Significant benefits to infant host defense, gastrointestinal maturation, neurodevelopment, and some aspects of nutritional status are observed when premature infants are fed human milk (1). For premature infants, the nutritional adequacy of human milk is optimal when a multinutrient supplement, or fortifier, is added to the diet (1). Protein and energy supplementation are associated with improved rates of weight gain, nitrogen balance, and indices of protein nutritional status (2–4). Supplementation with both calcium and phosphorus results in normalization of biochemical indices of mineral status (5–7).
A systematic review provided a meta-analysis of controlled trials of human milk fortification compared with the feeding of unfortified human milk (7). More than 600 infants with birth weights <1850 g were included in the analyses. The addition of multinutrient fortifiers to human milk resulted in short-term improvements in weight gain, length, head circumference, and bone mineral content during the hospital stay. Furthermore, no adverse effects of human milk fortification, such as feeding intolerance or necrotizing enterocolitis (NEC), were reported.
EFFECTS OF HUMAN MILK ON HOST DEFENSE
The relationship between diet and the incidence of infection in premature infants demonstrates that the feeding of mother's milk mitigates the high rate of infection common to hospitalized premature infants. These effects have been demonstrated even when fortified human milk has been used. In a retrospective review of medical records in a Washington, DC, neonatal intensive care unit, human milk-fed infants had a 26% incidence of documented infection compared with 49% in formula-fed infants (8). A semirandomized trial in the United Kingdom reported that necrotizing enterocolitis was reduced significantly by feeding premature infants human milk, either exclusively or partially supplemented with either formula or pasteurized donor human milk (9). That study identified the highest risk for NEC in the group of infants born before 28 weeks' gestation. The receipt of human milk was associated with significant protection from NEC at all gestation groups >27 weeks. When compared with human milk feeding, the receipt of formula was associated with a 2.5-fold increase in NEC (95% confidence interval [CI] 1.2–5.2; P < 0.02) for all cases and a 6.5-fold increase (95% CI 1.9–22; P < 0.001) for confirmed cases of NEC as identified from surgical pathology or postmortem examination. A significant 3-fold increase in NEC also was seen when a diet of exclusive formula feeding was compared with formula used as a supplement to human milk; confidence interval for all cases was 1.5 to 5.7 (P < 0.005) and for confirmed cases 1.4 to 6.5 (P < 0.005).
In a randomized comparison in a neonatal intensive care unit in Mexico City, NEC, diarrhea, urinary tract infection, and days of antibiotic therapy were significantly less in premature infants receiving human milk compared with formula (10).
The relationship between dose of human milk and protective effect was examined posthoc from data derived in a study of 2 feeding strategies for premature infants, trophic feeding at 4 versus 14 days and tube-feeding method, continuous versus intermittent bolus (11). The study recruited infants born before 30 weeks of gestation and enrollment was stratified by diet, either mother's own milk or preterm formula. Differences between groups favored early trophic feeding at 4 days and the intermittent bolus feeding method. However, for all measured outcomes, the diet was the most important variable. Infants predominantly fed human milk (averaged as more than 50 mL/kg/day, approximately one third of full milk feedings) had significantly lower rates of late-onset sepsis and/or NEC (31%) and a shorter hospital stay (mean, 73 days) compared with infants fed preterm formula (55% and 88 days, respectively). Although late-onset sepsis and/or NEC were greater in infants receiving preterm formula, those who received a combination of mother's own milk and preterm formula also had a high risk of sepsis and/or NEC, suggesting the lack of protection afforded by a lower dose of mother's own milk. A dose of more than 50 mL/kg/day of human milk also has been shown to protect against late-onset sepsis in a 4-week study of premature infants when compared with daily doses of 1 to 24 mL/kg and 25 to 49 mL/kg (12).
A reduction in infectious morbidity in human milk-fed premature infants has been reported in nearly 1 dozen studies in the past 25 years (13). Unfortunately, the reports have numerous methodological issues and are compounded by the inability to perform truly randomized trials in human milk-fed premature infants. Several variables need quantification in such studies, including the definition of breast milk (eg, partial, exclusive, mother's own, or donor milk) and how the milk was treated (fresh raw milk, heat treated). In addition, the measured outcome of infection must be defined rigorously and confounding factors considered uniformly. The studies also suggest that factors inherent in the mother's choice to provide breast milk and differences in sociodemographic variables affecting parent–infant contact be identified in each study (14,15).
DONOR HUMAN MILK
Thus, data are emerging that suggest a protective effect against infection in premature infants who are fed in hospital their mother's own milk compared with preterm formula. This results in a myriad of issues, because many mothers are unable to supply enough milk to meet the needs of their premature infants throughout their neonatal intensive care stay. Efforts to promote lactation among such mothers are ongoing, but alternative diets should be considered. Donor human milk has been proposed as an alternative (16).
The concern about transmission of infectious agents through breast milk led to the decline in donor human milk banks and to the obligatory requirement for pasteurization if donor milk is used in the United States (16). The common Holder pasteurization process heats milk to 62.5°C for 30 minutes (17). This process results in a decrease in activity of many of the functional bioactive factors in the milk (18,19). There are scant data to determine the efficacy of pasteurized donor milk in premature infants. A recent Cochrane review of studies conducted more than 20 years ago concluded that feeding premature infants term donor milk did not lower the risk of NEC compared with feeding formula (relative risk of NEC by feeding formula 2.5, 95% CI 0.85–7.26) (20).
Most recently, a randomized trial of extremely premature infants (born before 30 weeks' gestation) assigned to receive pasteurized donor human milk or preterm formula as supplements if their mothers' own milk was unavailable, compared morbidity of infants who received either donor milk or formula, with a reference group of premature infants fed exclusively their mothers' own milk (15). Protocols were used to ensure that human milk was fortified and fed uniformly, growth was assessed and faltering was treated by dietitians blind to diet group. No differences were found in the incidence of late-onset sepsis and/or NEC in the groups fed pasteurized donor milk vs formula, 23/78 versus 20/88, respectively (P = 0.42). The infants receiving donor human milk also required a greater intake of milk and more nutritional supplements, yet persisted with a slower rate of weight gain than infants receiving the formula. The infants who continued to receive their own mothers' milk had fewer episodes of late-onset sepsis and/or NEC (P = 0.034) and a shorter duration of hospital stay (P = 0.04) than those receiving either donor milk or formula. Thus, this randomized blinded trial in extremely premature infants found that as a substitute for mother's own milk, pasteurized donor human milk offered no observed short-term advantage over preterm formula. The data reiterated the benefit of mother's own milk for extremely premature infants.
SUMMARY AND CONCLUSIONS
There are significant host defense benefits from feeding extremely premature infants their mothers' own milk. It is unclear how much milk is protective or at what postnatal age the protective effects are maximized. Furthermore, it is unclear why some premature infants fed mother's milk continue to have significant infectious morbidity. This suggests that a specific dose of milk is needed to confer protection, or, alternatively, some milks may lack adequate concentrations of protective factors. A detailed composition analysis of milk obtained from women delivering before 30 weeks of gestation is needed to determine if the “immature” milk contains the same functional bioactive factors as more mature milk. Furthermore, lactation strategies should be sought that increase mother's own milk production.
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