Human Milk for Preterm Infants and Fortification

Transcription

1 Protein in the Feeding of Preterm Infants Bhatia J, Shamir R, Vandenplas Y (eds): Protein in Neonatal and Infant Nutrition: Recent Updates. Nestlé Nutr Inst Workshop Ser, vol 86, pp , (DOI: / ) Nestec Ltd., Vevey/S. Karger AG., Basel, 2016 Human Milk for Preterm Infants and Fortification Jatinder Bhatia Division of Neonatology, Department of Pediatrics, Medical College of Georgia, Augusta University, Augusta, GA, USA Abstract Breastfeeding is universally accepted as the preferred feeding for all newborn infants, including premature infants. The World Health Organization, American Academy of Pediatrics, Canadian Pediatric Society and the European Society for Pediatric Gastroenterology, Hepatology and Nutrition, among others, recommend exclusive breastfeeding for the first 6 months in term infants, while complementary feeding is introduced over the next several months. However, for preterm infants, fortification is recommended to meet requirements. Human milk composition varies with the duration of lactation, within a day and even during one expression, and composition may be altered by method of storage and pasteurization. In this monograph, the use of human milk for premature infants, its limitations, strategies to overcome said limitations and follow-up studies will be reviewed Nestec Ltd., Vevey/S. Karger AG, Basel Introduction More than 1 in 10 of the world s babies are born too soon and there remains a need for concerted efforts to not only prevent preterm birth, but to also ensure survival of both the mother and baby. Further, numerous interventions have been proposed for the care of preterm infants, including neonatal resuscitation, kangaroo care, oxygen requirement and neonatal intensive care. There are numerous missed opportunities to reach premature infants with essential interventions, including facility-based births, early initiation of breastfeeding, thermal and hygienic care and the extra care needed for preterm infants [1]. As early as

2 Table 1. WHO recommendations, rationale and evidence for nutrition actions [7] LBW infants, including VLBW infants, should be fed mother s own milk LBW and VLBW infants who cannot be fed their mother s own milk should be fed donor human milk (in safe settings and where affordable milk banking facilities are available) LBW and VLBW infants who cannot be fed mother s own milk or donor milk should be fed a standard infant formula; VLBW infants who fail to gain weight despite adequate feeding should be given a preterm formula LBW and VLBW infants who cannot be fed human, mother s or donor milk should be fed standard infant formula from the time of discharge until 6 months of age VLBW infants who are fed human milk should not be given bovine milk-based human milk fortifier; VLBW infants who fail to gain weight despite adequate breast milk feeding should be given human milk fortifiers, preferably based on human milk the start of the 20th century, Pierre Budin, a French obstetrician, focused on the care of the weaklings as premature babies were known then. He promoted warmth, breastfeeding and cleanliness. Initiation of breastfeeding within 1 h after birth has been shown to reduce infant mortality [2]. The benefits of breast milk for premature infants have been reviewed elsewhere [3, 4]. The short- and long-term benefits compared to formula feeding have been well established in relation to a lower incidence of infections, necrotizing enterocolitis and improved neurodevelopmental outcome [5, 6]. The WHO recommendations [7] are listed in table 1. While most preterm infants, notably those beyond 33 weeks of gestation, can be managed along the WHO guidelines, infants of very low birth weight (VLBW) have higher nutrient requirements than late preterm or term infants, and after the first 2 3 weeks of lactation, the protein content is insufficient to meet the nutritional requirements of the rapidly growing preterm infant [8 11]. Challenges in trying to provide exclusive human milk feedings for the VLBW infant to meet their nutritional requirements include inadequate supply of milk from the mother, the high variability in the nutrient content of the milk [12 14], clinical volume restrictions imposed by disease states and the nutrient limitations of the milk itself. Growth failure is a significant problem in preterm infants due to high nutrient requirements, increased catabolism due to illness and a delay in initiation of early parenteral and subsequent enteral nutrition. The concentrations of protein, calcium, phosphorus, zinc, energy and some electrolytes in human milk are limiting growth and bone health beyond the initial few weeks [15]. Concentrations of calcium and phosphorus vary less during lactation but are low with respect to the needs of premature infants. Consequently, preterm infants fed 110Bhatia

3 human milk alone show slower growth in comparison to those fed preterm formula with a higher protein content [16]. The most variable content in human milk is fat, which differs in content during lactation, throughout the day, among mothers and within a single milk collection. The energy variation in human milk largely comes from losses in fat or differences in fat in unfortified human milk [17]. Unfortified human milk would neither meet the growth requirements of >15 g/kg per day nor would it sustain good protein nutritional status as demonstrated by indices such as blood urea nitrogen (BUN), serum albumin and total protein. In a Cochrane review, Kuschel and Harding [18] concluded that Protein supplementation of human milk in relatively well preterm infants results in increases in short term weight gain, linear and head growth. Urea levels are increased, which may reflect adequate rather than excessive dietary protein intake. Similarly, premature infants fed unfortified human milk demonstrate progressive decline in serum phosphorus and increased alkaline phosphatase levels suggestive of metabolic bone disease in comparison to those fed preterm infant formula [19, 20]. Donor human milk has been recommended as a first alternative in feeding preterm infants when mother s own milk is not available. There are limited data comparing fortified donor milk versus formula. Pasteurization of donor milk results in losses of IgA and secretory IgA [21 23], lactoferrin, lysozyme, cytokines, growth factors and antioxidant capacity as well as lipase activity, IgM and white blood cells. Nonetheless, while human milk does not meet the high nutrient requirements of the VLBW infants, the problem is increased with donor milk since most donor milk is obtained from mothers who have established sustained lactation, and the protein content of donor milk is usually <1 g/dl, making fortification very important [24, 25]. Systematic reviews have reported that preterm infants fed formula regained birth weight earlier and had greater rates of weight gain, length and head growth compared to those that received donor human milk [26, 27]. One study compared fortified donor milk with preterm formula and also found a slower rate of weight gain compared to formula, while length and head circumference gains were similar [28]. Although the optimal weight gain in premature infants remains to be defined, data are reported that feeding of human milk is associated with an 8-point IQ advantage while controlling for confounding factors at 8 years of age [29]. Other studies not reviewed here also demonstrate significant long-term advantages. In comparison, in infants fed either unfortified donor human milk or preterm formula as sole enteral feeds or as supplements to mother s own milk, infants fed preterm formula demonstrated an improved neurocognitive outcome at 1 year, but no differences at 2 years [30]. The European Society for Pediatric Gastroenterology Hepatology and Nutrition (ESPGHAN), in their recent Human Milk and Its Fortification 111

4 Table 2. Macronutrient composition (means and ranges) Protein, g/dl Fat, g/dl Lactose, g/dl Energy, kcal/dl Term [45] 1.2 ( ) 3.6 (2.2 5) 7.4 ( ) 70 (57 83) Donor milk [46] 1.2 ( ) 3.2 ( ) 7.8 (6 9.6) 65 (43 87) Donor milk [13] 0.9 ( ) 3.6 ( ) 7.2 ( ) 67 (50 115) Reference standard [47] Preterm <29 weeks [35] 2.2 ( ) 4.4 ( ) 7.6 ( ) 78 (61 94) weeks [35] 1.9 ( ) 4.8 ( ) 7.5 ( ) 77 (64 89) Donor milk [48] 1.4 ( ) 4.2 ( ) 6.7 ( ) 70 (53 87) Adapted from Ballard and Morrow [32] and references therein: Michaelsen et al. [13], Bauer and Gerss [35], Nommsen et al. [45], Wojcik et al. [46], AAP Committee on Nutrition [47] and Landers and Hartmann [48]. Table 3. Nutrient recommendations according to Schanler [33], ESPGHAN [34] and Bauer and Gerss [35] Nutrients Enteral supply, units/kg Human milk, units/dl [35] [33] [34] Fluid, ml Energy, kcal Protein, g (4 4.5 <1 kg) Fat, g Calcium, mg Phosphorus, mg Vitamin D, IU ,000 Trace statement, concluded that no beneficial effect on neurocognitive outcome has been shown in the only available RCT [31]. They go on to note that the comparison was made between unfortified human milk and preterm formula and that the donor human milk was frequently drip milk having a low energy content not reflective of current practice. Fortification of Human Milk In tables 2 [32] and 3 [33 35], the macronutrient composition of human milk and nutrient recommendations are summarized. Table 4 summarizes the protein and energy requirements based on factorial and empirical methods, as described by Ziegler [36]. 112Bhatia

5 Table 4. Protein and energy requirements based on the study by Ziegler [36] 500 1,000 g 1,001 1,500 g Weight gain, g/kg per day Protein, g/kg per day Energy, kcal/kg per day Table 5. Comparison of human milk fortifiers (HMF) Nutrient Mead Johnson a HMF Similac Prolact + 4 HMF b H 2 MF Nutrient intake guidelines Energy, kcal/oz kcal/kg Protein, g/100 cal 4 c (4.8) 3.58 d (4) 2.8 e (3.4) g/kg c Calcium, mg/100 cal 145 (174) 152 (182) 150 (180) mg/kg Phosphorus, mg/100 cal 80 (96) 85 (102) 78 (94) mg/kg Iron, mg/100 cal 1.9 (2.3) 0.6 (0.7) 0.2 (0.3) 4 6 mg/kg Vitamin D, IU/100 cal 210 ( ) 150 (90 270) 34 (20 61) 800 1,000 IU/day Osmolality, mosm/kg H 2 O N/A 450 Amounts in parentheses are what is provided with goal feeds of 150 ml/kg per day; compare to recommended levels. a Acidified liquid HMF. b Extensively hydrolyzed protein concentrated liquid. c Assumes 1.6 g/200 calories. d Assumes 2.2 g/200 ml. e Assumes 2.2 g/200 ml. The primary goal of a nutritional strategy for VLBW infants is to maximize postnatal growth without adverse metabolic consequences. The acceptable growth rate is >15 g/kg per day, i.e. less than the theoretical estimates of a fetus in utero at a comparable gestational age. As the data in the tables indicate, human milk, except early in preterm lactation, is inadequate in nutrients to support the needs making fortification a necessary goal. Various human milk fortifiers have been developed, both bovine based and human milk based. Currently, in the United States, three human milk fortifiers are marketed, and worldwide other fortifiers are available. The two liquid fortifiers available differ in protein quality in that one is an extensively hydrolyzed casein product while the other is a partially hydrolyzed whey product ( table 5 ). The human milk fortifier is based on human milk and can be added in specified amounts to increase caloric density. Further, they have recently marketed a cream as a fortifier which contains 25% fat and provides 2.5 kcal/ml without additional minerals. As marketed, the fortifiers (bovine) use preterm human milk content as the base. There are three approaches to fortification: (1) standard fixed-dosage fortification of mother s own milk or donor human milk; (2) increased fortification Human Milk and Its Fortification 113

6 Table 6. Composition of human milk (HM) HM, mature/term Preterm HM, <29 weeks EGA Donor HM Energy, kcal/oz MJN LHMF, 4 vials ml Similac hydrolyzed, 4 packets ml Prolact + 4 H 2 MF, ml Protein, g/100 ml MJN LHMF, 4 vials ml Similac hydrolyzed, 4 packets ml Prolact + 4 H 2 MF, ml EGA = Estimated gestational age; MJN LHMF = Mead Johnson Nutritionals liquid HM fortifier. based on poor growth and/or low BUN values, and (3) adjustable fortification based on the analysis of human milk. The standardized approach assumes an average composition of milk at about 2 weeks of age ( 2.1 g/dl) and adds a fixed amount of fortifier to augment protein and energy; the latter is mainly provided by carbohydrate and fat. However, the declining concentration of protein as lactation proceeds makes this an unsatisfactory approach ( table 6 ). Further, with the current fortification strategies, protein intake comes close to or falls short of the expectations. As concluded by ESPGHAN, human milk fortification continues to be inadequate especially with regard to protein and decreased fat absorption due to loss of lipase activity following pasteurization and loss of fat during handling and administration. With regard to donor milk, standardized fortification falls very short of provision of protein and energy, and needs to be fortified in additional amounts. All fortifiers provide electrolytes and other nutrients to augment those present in human milk and generally satisfy the requirements as outlined. The exception may be vitamin D. Although the optimal requirement of vitamin D is uncertain as is the definition of inadequacy or adequacy, all fortifiers do not provide the amounts suggested by the American Academy of Pediatrics and certainly not those recommended by ESPGHAN. More research is needed to address this important question. Long-chain polyunsaturated fatty acids are provided by most fortifiers. One issue that is understudied is the effect of freezethawing and its effect on ph. There have been anecdotal reports of an increased incidence of metabolic acidosis. In a recent retrospective study, sustained metabolic acidosis as defined by a CO 2 value of <17 meq/l was not found after complete fortification with an acidified fortifier was achieved [37]. Most of the acidosis was observed during the provision of parenteral nutrition and the early 114Bhatia

7 stages of fortification. The effect was slightly more pronounced with donor milk again, bringing up the need for further research. Another approach to fortification is the use of growth and values of BUN [38]. The fortifier is added in stepwise amounts to maintain the BUN between 9 and 13 mg/dl and bringing the amount of protein closer to requirements. This is the approach currently used in our nursery; in the case of donor milk, the fortification increased to add a total of 6 kcal/oz to make up for the deficit in protein and energy. A third approach is the use of infrared milk analyzers to determine macronutrients in breast milk before fortification. Fusch et al. [39] collected breast milk samples (n = 1,188) from 63 mothers of both preterm and term infants. Near- and mid-infrared milk analyzers were compared to reference methods for fat, protein and lactose. For fat analysis, the near-infrared analyzer measured precisely but not accurately (y = 0.55x ; r 2 = 0.85) and mid-infrared measured precisely and accurately (y = 0.93x ; r 2 = 0.86); the analyzers were less precise for protein with r 2 values of 0.63 and 0.73, respectively. For lactose, the two analyzers demonstrated r 2 values of 0.01 and 0.02, suggesting imprecise measurements of the concentrations. In an earlier study by the same group [40], 12-hour batches of breast milk were analyzed using near-infrared spectroscopy and nutrients added to achieve 4.4 g fat, 3 g protein and 8.8 g carbohydrates per 100 ml. Infants less than 32 weeks who were already fully breastfed were fed the targeted fortified milk for 3 weeks. In the 10 infants (birth weight 860 ± 309 g, gestational age 26.3 ± 1.6 weeks), weight gain was reported as 19.9 g/kg per day. Osmolality of fortified milk was reported to be 436 ± 13 mosm/kg. Matchedpair analysis of 20 infants demonstrated a higher milk intake (mean 8 ml) but demonstrated similar weight gain of 19.7 ± 3.3 g/kg per day. This study demonstrated that targeted fortification could be safely implemented but failed to demonstrate improved gain over routine fortification. In an effort to predict all three macronutrients, fat, protein and lactose, from one key ingredient, a study was performed to evaluate whether the levels of these macronutrients could be predicted from one key component [41]. No correlation was found between the three nutrients suggesting that for target fortification to work, an analysis of all three macronutrients needs to be performed routinely. An example of target fortification is depicted in table 7 [42]. More recently, Radmacher et al. [43] confirmed that across lactation periods from >4 weeks, protein content declined as expected, with donor human milk having the lowest protein content. Fortification was then based on profiles in human milk. All unfortified human milk, as expected, failed to meet recommendations for VLBW infants; the macronutrient content of native milk was a major factor affecting the resulting content after fortification and not all samples Human Milk and Its Fortification 115

8 Table 7. Protein, carbohydrate, fat and energy after target fortification (TFO; adapted from Rochow et al. [42]) Component ESPGHAN recommendation Native breast milk Amount added by FDF FDF TFO 1.2±0.3 c Protein, g/dl a / b 1.2 ( ) Carbohydrates, g/dl ± ( ) Fat, g/dl ±0.8 c 3.6 ( ) Energy, kcal/dl ±9 c 67 (62 73) ±0.3 c 2.3 ( ) ± ( ) ±0.8 c 4.6 ( ) 15 82±9 c 82 (77 88) 2.9± ( ) 8.6± ( ) 4.8±0.8 c 4.6 ( ) 89±8 c 89 (83 94) Means ± SD and medians (interquartile ranges); data for 1 day are shown. FDF = Fixeddose fortification. a Protein intake for infants with body weight <1 kg. b Protein intake for infants with body weight of kg. c Normally distributed values. resulted in milks that could deliver 120 kcal/kg, but resulted in differing contents of protein, some well above recommended intakes. Thus, when human milk analyzers are approved for clinical use in the United States, practitioners will have to individualize fortification based on the variability in the mother s own milk and the low content of donor human milk. Adequacy of achieved intakes will depend on the gestational age and postnatal age of the infant making fortification an important tool in the care of these infants. The human milk-based fortifier can be added in different ratios, thus increasing both protein and energy to near or adequate levels. A recent study evaluated premature infants who received an exclusive human milk-based diet and a human milk-derived cream on growth of premature infants. Infants with a birth weight of 750 1,250 g were randomly assigned to control or the cream-added groups [44]. The control group received mother s own milk or donor human milk with a donor human milk-derived fortifier. The cream group received a human milk-derived cream if the human milk tested <20 kcal/30 ml. Seventyeight infants were studied; the cream group demonstrated a nonsignificantly higher weight gain (14 ± 2.5 vs g/kg per day, respectively). Length gain was also greater in the cream group (1.03 ± 0.33 vs ± 0.41 cm/week, respectively; p = 0.02). Although the cream group demonstrated improved weight and length gain, both groups fell short of recommended weight gain and, in addition, demonstrated poorer gain in both weight and length in the control group. 116Bhatia

9 Energy intakes were not reported nor were protein intakes; the cream provided 2.5 kcal/ml. Clinically, until better fortification strategies are optimized, the approach of adjustable fortification appears to result in a satisfactory growth pattern without adverse effects. Bedside analyzers, which are used in some units, measure total nitrogen, which would overestimate human milk protein content by about 17% [37]. Customizing fortification brings macronutrients closer to or above recommended needs, but does safeguard against excessive intakes, which have their own potential adverse effects. In summary, human milk remains the preferred feeding for preterm infants given its protective properties and beneficial prevention effects (such as necrotizing enterocolitis and sepsis). Since human milk (preterm and term) remains nutritionally inadequate, especially for VLBW infants, it has to be fortified. Adequate fortification is currently possible by using available fortifiers. Customizing fortification is very promising, but remains labor intensive. More research is needed to optimize both the content of fortifiers as well as methods of fortification. Disclosure Statement The author declares no conflict of interest exists in relation to the content of the chapter. References 1 Kinney MV, Kerber KJ, Black RE, et al: Sub- Saharan Africa s mothers, newborns, and children: where and why do they die? PLoS Med 2010; 7:e Bhutta ZA, Ahmed T, Black RE, et al: What works? Interventions for maternal and child undernutrition and survival. Lancet 2008; 37: Bhatia J: Human milk and the premature infant. J Perinatol 2007; 27: S71 S74. 4 Bhatia J: Human milk and the premature infant. Ann Nutr Metab 2013; 62(suppl 3): Edmond KM, Kirkwood BR, Amanda-Etego S, et al: Effect of early feeding practices on infection-specific neonatal mortality: an investigation of the causal links with observational data from rural Ghana. Am J Clin Nutr 2007; 86: Hurst NM: The 3 M s of breast-feeding the preterm infant. J Perinat Neonatal Nurs 2007; 21: Part I. Recommendations, rationale and evidence for nutrition actions; in World Health Organization: Essential Nutrition Actions: Improving Maternal, Newborn, Infant and Young Child Health and Nutrition. Geneva, WHO, Jones E, Bell S, Shankar S: Managing slow growth in preterm infants fed on human milk. J Neonatal Nurs 2013; 19: Weber A, Loui A, Jochum F, et al: Breast milk from mothers of very low birthweight infants: variability in fat and protein content. Acta Paediatr 2001; 90: Jones E, King J: Feeding and Nutrition in the Preterm Infant. Edinburgh, Elsevier Churchill Livingstone, Human Milk and Its Fortification 117

10 11 Nutrition: Enteral Nutrition for the Preterm Infant. London, Great Ormond Street Hospital, 2011 (updated 2014), health-professionals/clinical-guidelines/nutrition-enteral-nutrition-preterm-infant. 12 Lemons JA, Moye L, Hall D, Simmons M: Differences in the composition of preterm and term human milk during early lactation. Pediatr Res 1982; 16: Michaelsen KF, Skatte L, Badsberg JH, et al: Variation in macronutrients in human bank milk, influencing factors and implications for human milk banking. J Pediatr Gastroenterol Nutr 1990; 11: Ziegler EE: Breast-milk fortification. Acta Pediatr 2001; 90: Schanler RJ: Suitability of human milk for the low-birthweight infant. Clin Perinatol 1995; 22: Lucas A, Gore SM, Cole TJ, et al: Multicentre trial on feeding low birthweight infants: effects of diet on early growth. Arch Dis Child 1984; 59: Greer FR, McCormick A, Loker J: Changes in fat concentration of human milk during delivery by intermittent bolus and continuous mechanical pump infusion. J Pediatr 1984; 105: Kuschel CA, Harding JE: Multicomponent fortified human milk for promoting growth in preterm infants. Cochrane Database Syst Rev 2004; 1:CD Rowe JC, Wood DH, Rowe DW, Raisz LG: Nutritional hypophosphatemic rickets in a premature infant fed breast milk. N Engl J Med 1979; 300: Pettifor JM, Stein H, Herman A, et al: Mineral homeostasis in very low birth weight infants fed either mother s own milk or pooled pasteurized preterm milk. J Pediatr Gastroenterol Nutr 1986; 5: Hamprecht K, Maschmann J, Müller D, et al: Cytomegalovirus (CMV) inactivation in breast milk: reassessment of pasteurization and freeze-thawing. Pediatr Res 2004; 56: Koenig A, de Albuquerque Diniz EM, Barbosa SF, et al: Immunologic factors in human milk: the effects of gestational age and pasteurization. J Hum Lact 2005; 21: Ford JE, Law BA, Marshall VM, et al: Influence of the heat treatment of human milk on some of its protective constituents. J Pediatr 1977; 90: Vieira AA, Soares FV, Pimenta HP, et al: Analysis of the influence of pasteurization, freeze/thawing, and offer processes on human milk s macronutrient concentrations. Early Hum Dev 2011; 87: Wojcik KY, Rechtman DJ, Lee ML, et al: Macronutrient analysis of a nationwide sample of donor breast milk. J Am Diet Assoc 2009; 109: Boyd CA, Quigley MA, Brocklehurst P: Donor breast milk versus infant formula for preterm infants: systematic review and metaanalysis. Arch Dis Child Fetal Neonatal Ed 2007; 92:F169 F Quigley MA, Henderson G, Anthony NY, et al: Formula versus donor breast milk for feeding preterm or low birth weight infants. Cochrane Database Syst Rev 2007; 4: CD Schanler RJ, Lau C, Hurst NM, et al: Randomized trial of donor human milk versus preterm formula as substitutes for mother s own milk in the feeding of extremely premature infants. Pediatrics 2005; 116: Lucas A, Morley R, Cole TJ, et al: Breast milk and subsequent intelligence quotient in children born preterm. Lancet 1992; 339: Lucas A, Morley R, Cole TJ, et al: A randomized multicentre study of human milk versus formula and later development in preterm infants. Arch Dis Child Fetal Neonatal Ed 1994; 70:F141 F Arslanoglu S, Corpeleijn W, Moro G, et al: Donor human milk for preterm infants: current evidence and research directions. J Pediatr Gastroenterol Nutr 2013; 57: Ballard O, Morrow AL: Human milk composition: nutrients and bioactive factors. Pediatr Clin North Am 2013; 60: Schanler RJ: Approach to enteral nutrition in the premature infant. UpToDate, 2014, approach-to-enteral-nutrition-in-thepremature-infant. 34 Agostini C, Buonocore G, Carnielli VP, et al: Enteral nutrient supply for preterm infants: commentary from the European Society of Paediatric Gastroenterology, Hepatology and Nutrition Committee on Nutrition. J Pediatr Gastroenterol Nutr 2010; 50: Bauer J, Gerss J: Longitudinal analysis of macronutrients and minerals in human milk produced by mothers of preterm infants. Clin Nutr 2011; 30: Bhatia

11 36 Ziegler EE: Human milk and human milk fortifiers; in Koletzko B, Poindexter B, Uauy R (eds): Nutritional Care of Preterm Infants: Scientific Basis and Practical Guidelines. World Rev Nutr Diet. Basel, Karger, 2014, vol 110, pp Sternad L, Gates A, Bhatia J: Does the addition of a liquid human milk fortifier result in sustained metabolic acidosis in very low birth weight infants? Annu Meet Pediatr Acad Soc, San Diego, Arslanoglu S, Moro GE, Ziegler EE: Adjustable fortification of human milk fed to preterm infants: does it make a difference? J Perinatol 2006; 26: Fusch G, Rochow N, Choi A, et al: Rapid measurement of macronutrients in breast milk: how reliable are infrared milk analyzers? Clin Nutr 2015; 34: Rochow N, Fusch G, Choi A, et al: Target fortification of breast milk with fat, protein and carbohydrates for preterm infants. J Pediatr 2013; 163: Fusch G, Mitra S, Rochow N, Fusch C: Target fortification of breast milk: levels of fat, protein or lactose are not related. Acta Paediatr 2015; 104: Rochow N, Fusch G, Zapanta B, et al: Target fortification of breast milk: how often should milk analysis be done? Nutrients 2015; 7: Radmacher PG, Lewis SL, Adamkin DH: Individualizing fortification of human milk using real time human milk analysis. J Neonatal Perinatal Med 2013; 6: Hair AB, Blanco CL, Moreira AG, et al: Randomized trial of human milk cream as a supplement to standard fortification of an exclusive human milk-based diet in infants g birth weight. J Pediatr 2014; 165: Nommsen LA, Lovelady CA, Heinig MJ, et al: Determinants of energy, protein, lipid, and lactose concentrations in human milk during the first 12 mo of lactation: the DARLING Study. Am J Clin Nutr 1991; 53: Wojcik KY, Rechtman DJ, Lee ML, et al: Macronutrient analysis of a nationwide sample of donor breast milk. J Am Diet Assoc 2009; 109: AAP Committee on Nutrition: Pediatric Nutrition Handbook, ed 6. Elk Grove Village, American Academy of Pediatrics, Landers S, Hartmann BT: Donor human milk banking and the emergence of milk sharing. Pediatr Clin North Am 2013; 60: Human Milk and Its Fortification 119

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