INTRODUCTION — Human milk is the recommended diet for the preterm infant. However, the preterm infant is metabolically and nutritionally challenged as it transitions from in utero to an external environment of intensive care to support organ function and growth. To support these functions, it may be necessary to fortify raw milk to deliver required levels of specific nutrients (table 1).
This topic review will discuss the components of human milk and preterm formula and compare these with the nutritional requirements of the premature infant. Other issues relevant to enteral nutrition for premature infants are covered in the following topic reviews:
OVERVIEW — The nutrient content in human milk varies substantially between and within lactating women, depending on lactational stage, time of expression, maternal characteristics, and method used for pasteurization. Additionally, nutrient content differs between mother's own milk (unpasteurized), donor milk (pasteurized), commercially available preterm formulas, and human milk fortifiers (HMFs). The unique nutritional needs of a premature infant determines the nutritional strategy, which may require the use of one or more of these dietary options.
Requirements and fortification — Recommended protein intake for fully enterally fed preterm infants is 3.5 to 4.5 g/kg/day (or 3.2 to 4.1 g/100 kcal) (table 1). Higher protein intake (>4.0 g/kg/day) may be considered for those with growth failure .
●Fortified human milk – Human milk must be fortified to achieve an adequate protein intake within the feeding volume that can reasonably be delivered to a very low birth weight infant. Protein content in unpasteurized human milk ranges from 1.5 to 2.2 g/dL during the first one to two postnatal weeks and then decreases to 1.0 to 1.4 g/dL at three weeks and later (mature milk) (table 2) . At the lower end of this range of protein concentration (1 g/dL), a fully enterally fed preterm infant with a weight of 1000 g would need to ingest 350 to 450 mL/day, which is more than double the volume that is tolerated by most preterm infants. Fortifying the human milk by adding a human milk fortifier (HMF) increases the protein content of the feed to 2.5 to 3.25 g/dL (using a bovine-based HMF) or to 1.9 to 3.5 g/dL (using a human milk-based HMF) (table 3). Thus, a fortified feed provides sufficient protein in a volume of 120 to 150 mL/day, which is typically tolerated by preterm infants.
●Preterm formula – In preterm infant formula, protein concentrations range from 2.2 to 3.3 g/dL, depending on caloric density, manufacturer, and formulation (standard versus high protein).
Whey versus casein — The protein content in human milk is distributed among three compartments. The majority of proteins are in the whey or casein fractions, with a small amount in the lipid fraction, residing within the fat globule cell membranes . The whey and casein fractions differ in their physical properties and representative proteins.
●Whey – The whey fraction is the soluble, non-curdled fraction of milk after acidification or fermentation and provides approximately 20 percent of milk protein . These include alpha-lactalbumin, lactoferrin, lactoperoxidase, and lysozyme, as well as hundreds of other whey proteins that are less well characterized [4,5]. These whey proteins have several immunomodulatory and gastrointestinal functions.
●Casein – The casein fraction in milk is the curdled portion after the acidification or fermentation of milk. It is the smaller fraction but is protein dense so that it provides approximately 80 percent of milk protein . There are three major subunits of caseins: alpha (a)-, beta (b)-, and kappa (k)-caseins. Bovine and human milk contain all three subunits, but a-caseins represent only a small component in human milk [4,5]. b-casein is the most prevalent of the three subunits in both bovine and human milk .
Casein polypeptide chains include bioactive peptides, which have several important actions, including immunomodulatory and antibacterial properties, antithrombotic and antihypertensive activity, effects on gastrointestinal motility, and opioid receptor agonism, as determined by in vitro studies .
●Human milk – The whey:casein ratio in human milk is approximately 80:20, with only a slight decline during lactation, as determined by a study using modern and precise methods . This is in contrast with historical reference values, which suggested that the whey:casein ratio in mature human milk is 60:40 or 50:50 . However, as with all nutrients in human milk, there is tremendous interindividual variation in the whey:casein ratio.
●Preterm formula – The whey:casein ratios in formula vary by brand and type. In general, formulas for preterm infants typically have ratios of 80:20. The high whey:casein ratio is designed to make the preterm formula similar to human milk and is thought to improve digestibility compared with formulas with lower ratios (eg, 60:40, which is typical for term infant formulas) .
Amino acid composition — The amino acid profile of human milk has a somewhat different amino acid profile and more free amino acids compared with preterm formula. These differences may explain some of the physiologic and health benefits of human milk over formula.
●Human milk – Most of the amino acids in human milk are in the whey and casein proteins. Glutamic acid is the predominant amino acid , followed by serine, taurine, glutamine, alanine, and aspartic acid [8,9]. Essential amino acids (ie, amino acids that cannot be synthesized from other amino acids) are well represented, especially isoleucine, leucine, lysine, threonine, and valine . The amino acid profile varies by the whey and casein components . In general, concentrations of arginine, cystine, lysine, methionine, and tryptophan are greater in whey versus casein and, thus, these amino acids are more prominent in samples with high whey:casein ratios [10,11].
In addition, 10 to 25 percent of the nitrogen in human milk is nonprotein nitrogen. Sources of nonprotein nitrogen include urea (almost one-half of total nonprotein nitrogen), creatinine, nitrogen-containing oligosaccharides, nucleic acids, and free amino acids . Of the free amino acids, glutamine, glutamate, and taurine are the most abundant [8,13,14]. Free amino acids are beneficial to the developing infant because they are rapidly absorbed and serve as nitrogen sources and substrates for neurotransmitters and antioxidants, provide energy substrates for the developing gut, and support immune development [14,15].
Total protein and free amino acid concentrations are higher in preterm versus term milk . Additionally, as lactation progresses, the pool of free amino acids decreases, except that the absolute concentrations increase for glutamic acid, glutamine, serine, alanine, and cystine .
●Preterm formula – The amino acid profile of formula depends in part on its whey:casein ratio. Preterm formulas include additional bovine whey so that the whey:casein ratio more closely resembles human milk. Nonetheless, the amino acid profile differs, reflecting the profile of bovine whey compared with human whey. In addition, formulas have a lower content of nonprotein nitrogen (approximately 5 percent) and, in contrast with human milk, the predominant free amino acids are taurine and methionine.
●Fortified human milk – Human milk usually requires fortification to achieve an adequate intake of fat. Fat content in unpasteurized human milk varies widely, from approximately 2.6 to 3.7 g/dL . Assuming a fat concentration of 3 g/dL, a fully enterally fed preterm infant weighing 1000 g would need to ingest 160 to 220 mL/day to meet the target for fat intake. This volume is near or above the volume that most preterm infants can tolerate, even when they are healthy. Fortifying the human milk by adding a human milk fortifier (HMF) increases the fat content of the feed to 4.4 to 4.8 g/dL (using a bovine-based HMF) or to 4.7 to 6.4 g/dL (using a human milk-based HMF). Thus, a fortified feed provides sufficient fat in a volume of 100 to 140 mL/day, which is typically tolerated by these infants. (See "Human milk feeding and fortification of human milk for premature infants", section on 'Fortification of human milk'.)
●Preterm formula – In preterm infant formula, fat concentrations vary by manufacturer and caloric density, ranging from 3.4 to 6.7 g/dL.
Total fat content — Total fat represents 3.9 percent of human milk  and provides up to 40 to 50 percent of total energy intake through the first six months of age [17,18]. Total fat content is generally higher in preterm compared with term milk (table 2) .
The fat content in human milk demonstrates the highest interindividual variation among the three major macronutrients (fat, protein, and carbohydrates), with a coefficient of variation of almost 40 percent . Fat content also varies substantially among samples produced by an individual woman, with higher fat content in:
●Later in the day [19,20]
●Longer duration of a feeding 
●Longer interval between feedings
In one series of term milk samples, the average total fat concentration in milk expressed early in the feeding (foremilk) was 3.2 g/dL, compared with 5.6 g/dL in milk expressed later in the feeding (hindmilk) .
Triglycerides — Almost all lipids in human milk are packaged as triglycerides (also known as triacylglycerides), which are comprised of three fatty acid chains on a glycerol backbone .
●Classification – Fatty acids are classified by :
•Carbon chain length:
-Short-chain fatty acids have 2 to 5 carbons
-Medium-chain fatty acids have 6 to 12 carbons
-Long-chain fatty acids have 13 to 21 carbons
-Very long-chain fatty acids have 22 or more carbons
•Degree of "saturation":
-Saturated fatty acids have only single bonds between carbons (ie, a maximum number of hydrogens per carbon)
-Monounsaturated fatty acids have one double bond between carbons
-Polyunsaturated fatty acids have multiple double bonds between carbons
●Key lipids in human milk – Eighty-five percent of fatty acids in human milk are saturated or monounsaturated, while polyunsaturated fatty acids represent 15 percent [17,18]. Each of these classes has important health benefits for the preterm infant.
•Saturated fatty acids – Palmitic acid (C16:0) is by far the most common saturated fatty acid in human milk and represents 20 to 25 percent of all fatty acids throughout lactation (table 4) . The form of palmitic acid differs slightly between human milk (in which most is esterified in the sn-2 position) compared with formulas (in which it is esterified in the 1,3 position). Clinical implications of this distinction have not been determined, although an association between sn-2 esterification and softer stool consistency has been suggested based on low-quality evidence .
•Monounsaturated fatty acids – Oleic acid (C18:1n-9) is a monosaturated fatty acid and represents 30 to 36 percent of the fatty acids in human milk throughout lactation.
•Long-chain polyunsaturated fatty acids (LCPUFAs) – LCPUFAs represent 15 percent of all fatty acids in human milk (table 4). They can be grouped as omega-3 (n-3) or omega-6 (n-6) fatty acids depending on the position of the double bond. Arachidonic acid (ARA; n-6) and docosahexaenoic acid (DHA; n-3) are important components of neural tissue and are therefore important for neurodevelopment. Both ARA and DHA are represented in human milk in small amounts, with larger amounts of the ARA precursor, linoleic acid.
Since the early 2000s, infant formulas, including those intended for preterm infants, have been routinely supplemented with ARA and DHA, although systematic meta-analysis has not shown clear health benefits of this strategy . The possible effects and limited clinical evidence are discussed in a separate topic review. (See "Long-chain polyunsaturated fatty acids (LCPUFA) for preterm and term infants".)
•Medium-chain fatty acids or medium-chain triglycerides (MCTs) represent a small proportion of human milk . In contrast, MCTs represent up to 50 percent of total fat in formula in an effort to compensate for the impaired fat digestion in infants and increase overall absorption of fats and energy delivery to optimize growth . However, despite these theoretical benefits, increasing the MCT content in infant formula has not been associated with improved growth . (See 'Delivery and digestibility of lipids' below.)
Complex lipids — Complex lipids represent 0.2 to 1 percent of total lipids, with a concentration of 100 to 400 mg/L [18,27]. Although this is a small fraction compared with triglycerides, it includes several substances with critical biologic roles, including cholesterol, sphingolipids (eg, ceramides), gangliosides, phospholipids, and plasmalogens.
Delivery and digestibility of lipids
Milk fat globule membranes — In human milk, lipids are packaged in milk fat globules, a tri-membrane globule in which complex lipids and critical bioactive proteins are embedded into the outer membrane [17,18]. Possible benefits from these complex lipid and protein components, and improved delivery of fats compared with free lipids, have been suggested but not established. Two small randomized trials in full-term infants found that infants fed formula supplemented with milk fat globule membranes and lactoferrin had higher scores on measures of cognitive development at 12 to 18 months of age [28-30], but there was no difference in outcomes by age 6.5 years . Milk fat globule membrane-supplemented formula has not been directly compared with human milk, and no trials have been conducted in preterm infants.
Pancreatic lipase — Infants are born with developmental pancreatic insufficiency, with inefficient hydrolysis and absorption of fats due to limited pancreatic production and excretion of lipase. In mother's own milk, pancreatic enzymes are present, which aid in infant digestion of fats. By contrast, formula lacks digestive enzymes and pasteurization of human milk destroys these digestive enzymes. As a result, hydrolysis and absorption of triglyceride fatty acids is reduced for pasteurized human milk and formula compared with mother's own milk .
Supplementation of formula or pasteurized human milk with pancreatic enzymes is not recommended for preterm infants. In a randomized trial, administration of recombinant lipase did not improve growth outcomes and increased risk of gastrointestinal complications .
Requirements and fortification — The recommended carbohydrate intake in fully enterally fed preterm infants is 11.6 to 13.2 g/kg/day (or 10.5 to 12 g/100 kcal) .
●Fortified human milk – Human milk often requires fortification to achieve the recommended intake of carbohydrates. The carbohydrate content of unpasteurized mother's own milk is approximately 7.0 to 7.3 g/dL [1,34]. To meet this requirement, a fully enterally fed preterm infant with a weight of 1000 g would need to ingest approximately 170 mL/kg/day, which is more than some infants can tolerate. Thus, fortification of human milk may be necessary to meet the goals for carbohydrate intake, in addition to the goals for other macronutrients, as outlined above. Fortifying the human milk by adding a human milk fortifier (HMF) increases the carbohydrate content of the feed to approximately 8.7 g/dL (using a bovine-based HMF) or 8.2 to 8.5 g/dL (using a human milk-based HMF).
●Preterm formula – The carbohydrate content in preterm infant formula varies by manufacturer and ranges from 7.0 to 10.9 g/dL.
Lactose — Lactose, a disaccharide chain of glucose and galactose, is the predominant carbohydrate in human milk, representing 70 to 85 percent of carbohydrates , and in many standard term formulas. Lactose concentrations in human milk increase during lactation . Compared with term infants, preterm infants are less able to digest lactose because of their developmental deficiency of lactase. Among infants with gestational age 26 to 34 weeks, lactase is only 30 percent of term levels [36,37].
Because preterm infants have limited ability to digest lactose, formula manufacturers typically replace some of the lactose with corn syrup and short-chain glucose polymers. However, even when it is malabsorbed in the small intestine, lactose has important biologic benefits:
●Lactose that escapes digestion in the small intestine may undergo bacterial fermentation and absorption in the colon, a process known as the colonic salvage pathway
●Lactose in the colon enhances intestinal growth of the beneficial microbiota, Lactobacillus and Bifidobacteria 
Oligosaccharides — Oligosaccharides are short-chain, complex carbohydrates. They have several important biologic benefits, including prebiotic (ie, promoting growth of beneficial microbiota), immunomodulatory, and antimicrobial functions .
Human milk contains hundreds of different oligosaccharide variants or types, and this is unique to human milk compared with other mammalian milks. The oligosaccharide concentration is high in colostrum and falls as milk matures . However, the oligosaccharide profile remains fairly consistent throughout lactation, suggesting that it is determined by intrinsic genetic factors rather than exogenous factors such as maternal health and diet .
Like other human milk components, the oligosaccharide component varies between individuals. Limited evidence suggests that variation in the oligosaccharide profile of mother's milk may contribute to the infant's risk for certain morbidities, such as necrotizing enterocolitis. As an example, lower concentrations of disialyllacto-N-tetraose (DSLNT) in mother's milk were associated with an increased risk of necrotizing enterocolitis in a population of preterm infants with a birth weight <1500 g [42,43].
Several randomized trials in term infants have evaluated the effects of supplementing infant formula with synthetic oligosaccharides. Infants fed the oligosaccharide-supplemented formula had intestinal microbiota patterns similar to breastfed infants, reduced plasma inflammatory cytokines, reduced respiratory infections, and reduced use of antibiotics [44-48]. In formula-fed moderately preterm infants, small studies found that oligosaccharide supplements improved enteral tolerance; increased intestinal bifidobacteria colonization; and decreased stool viscosity, pH, and frequency [49-52]. In contrast, they were no differences, compared with controls, in markers of intestinal inflammation, intestinal permeability, infectious morbidity, or vaccine responsiveness [53-57]. Large studies of oligosaccharide supplementation in the feedings of extremely preterm infants are lacking.
DONOR MILK — Milk from human donors must be pasteurized to reduce the risk of biologic hazards, in addition to other safety measures [58,59]. The type of pasteurization process, in addition to the age of the donor, has some effects on the nutrient content of donor milk. Compared with typical mother's own milk, donor milk has decreased protein, decreased digestive enzyme activity, and decreased concentration of long-chain polyunsaturated fatty acids (LCPUFAs). (See "Human milk feeding and fortification of human milk for premature infants", section on 'Use of donor milk'.)
ELECTROLYTES, TRACE ELEMENTS, MINERALS, AND VITAMINS — Nutrient requirements for preterm infants are summarized in the table (table 1).
Sodium — Sodium requirements in the preterm infant are 69 to 115 mg/kg/day (3 to 5 mEq/kg/day) or 63 to 105 mg/100 kcal (2.7 to 4.6 mEq/100 kcal) . Late-onset hyponatremia (serum sodium concentrations <130 mmol/L after the second postnatal week) is common, occurring in up to 20 percent of preterm infants. Infants fed only human milk or fortified human milk are at greater risk compared with infants who are fully or partially formula fed. The most immature infants are at greatest risk, with up to 40 percent of infants with a birth weight <1000 g experiencing late-onset hyponatremia.
Sodium content in early preterm milk is higher compared with term milk but rapidly falls during the first two postnatal weeks to term levels (approximately 12 to 25 mg/dL) [60,61]. Fortifying the human milk by adding a human milk fortifier (HMF) adds an additional 27.6 to 41.4 mg/dL (1.2 to 1.8 mEq/dL) for bovine-based HMF or 50.6 to 55.2 mg/dL (2.2 to 2.4 mEq/dL) for human milk-based HMF. However, even after fortification of human milk, preterm infants occasionally require an additional 45 to 140 mg/kg/day (2 to 6 mEq/kg/day) of sodium, typically provided by adding sodium chloride supplements to the feed (eg, a 23.4% saline solution supplies 4 mEq/mL). The risk for late-onset hyponatremia and need for additional sodium supplementation typically continues for the first one to two months of life. Most infants no longer need sodium supplements by the time of hospital discharge .
The sodium content in preterm formula is 30 to 71 mg/dL (1.3 to 3.1 mEq/dL). Although preterm formula provides more sodium than does unfortified human milk, some formula-fed infants may still develop late-onset hyponatremia and require sodium supplements.
Calcium and phosphorus — Calcium requirements are approximately 150 to 220 mg/kg/day, and phosphorus requirements are 75 to 140 mg/kg/day .
Human milk must be supplemented with calcium and phosphorus to meet these needs and support bone development in the preterm infant. Routine supplementation with these minerals has dramatically reduced the risk of rickets and incidental fractures. However, preterm infants have an increased risk of metabolic bone disease despite supplementation; the risk is inversely proportional to gestational age and birth weight. Indeed, 40 to 60 percent of extremely low gestational age newborns will have radiologic and/or biochemical evidence of metabolic bone disease [64,65]. (See "Management of bone health in preterm infants".)
Vitamin D and iron — Human milk is low in vitamin D and iron. Preterm infants fed human milk require supplementation to meet their needs. (See "Breastfeeding the preterm infant", section on 'Vitamin D and iron supplements'.)
Other vitamins and minerals — Human milk does not contain sufficient quantities of zinc, potassium, and magnesium to meet the needs of premature infants; these nutrients are generally included in HMFs and preterm formulas. The recommended intakes of these and other nutrients are listed in the table (table 1).
Zinc requirements for preterm infants are approximately 1.4 to 2.5 mg/kg/day, which is substantially more than the amount supplied by feeds of unfortified human milk . These requirements are based primarily on micronutrient balance studies and indirect evidence from other populations for which zinc is important for growth and immune function , as well as limited clinical evidence for growth benefits in preterm infants [67,68]. Higher supplemental doses have no demonstrated benefit and may adversely affect copper absorption.
SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Breastfeeding and infant nutrition".)
SUMMARY AND RECOMMENDATIONS
●Overview – Human milk is the recommended diet for the preterm infant. Human milk supplies most essential nutrients as well as some biologically active components that support optimal physical and neurologic development, immune function, and a healthy microbiome and also help to prevent morbidities such as necrotizing enterocolitis. (See 'Overview' above.)
Compared with term infants, preterm infants have markedly higher requirements for certain nutrients. Recommended intakes for very low birth weight infants are shown in the table (table 1).
●Fortification of human milk – Despite its advantages, human milk does not supply sufficient amounts of certain nutrients within the feeding volume that is tolerated by preterm infants (table 2). Therefore, supplementation with a human milk fortifier (HMF) is necessary to supply sufficient protein, calcium, phosphorus, and sodium to support growth and to prevent metabolic bone disease and late-onset hyponatremia. The content of these nutrients in unfortified and fortified human milk is outlined in the table (table 3). (See "Management of bone health in preterm infants", section on 'Calcium and phosphorus requirements' and 'Sodium' above.)
HMFs also provide supplemental zinc, potassium, and magnesium to meet the estimated needs of preterm infants. (See 'Other vitamins and minerals' above and "Human milk feeding and fortification of human milk for premature infants".)
●Protein – Human milk has a higher whey:casein ratio (approximately 80:20) compared with cow's milk. In addition, 10 to 25 percent of the protein in human milk is nonprotein nitrogen, including free amino acids, which are beneficial to the preterm infant because they are more rapidly absorbed. Preterm formulas include additional bovine whey so that the whey:casein ratio resembles human milk, but the amino acid profile still differs from human milk and nonprotein nitrogen is lower. The protein content of human milk decreases substantially as lactation progresses. (See 'Protein' above.)
●Lipids – The lipid content of human milk varies markedly between women and between samples from an individual woman. Fat content generally increases during lactation (more mature milk) and is higher in samples collected later in the day, with longer inter-feeding intervals, or at the end of a feed (hindmilk). Almost all lipids in human milk are various forms of triglycerides (short-, medium-, or long-chain; saturated, mono-, or polyunsaturated). Small but biologically important components of fats are complex lipids (including cholesterol and sphingolipids). (See 'Lipids' above.)
●Carbohydrates – Lactose is the predominant carbohydrate in human milk. Because preterm infants have a developmental lactase deficiency, they may not be able to absorb all of the lactose in a human milk feed. However, malabsorbed lactose may be fermented and absorbed in the colon (colonic salvage) and also promotes development of healthy colonic microbiota. Human milk also contains oligosaccharides. These short-chain, complex carbohydrates have several important biologic benefits, including prebiotic (ie, promoting growth of beneficial microbiota), immunomodulatory, and antimicrobial functions. (See 'Carbohydrates' above.)
ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges Richard J Schanler, MD, who contributed to earlier versions of this topic review.
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