K (μg) | 5.7 | 6.0 | <0.2 | 8.3 | 4.4 |
| Vitamin B1 (μg) | 184 | 125 | 4 | 233 | 150 |
| Vitamin B2 (μg) | 260 | 310 | 15 | 417 | 220 |
| Vitamin B6 (μg) | 140 | 125 | 4.1 | 211 | 115 |
| Vitamin B12 (μg) | 0.64 | 0.27 | 0.05 | 0.64 | 0.18 |
| Niacin (μg) | 3700 | 2500 | 52.4 | 3570 | 3000 |
| Folic acid (μg) | 31 | 18.5 | 5.4 | 23 | 25 |
| Pantothenic acid (μg) | 920 | 950 | 74.8 | 1500 | 730 |
| Biotin (μg) | 3.4 | 18.5 | Not available | 26 | 2.7 |
| Vitamin C (mg) | 15.2 | 18.5 | <0.2 | 25 | 12 |
| Calcium (mg) | 116 | 90 | 103 | 117 | 90 |
| Phosphorus (mg) | 63 | 50 | 53.8 | 67 | 50 |
| Iron (mg) | 1.76 | 0.9 | 0.1 | 0.35 | 1.44 |
| Zinc (mg) | 0.96 | 0.75 | 0.7 | 1.0 | 0.72 |
| Copper (μg) | 60 | 125 | 64 | 170 | 44 |
| Manganese (μg) | 10 | 6 | <12 | 7.2 | 10 |
| Sodium (mg) | 27 | 22 | 37 | 15 | 16 |
| Potassium (mg) | 45 | 65 | 50 | 63 | 29 |
| Chloride (mg) | 28 | 41 | 29 | 38 | 13 |
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