Human milk feeding and fortification of human milk for premature infants

INTRODUCTION — Mother's own milk is the preferred feeding source for premature infants because it is associated with an array of important short- and longer-term health benefits [1,2]. Pasteurized milk from a human donor should be given when mother's milk is not available or is contraindicated [3]. While donor milk may reduce the risk of necrotizing enterocolitis (NEC), it does not confer many of the other important health benefits of mother's own milk.

The nutritional requirements of preterm infants cannot be met with exclusive human milk feedings, because they require more protein, energy, fatty acids, minerals, and micronutrients than do healthy term newborns. For this reason, human milk fortification is needed. There are many commercially available fortifiers that vary by form (powder versus liquid), macronutrient content, degree of hydrolysis of proteins, and source (bovine versus human).

This topic review will discuss health benefits of human milk (mother's milk and donor milk) and human milk fortification, including fortifier types and timing of administration. Other topics with related information are:

●(See "Nutritional composition of human milk and preterm formula for the premature infant".)

●(See "Approach to enteral nutrition in the premature infant".) – Focuses on enteral feeds in the neonatal intensive care unit

●(See "Breast milk expression for the preterm infant".)

●(See "Breastfeeding the preterm infant".)

●(See "Growth management in preterm infants".) – Focuses on feeding after neonatal intensive care unit discharge

BENEFITS OF MOTHER'S MILK — Mother's milk contains a range of biologic components, including immunoglobulins, cytokines, growth factors, hormones, and prebiotic oligosaccharides, that confer health benefits compared with formula feeds [4,5]. Benefits of mother's milk for the infant include improvements in gastrointestinal function, digestion and absorption, cognitive and visual development, and host defense as well as enhanced maternal-infant bonding. (See "Infant benefits of breastfeeding".)

Particular benefits for premature infants include:

●Protection against necrotizing enterocolitis (NEC)

●Protection against late-onset sepsis

●Protection against chronic lung disease

●Improved neurodevelopment

In general, the greater the proportion of mother's milk in the diet (versus formula), the stronger the association with these health benefits. The evidence for these benefits is summarized below and described in more detail in the linked topic reviews.

●Protection against NEC – Feeding mother's milk to a premature infant significantly decreases the incidence of NEC compared with formula feeding [6-9]. The evidence is discussed in a separate topic review. (See "Neonatal necrotizing enterocolitis: Prevention", section on 'Human milk feeding'.)

Human milk components that appear to protect against NEC include immunoglobulins, acetylhydrolase (which antagonizes platelet-activating factor, a major trigger for NEC in premature infants), and human milk oligosaccharides (which promote the growth of a healthy gut microbiome). (See "Neonatal necrotizing enterocolitis: Pathology and pathogenesis", section on 'Human milk'.)

●Protection against infection – Some studies show that premature infants fed mother's milk have reduced rates of late-onset sepsis [10-12]. Possible explanations for these beneficial effects include [4]:

•Presence of maternal antibodies in human breast milk (ie, secretory immunoglobulin A [sIgA] and other immunoglobulins provided by the enteromammary immune system). Skin-to-skin contact between mother and infant may also elicit maternal antibodies to nosocomial pathogens.

•Mother's milk feeding may decrease the proportion of pathogenic microorganisms in infant fecal flora.

•Mother's milk also contains other factors that may be important in host defense, including lactoferrin, lysozyme, oligosaccharides, cytokines, enzymes, growth factors, nucleotides, and cellular components.

●Improved neurodevelopment – Several studies of hospitalized preterm infants have shown that consumption of mother's milk, compared with preterm formula, is associated with improved neurodevelopment in a dose-response relationship [1,13-17]. These benefits were observed even when mother's milk was associated with slower growth, although slower growth is generally associated with worse neurodevelopment. However, some other studies and a meta-analysis did not detect such an effect [8,9,18]. Reasons for the discrepant findings may include sample size, adjustment for comorbidities, and differences in categories of exposure to mother's milk (eg, exclusively mother's milk versus "mostly" mother's milk).

Mechanisms that may explain the relationship between mother's milk consumption and improved neurodevelopment include biologic components of mother's milk that may contribute to brain growth [19] and mother-infant bonding, which has been linked to mother's milk feeding and promotes improved neurodevelopment among preterm infants.

●Protection against chronic lung disease – Several studies have found a dose-dependent reduction in chronic lung disease among preterm infants fed mother's own milk during the birth hospitalization [1]. Proposed mechanisms include increased delivery of bioactive components of mother's milk that reduce oxidative stress and inflammation in the premature lung and/or reduced incidence of NEC and sepsis, which contribute to development of chronic lung disease. (See "Bronchopulmonary dysplasia (BPD): Prevention", section on 'Breast milk'.)

USE OF DONOR MILK — Many mothers are unable to provide sufficient mother's milk to meet the needs of their preterm infant during the birth hospitalization and following discharge. In the United States, approximately one-half of very low birth weight (VLBW) infants were being fed human milk (primarily mother's own milk but sometimes donor human milk) at the time of hospital discharge [20]. Because mother's own milk has the most health benefits for the infant, every effort should be made to support effective lactation by the birth mother [1]. (See "Breast milk expression for the preterm infant".)

When mother's own milk is not available or is insufficient, pasteurized human milk from a donor may be used. Donor milk also may be used as a "bridge" until the mother's milk supply improves with time and intensive lactation support.

●Indications for donor milk – Pasteurized human donor milk should be used when mother's milk is not available for VLBW infants (<1500 g), as recommended by guidelines from the American Academy of Pediatrics [2,3] and the European Society for Paediatric Gastroenterology, Hepatology and Nutrition [21]. Some neonatal intensive care units also use human donor milk for infants above 1500 g [22].

If donor human milk is used, it may be given to preterm infants as soon as they are deemed able to tolerate enteral feedings. There are no clear guidelines for when to discontinue the use of donor human milk, but common practice is to continue until the infant reaches approximately 34 weeks postmenstrual age, weighs 2000 g, and/or is ready for hospital discharge [22].

●Rationale – Donor milk (when provided exclusively or as a supplement to mother's own milk) is associated with decreased risk of necrotizing enterocolitis (NEC) and feeding intolerance compared with preterm formula [1,23-25]. By contrast, benefits of donor milk on neurodevelopment, or risk for late-onset sepsis, chronic lung disease, or retinopathy of prematurity, have not been demonstrated [23,24,26]. Explanations for the apparent advantage of mother's own milk are that donor milk has reduced bioactivity due to the pasteurization process, multiple freeze-thaw cycles, container changes, and prolonged storage times.

●Safety – Due to the vulnerable medical status of premature infants, donor milk should always be obtained from an established human milk bank that follows safety regulations for optimal milk collection, pasteurization, storage, and shipping [27,28]. In North America, accredited nonprofit human milk banks can be found through the Human Milk Banking Association of North America; several for-profit companies also sell appropriately processed donor milk. Safety standards are also maintained by central organizations in many other countries or regions, including the United Kingdom Association for Milk Banking, the European Milk Bank Association, and Banco de Leite Humano in Brazil. Information for some other countries and regions can be found at the PATH human milk banking resources page. Donor milk obtained over the internet and/or that is not pasteurized by an established milk bank should not be used.

Some Muslim families may be reluctant to use pooled human donor milk due to Islamic belief about milk kinship, although the interpretation varies among different Muslim communities. This issue calls for culturally sensitive conversations to help the family make a fully informed decision and explore alternatives to pooled donor milk, if needed [29].

GROWTH LIMITATIONS OF HUMAN MILK — Although human milk is the optimal diet for preterm infants, a human milk fortifier (HMF) must be added so that it delivers sufficient nutrients to meet the infants' needs. Unfortified human milk does not supply sufficient quantities of protein, energy, fatty acids, minerals, and other micronutrients that are needed for preterm infants to achieve fetal growth trajectories [30]. (See "Nutritional composition of human milk and preterm formula for the premature infant".)

Although preterm mother's milk has more protein and energy than term milk, the content of these macronutrients is still less than the recommended needs for preterm infants (table 1) [31,32]. The protein deficit is particularly severe for donor milk, which is predominantly derived from pooled samples of mothers of term infants who donate milk that is pumped several months after birth [33]. Further, the process of pasteurization can reduce lipase activity, which may decrease the fat digestibility and further inhibit growth [34]. The deficit in energy is also exacerbated because preterm infants typically receive their feedings via naso- or orogastric tubes. This mode of delivery decreases nutrient delivery to the infant because the fats stick to the tubing, particularly when the feed is infused at slower rates [35].

Multiple observational and randomized trials have shown that preterm infants fed preterm formula have more rapid growth during the hospital period than those fed mother's milk and/or donor milk, even when an HMF is used [25,36]. Nonetheless, human milk feeding (with appropriate fortification) is associated with faster attainment of full feeds and earlier neonatal intensive care unit discharge in some centers, presumably because of its benefits for feeding tolerance and protective effect against comorbidities [37].

FORTIFICATION OF HUMAN MILK

Indications and fortifier types — Human milk feeds for hospitalized very low birth weight (VLBW) infants and other infants at risk for growth failure should be supplemented with multinutrient human milk fortifier (HMF) [1,38]. HMFs are designed to be mixed with human milk prior to administration. Multiple fortifiers are commercially available, which vary in several ways (table 2):

●Liquid versus powder form – Bovine-derived HMFs come in powder and liquid forms. We and many other institutions use liquid rather than powdered fortifiers because of case reports of transmission of Cronobacter sakazakii in powdered fortifiers or formulas (including an incident in February 2022 involving powdered formulas from a specific facility) [39-42]. Products in a powder form cannot be sterilized in the same manner as liquids and, thus, are at risk for bacterial contamination, although the risk is very low due to manufacturing standards and extensive testing. Powdered HMFs are commonly used outside of the United States, with minimal safety problems. Moreover, it should be recognized that bovine liquid HMFs displace the volume of human milk given to the infant and thus reduce the proportion of human milk in the diet compared with powdered HMFs [43].

●Protein content – Commercially available HMFs generally provide at least moderate- or high-protein supplements, adding between 1 and 2.2 g of protein per 100 mL final volume to provide a total protein content between 2.6 and 3.5 g/100 mL of fortified human milk (table 2). Limited evidence suggests that those on the higher end of this range (adding ≥1.4 g/100 mL final volume) may result in modest increases in weight gain (mean difference 0.7 g/kg/day) during the neonatal admission compared with HMFs with protein content on the lower end of this range (adding 1 to <1.4 g/100 mL) [44].

●Protein structure (intact versus hydrolyzed) – Bovine HMFs also vary in the extent to which the proteins are hydrolyzed. Hydrolyzed protein fortifiers are thought to be more readily absorbed in the preterm gut and therefore lead to improved feeding tolerance with higher concentrations of protein. One randomized trial of 150 preterm infants compared powdered HMF with a hydrolyzed liquid HMF with 20 percent more protein content and found similar feeding tolerance and improved growth among the infants fed hydrolyzed HMF [45]. This finding and others provide evidence in support of hydrolyzed HMF over powdered fortifiers with nonhydrolyzed protein; however, the difference in the growth outcome may be related to the lower protein content of the powdered HMF rather than the hydrolysis. There are no randomized controlled trials comparing forms of HMFs with hydrolyzed versus intact proteins but with similar protein content.

●Acidified versus non-acidified – For some liquid HMFs, the sterilization process involves acidification followed by heat treatment. These forms of HMFs have been associated with transient metabolic acidosis in preterm infants but not changes in growth, so the clinical relevance of this factor is unclear [46].

●Bovine versus human – Another type of HMF is derived from pasteurized human donor milk (human milk-derived HMF). The relative advantages of human-derived HMF compared with bovine-derived HMF have not been fully explored. In a randomized trial, the risk of necrotizing enterocolitis (NEC) and growth parameters were not statistically different among very preterm infants who were fed human milk supplemented with bovine-derived HMF compared with human milk-derived HMF [47]. However, a subsequent meta-analysis that included this and two other trials found that use of a bovine-derived HMF led to significantly worse outcomes for NEC, retinopathy of prematurity, interruption of feeding, and a composite morbidity index [48-50]. Potential concerns about human milk-derived HMFs are the high cost, disparate access to these products across different institutions and countries, and displacement of the volume of mother's milk given to the infant (the latter issue also applies to bovine-derived liquid HMFs). Although some centers consider the cost of these products to be prohibitive, an analysis suggests an overall cost savings when considering the high cost of NEC and other comorbidities [51]. Until the comorbidity outcomes are confirmed and these issues are addressed, the author does not recommend human-derived HMF for general use in neonatal intensive care units, but this remains an area of controversy and ongoing investigation.

●Micronutrient content – Micronutrient and vitamin content of HMFs may vary, and, therefore, individualization of supplements might be needed. All HMFs are designed to provide supplemental calcium and phosphorus to meet the high needs of a premature infant, but the content of these minerals differs somewhat among the HMFs available in the United States and also compared with those available in Europe. (See "Nutritional composition of human milk and preterm formula for the premature infant", section on 'Electrolytes, trace elements, minerals, and vitamins' and "Management of bone health in preterm infants", section on 'Calcium and phosphorus requirements'.)

●Lipid – The fat content also varies among HMFs. Powdered HMFs typically contribute an additional 0.35 to 1 g lipid per 100 mL of prepared milk in addition to the lipid content of the human milk itself, and liquid HMF can add as much as 2.3 g lipid per 100 mL of prepared milk [52].

In-hospital fortifier use — The optimal timing to initiate fortification has not been established. Many neonatal intensive care units initiate fortification when feeding volumes reach 80 to 100 mL/kg/day, but some initiate fortification at lower feeding volumes [1]. Several studies found that adding a human milk-derived HMF beginning at a feeding volume of 20 to 40 mL/kg/day was not associated with feeding intolerance or NEC [23,53,54].

Fortification is typically continued throughout the preterm infant hospitalization, and titration of fortifiers should be based on growth and other markers of nutritional status. This is particularly important among preterm infants fed predominantly or exclusively donor milk, which has lower protein and energy content compared with mother's milk (see "Approach to enteral nutrition in the premature infant"). Point-of-care analyzers that measure the macronutrient content of milk are available for clinical use in some institutions. The use of these tools to facilitate individual fortification strategies is emerging [55].

Examples of the macronutrient content of fortified human milk is shown in the table, based on average content of preterm milk and HMFs commonly used in the United States (table 2).

Post-discharge fortifier use — More than one-half of VLBW infants have extrauterine growth failure (weight for gestational age less than 10^th percentile) at hospital discharge [56]. Many providers recommend that fortification be continued after discharge home to support ongoing "catch-up growth." However, studies of this practice on growth and neurodevelopment outcomes are lacking [1].

Decisions about fortifier use should optimally be made in conjunction with maternal goals for lactation, bottle feeding with expressed milk, fortifier versus formula, and the infant's growth status. For example, if a mother would like to breastfeed directly, the first step might be to transition some feeds to direct breastfeeding while maintaining other feeds of expressed mother's milk with HMF prior to hospital discharge. If the infant's growth is acceptable, the proportion of feeds from direct breastfeeding may be gradually increased while feeds of fortified expressed milk are gradually decreased. (See "Approach to enteral nutrition in the premature infant", section on 'Infants who can feed orally'.)

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" and "Society guideline links: Nutrition support (parenteral and enteral nutrition) for neonates including preterm infants".)

SUMMARY AND RECOMMENDATIONS

●Benefits of mother's milk – We recommend mother's own milk rather than preterm formula for premature infants (Grade 1B). Compared with preterm formula, mother's milk feeds are associated with reduced rates of necrotizing enterocolitis (NEC), late-onset sepsis, and possibly chronic lung disease, as well as improved neurodevelopment. (See 'Benefits of mother's milk' above.)

●Lactation support – Because mother's own milk has the most health benefits for the infant, every effort should be made to support effective lactation by the birth mother. This typically involves early and frequent breast milk expression using a breast pump, enhanced by focused lactational counseling. (See "Breast milk expression for the preterm infant".)

●Role for donor milk – When mother's own milk is not available for very low birth weight (VLBW) infants or other infants with a high risk of NEC, we suggest feeding with pasteurized milk from a human donor rather than preterm formula (Grade 2B). Donor milk is associated with decreased risk of NEC and feeding intolerance compared with preterm formula. Donor milk is inferior to mother's milk because it is not associated with some other health benefits and it has somewhat lower quantities of protein and energy. Donor milk can be continued for the duration in which VLBW infants are at risk for NEC, which is through approximately 32 to 34 weeks corrected gestational age. (See 'Use of donor milk' above.)

●Fortification of human milk

•Human milk feedings for VLBW infants and other preterm infants at risk of growth failure must be fortified with a human milk fortifier (HMF) to meet their nutritional needs. Commercially available HMFs vary in multiple ways (table 2). We suggest liquid preparations of HMFs due to concern for transmission of Cronobacter sakazakii in powdered HMFs, based on limited evidence from anecdotal reports (Grade 2C). Clear advantages of protein hydrolysis or human-derived HMF over bovine-derived HMF have not been shown. (See 'Indications and fortifier types' above.)

•Decisions about continuing HMFs after hospital discharge depend on the growth status of the infant and the mother's goals for lactation, direct breastfeeding, and bottle feeding. (See 'Post-discharge fortifier use' above and "Approach to enteral nutrition in the premature infant", section on 'Infants who can feed orally'.)

ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges Richard J Schanler, MD, who contributed to earlier versions of this topic review.