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Human Milk Fortification with Differing Amounts of Fortifier and Its Association with Growth and Metabolic Responses in Preterm Infants Hayriye Gozde Kanmaz, Banu Mutlu, Fuat Emre Canpolat, Omer Erdeve, Serife Suna Oguz, Nurdan Uras and Ugur Dilmen J Hum Lact 2013 29: 400 originally published online 29 November 2012 DOI: 10.1177/0890334412459903 The online version of this article can be found at: http://jhl.sagepub.com/content/29/3/400

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459903 03Journal of Human LactationKanmaz et al 2012

JHLXXX10.1177/08903344124599

Original Research

Human Milk Fortification with Differing Amounts of Fortifier and Its Association with Growth and Metabolic Responses in Preterm Infants

Journal of Human Lactation 29(3) 400­–405 © The Author(s) 2012 Reprints and permissions: sagepub.com/journalsPermissions.nav DOI: 10.1177/0890334412459903 jhl.sagepub.com

Hayriye Gozde Kanmaz, MD1, Banu Mutlu, MD1, Fuat Emre Canpolat, MD1, Omer Erdeve, MD1, Serife Suna Oguz, MD1, Nurdan Uras, MD1, and Ugur Dilmen1

Abstract Background: Fortification of human milk (HM) is a common clinical practice to adapt breast milk to the nutritional needs of very low birth weight (VLBW) infants.The optimal method for HM fortification remains to be determined, and a variety of protocols are currently used in neonatal intensive care units. Objective: It is believed that standard fortification is insufficient to meet the needs of VLBW infants. Therefore, we designed a randomized prospective study that investigated the effects of varying levels of blind fortification on short-term growth and metabolic responses of preterm infants. Methods: Eligible infants were randomized into 3 groups: standard fortification (SF), moderate fortification (MF), and aggressive fortification (AF). Short-term growth, feeding intolerance, and urea, calcium, phosphorus, and alkaline phosphatase levels were assessed. Results: There were 26, 29, and 29 infants in the SF, MF, and AF groups, respectively.The baseline characteristics of the groups were similar. Daily weight gain and length at discharge did not differ among the groups; however, head circumference was significantly higher in the MF and AF groups compared with the SF group. Urea, calcium, phosphorus, and alkaline phosphatase levels were similar between the groups. Conclusion: We demonstrated that blind fortification of HM, even with higher amounts than recommended by manufacturers, did not cause any measured adverse effects on the metabolic response of preterm infants. Anthropometric measurements (except head circumference) were not different between the different dosages of fortification. Keywords breastfeeding, fortification, growth, human milk, metabolic response, prematurity

Well Established

Background

Fortification of human milk is essential because breast milk content is insufficient to meet the needs of very low birth weight (VLBW) infants. Fortification protocols should be improved to better meet the needs of preterm infants.

Fortification of human milk (HM) is needed because its levels of protein, calcium, phosphorus, and many other nutrients are insufficient to meet the needs of VLBW infants for Date submitted: December 1, 2011; Date accepted: August 8, 2012.

Newly Expressed

1

Zekai Tahir Burak Maternity Teaching Hospital, Ankara, Turkey

Aggressive fortification by adding higher amounts of human milk fortifier did not significantly affect growth rates and metabolic responses in VLBW infants. The need for further studies to optimize human milk fortification protocols remains.

Corresponding Author: Hayriye Gozde Kanmaz, MD, Zekai Tahir Burak Maternity Teaching Hospital, Zekai Tahir Burak Kadin Sagligi Egitim ve, Arastirma Hastanesi, Talatpasa Bulvari, Samanpazari, Ankara 06340, Turkey. Email: [email protected]

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Kanmaz et al appropriate extrauterine growth.1 Commercially produced multicomponent human milk fortifiers (HMFs), which provide additional protein, carbohydrates, minerals, vitamins, and trace elements, are usually used for preterm HM supplementation. A meta-analysis has revealed that supplementing HM with fortifiers improved metabolic indices within a short period of time, with an increase in anthropometric parameters.2 That analysis of 10 controlled trials revealed that addition of a multicomponent HMF improved growth rate in preterm neonates weighing < 1850 g. Blind fortification is the methodology commonly used in most neonatal intensive care units (NICUs), which consists of adding fixed concentrations of fortifier to maternal milk. An empirical dose of the different components is administered, which does not always correspond to the nutritional requirements of the individual infant. Although this method is easy to use, the results obtained in terms of growth are not always satisfactory. In fact, as many studies have revealed, the weight increase is lower than that obtained with the use of preterm milk formula.2-7 Furthermore, this practice has a risk of excessive protein intake, and feeding intolerance is still a concern with the use of commercial formula–derived HMF. Very preterm infants frequently develop postnatal growth failure while in the NICU.8 Providing early parenteral nutrition and then offering human milk with further fortification should improve growth and development and avoid the risks associated with rapid catch-up growth. Maternal milk is the food of choice, and fortification schedules need to be revised to meet the new guidelines.9 It is believed that standard fortification is insufficient to meet the needs of VLBW infants. Therefore, we designed a randomized prospective study in which blind fortification was administered in 3 different amounts. The purpose of this study was to investigate the effect of varying doses of HM fortification on short-term growth and to evaluate the impact of HMF doses higher than manufacturers’ recommendations on metabolic responses of preterm infants in terms of urea, calcium, phosphorus, and alkaline phosphatase (ALP) levels.

Methods This study was conducted in the NICU at Zekai Tahir Burak Maternity Teaching Hospital, Ankara, Turkey. Infants of gestational age ≤ 32 weeks and birth weight (BW) ≤ 1500 g were enrolled in this randomized controlled study. Between November 2010 and August 2011, 105 preterm infants were enrolled, and 84 of them completed the study. Clinically stable infants who were fed with HM were included. Infants who had major congenital anomalies, chronic illnesses, respiratory support requirements, or sepsis and those who were receiving mixed feeding (preterm formula/ breast milk) were excluded. Parenteral nutrition was initiated immediately after delivery for all infants. Amino acids (TrophAmine 6%; Eczacıbaşı/ Baxter, Istanbul, Turkey) were started at a dose of 2.3 g/kg/d and reached 4 g/kg/d on day 3 of life, and lipid emulsion

(Lipofungin MCT/ LCT 20%; B. Braun, Melsungen, Germany) was started at a dose of 1 g/kg/d on day 2, reaching 3-4 g/kg/d on day 4. Parenteral glucose was started at 6 mg/kg/min on the first day of life and increased as tolerated to 12 mg/kg/min. All enrolled patients received 80-100 kcal/ kg/d at the end of the first week. Minimal enteral nutrition with full-strength HM was initiated on the first day of life at a dose of 10-20 mL/kg/d and increased as tolerated according to the nutrition protocol of the nursery in the second week of life. Full enteral feeding was defined as 150-170 mL/kg/d. Fortification was commenced when infants reached 90-100 mL/kg enteral feeding. Human milk was fortified with Eoprotin (Milupa, Germany), which is derived from a cow’s milk product. The contents of 3 g Eoprotin include 11 kcal energy, 0.6 g protein, 0.02 g fat, 2.1 g carbohydrates, 38 mg calcium, 2.1 g magnesium, 20 mg sodium, 2.4 mg potassium, 15 mg chloride, 0.03 mg vitamin A, 0.3 IU vitamin E, 0.2 µg vitamin K, and 15 mg vitamin C, with an osmolality of 50 mosm/L. Infants who met the inclusion criteria were randomized into 3 groups when full feedings were achieved, and sealed envelopes were used for randomization. Group 1 (standard fortification; SF) received 1.2 g (1 scoop) of HMF added to each 30 mL of HM; estimated protein intake was 3 g/kg/d, and estimated osmolality was 340 mosm/L, as recommended by the manufacturer. Group 2 (moderate fortification; MF) received 1.2 g (1 scoop) of HMF added to each 25 mL HM; estimated protein intake was 3.3 g/kg/d, and estimated osmolality was 360 mosm/L. Group 3 (aggressive fortification; AF) received 1.2 g (1 scoop) of HMF added to each 20 mL HM; estimated protein intake was 3.6 g/kg/d, and estimated osmolality was 380 mosm/L. The appropriate amount of Eoprotin was added immediately before each feeding. From 30 days of age, all infants were provided with 2 mg/kg iron in the form of ferrous sulfate. Gestational age, sex, and BW were initially recorded. Daily weight gain, weekly increase in head circumference, and length at discharge were assessed. All anthropometric measurements were performed by research nurses who were experienced in neonatal care and blind to the study groups. Body weight was determined daily using electronic scales (± 10 g). The average of at least 2 measurements was taken. Length was measured at discharge by 2 measurers to the nearest 0.1 cm using a measuring board with fixed headboard and movable footboard. Head circumference was measured around the widest part of the occipital-frontal circumference, twice weekly to the nearest 0.1 cm using a nonstretchable tape measure. Weight gain in grams per day was calculated as the difference between the initial and the final weight, divided by the number of days elapsed, and this result was converted to grams per kg per day by dividing gain in grams per day by the average weight during the observation period.10 Feeding intolerance (gastric residuals, abdominal distension, and withheld feedings), frequency of stooling and

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vomiting were evaluated daily. Serum urea levels were obtained immediately before initiation of fortification, 14 days after fortification, and at 40 weeks post-conception. Calcium, phosphorus, and ALP levels were obtained on day 30 of life and at 40 weeks post-conception. Blood gases were analyzed weekly. Serum urea, calcium, phosphorus, and ALP levels and blood gases were detected with a Siemens Advia 2400 automatic analyzer (Tarrytown, New York, USA). Excessive protein intake was defined as high urea levels (> 30 mg/dL), and metabolic acidosis as high serum osmolarity (> 290 mOsm/kg). This study was approved by the local ethics committee, which is located in Zekai Tahir Burak Maternity Teaching Hospital, and parental consent was obtained for all infants.

Statistical Analysis SPSS (version 17, SPSS Inc, Chicago, Illinois, USA) was used for statistical analysis. Data were expressed as mean ± SD. Differences in the means of variables were tested using both parametric and nonparametric tests depending on the distribution of the variables. Kruskal-Wallis, Mann-Whitney U, and 1-way ANOVA tests were used to compare indices between the groups. A P value < .05 was considered significant. One-way ANOVA with Bonferroni post hoc test was used to evaluate significant differences between groups. Power analysis performed for the hypothesis of 5 g/kg/d better weight gain yielded > 80% power.

Results The SF, MF, and AF groups had 26, 29, and 29 infants, respectively. The groups were similar with respect to gestational age; BW, head circumference, and length at birth; Apgar score; age; and weight at the initiation of fortification (P > .05). The clinical course before study entry was similar in each group. Full feedings were achieved at a median age of 12 days in SF, 12 days in MF, and 10 days in AF groups. The volume of fortified HM consumed was 155 ± 4.6, 154 ± 6, 156 ± 6.9 mL/kg/d, respectively, in SF, MF and AF groups and was similar in all 3 groups (P = .59). Baseline characteristics are summarized in Table 1. Daily weight gain and length at discharge did not differ among the groups (P > .05; Table 2). There was a significant difference in head circumference between the groups (P < .05). Weekly increases in head circumference were significantly greater in the MF and AF groups than the SF group (Figure 1). Although there was an outlier for head circumference in the MF group that was included to the statistical analysis, exclusion of this case did not cause a significant change in the results. There were no significant differences in urea levels between the groups (Table 3). Urea levels showed a tendency to decrease over time in each group. Mean urea levels were

25.4 ± 14 mg/dL at the initiation of fortification and decreased to 8.6 ± 2.7 mg/dL at 40 weeks gestational age (Table 3). Although calcium and phosphorus levels were similar, ALP levels were lower in the AF and MF group than in the SF group, but the difference was not significant (Table 3). No significant difference was demonstrated in feeding intolerance, residuals, abdominal distension, and frequency of stooling between the groups. Feeding intolerance was diagnosed in 4 infants (15.3%) in the SF group, 5 (17.2%) in the MF group, and 4 (13.7%) in the AF group. One patient in the MF group was diagnosed with necrotizing enterocolitis (NEC). Weekly analysis of blood gases showed values in the normal range, and none of the infants suffered from metabolic acidosis. Duration of hospitalization and adjusted age on discharge were not directly related to type of fortification. The mean duration of hospitalization was 58.8 ± 20.9, 61.3 ± 19.1, and 51.5 ± 14.7 days in the SF, MF, and AF groups, respectively, and these differences were not significant (P = .13).

Discussion This study demonstrated that HM fortification with higher doses than recommended appears to be safe, yet higher doses of HMF did not result in better short-term growth or increased urea levels that should reflect higher protein intake. However, increase in head circumference, which could be an indicator of better neurodevelopmental outcome, was greater in the MF and AF groups, a finding that deserves further evaluation. Fortification of HM is a common clinical practice to adapt breast milk to the nutritional needs of VLBW infants.2 Some documentation indicates that fortification as used in routine clinical practice improves growth,10 and other outcomes such as bone mineral content, but a few other studies have failed to find significant effects. There is also evidence that despite fortification with commercial fortifiers, the growth of infants fed breast milk is consistently slower than that of formula-fed infants.11,12 Desired postnatal weight gain in VLBW infants is 15-20 g/kg/d, and in this study, we achieved 19.7 ± 4.43 g daily weight gain in the SF group. Furthermore, we demonstrated that daily weight gain was not improved by adding higher amounts of HMF. In contrast to previous studies demonstrating that growth rate improves in preterm infants fed HMF, daily weight gain and length at discharge did not differ among groups in our study. However, the increase in head circumference was greater in the MF and AF groups than in the SF group. Lucas et al assessed developmental outcome at 18 months of age and did not find any improvement in developmental scores attributable to the use of a commercially available fortifier.13 Long-term follow-up of these patients is ongoing, and neurodevelopmental assessment of this cohort will clarify the effect on head circumference in the future. The optimal method for HM fortification remains to be determined, and a variety of protocols are currently used in

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Kanmaz et al Table 1. Baseline Characteristics of Study Subjects Standard Fortification

Moderate Fortification

Aggressive Fortification

P

28.8 (2) 1088 (195) 26.2 (1.66) 8 12/14 12 (8) 31 (3.6) 1106 (204) 37 (1.6)

28.6 (1.8) 1080 (223) 26.2 (1.64) 7 14/15 12 (8) 30.5 (3.2) 1066 (200) 36 (2.7)

28.8 (2) 1108 (213) 26.2 (1.57) 8 11/18 10 (6) 30.5 (3.2) 1097 (193) 36 (1)

.27a .87a .68a .89b .63c .18b .18a .73a .47a

Gestational age, wk (SD) Birth weight, g (SD) Head circumference at birth, cm (SD) APGAR scores at 5 min, median Sex, female/male Postnatal day reached full enteral feeding, median (interquartile range) Gestational week at initiation of fortification, median (interquartile range) Weight at initiation of fortification, g (SD) Gestational wk at discharge, median (interquartile range) a

One-way ANOVA. Kruskal-Wallis. Fisher exact tests used for statistical analysis.

b c

Table 2. Anthropometric Measurements of the Groups Standard Fortification Moderate Fortification Aggressive Fortification Daily weight gain, g/d Daily weight gain, g/kg/d Weekly increase in head circumference, cm Length at discharge, cm

19.7 (4.43) 16.4 (2.2) 0.69 (0.21) 41.7 (2.33)

20.6 (5) 17.1 (3.4) 0.92 (0.22) 42.05 (2.17)

a

Statistical analysis was performed with 1-way ANOVA.

Weekly Increase in Head Circumference, cm/wk

Figure 1. Weekly Increase in Head Circumferences (cm/wk) of the Groups

Abbreviations: AF, aggressive fortification; MF, moderate fortification; SF, standard fortification.

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21.4 (4.7) 17.8 (3.2) 0.82 (0.21) 41.7 (2.32)

Pa .38 .24 .001 .85

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Journal of Human Lactation 29(3)

Table 3. Laboratory Analysis of All Groups Standard Fortification Urea1, mg/dL, median (IQR) Urea2, mg/dL (SD) Urea3, mg/dL (SD) Ca1, mg/dL (SD) Ca2, mg/dL (SD) P1, mg/dL (SD) P2, mg/dL (SD) ALP1, U/L (SD) ALP2, U/L (SD)

Moderate Fortification

20.3 (24.1) 11 (4) 8.4 (2.5) 9.6 (0.59) 9.5 (0.38) 5.2 (0.69) 5.8 (0.8) 1106 (390) 1066 (335)

24.3 (26.6) 11.3 (4) 8.6 (3) 9.59 (0.51) 9.35 (0.66) 5 (1) 5.9 (0.7) 1020 (355) 896 (392)

Aggressive Fortification 21.6 (20) 11.5 (3.9) 8.7 (2.5) 9.28 (0.09) 9.53 (0.43) 5.6 (1.3) 5.9 (0.7) 936 (252) 878 (247)

Pa .33b .9 .92 .54 .24 .67 .79 .18 .07

Urea1 levels obtained before initiation of fortification. Urea2 levels obtained 14 d after fortification. Urea3 levels obtained at corrected age gestational wk 40. Ca1, P1, ALP1 levels obtained at postnatal d 30. Ca2, P2, ALP2 levels obtained at corrected age gestational wk 40. a ANOVA test was used for statistical analysis. b Kruskal-Wallis test was used for statistical analysis.

NICUs. Tailored fortification is a promising method that corresponds better to the ideal requirements of VLBW infants, but it requires highly sophisticated equipment, which is not always available in NICUs because of its high cost.14 Adjustable fortification does not require analysis of the maternal milk and it is easy to apply.15,16 However, it is based on a twice-weekly blood urea nitrogen assay, which does not always completely reflect protein input, especially in the first weeks of life in extremely LBW infants, because of a high rate of catabolism.17 This situation is less clear-cut in preterm infants. It takes time to establish adequate energy intake during early life in sick, immature infants, and protein is catabolized and urea increases regardless of protein intake or renal function.18,19 At the same time, urea synthetic and/or renal excretory capacity may be limited in the immature infant.20,21 Thus, early studies have suggested that urea is not a valid measure of protein intake in preterm infants.17,20-22 We demonstrated that urea levels decreased gradually with advanced postnatal age in all 3 groups and were not significantly affected by higher amounts of protein intake. Although Arslanoglu et al have suggested that blood urea nitrogen level is an excellent index for adequacy of protein intake, our results failed to support this conclusion.10 More intensive fortification of HM did not lead to higher urea levels reflecting higher protein intake in the MF and AF groups compared with the SF group. Blind addition of HMF without the benefit of knowing the protein content of the HM being fortified was a limitation of the present study. The amount of protein that was added ranged from 0.6 to 1.0 g/100 mL HM. This practice aims to raise the protein content of milk with the lowest possible protein content to an adequate level and accepts that milk with higher protein content is fortified to a level that provides somewhat more protein than is necessary. Although this is a reasonable practice that seems to be working, there are no published reports providing evidence of its efficacy or safety. Bauer and Gerss reported that protein values of preterm HM

decreased linearly with progressive week of lactation and preterm milk contains protein levels between 1.8 and 2.4 g/dL during the first month of lactation.23 They also demonstrated that carbonhydrate concentration of HM increased gradually during the postpartum weeks of lactation, as well as fat content independent of milk volume, which could be accepted as the rationale of fortifying HM with protein rather than carbohydrate or fat. Furthermore, 1 of the risks of this practice is excessive protein intake. Given the clinical and laboratory findings of this study, we considered that blind fortification appears safe because the conditions that could be attributed to excessive protein intake, that is, feeding intolerance was similar between groups. In clinical practice, there are still some concerns about feeding intolerance as a result of the use of formula-derived HMF. Many trials that have investigated this topic withdrew infants with feeding intolerance and did not report the results. A Cochrane review has shown that risk of feeding intolerance did not significantly increase in HMF-treated infants (RR 2.85; 95% CI, 0.62-13.1).2 Although we did not have a nonfortified group in our study, we did not find significant differences in feeding intolerance among the groups, and only 1 patient (in the MF group) suffered from NEC. Human milk fortifiers contain different quantities and qualities of minerals, and their effect on bone mineral content is still unclear.2,24-26 To evaluate bone mineral content, we studied calcium, phosphorus, and ALP levels and found that these parameters were similar among the groups, although we observed a trend toward decreased ALP levels at term in the MF and AF groups that was not statistically significant (Table 3). This finding could be attributed to better bone mineral content, and it can be speculated that aggressive fortification of HM prevents infants from osteopenia, however, long-term follow-up and more detailed studies are required to support this implication.

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Kanmaz et al If we considered serum urea levels >10 mg/dL as an indicator of adequate protein intake, standard fortification of HM failed to meet the needs of VLBW infants. However, adding higher amounts of HMF did significantly affect growth rate and serum urea level. Desired daily weight gain mimicking intrauterine growth rates (15–20 g/kg/d) was achieved in all 3 groups. The effect of HMF itself on growth rate and metabolic responses could not be studied because we did not have a group that was fed with nonfortified HM only.

Conclusion In conclusion, although blind fortification of HM with higher levels than recommended by manufacturers did not cause any measured side effects and appears to be safe, higher amounts of HMF did not lead to better short-term growth. As a result of the greater increase in head circumference in the intensive fortification groups, we suggest that there is a need for further studies to optimize HM fortification and to investigate its long-term effects in VLBW infants. Declaration of Conflicting Interests The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding The authors received no financial support for the research, authorship, and/or publication of this article.

References   1. Fomon SJ, Ziegler EE, Vazquez HD. Human milk and the small premature infant. Am J Dis Child. 1977;131:463-467.  2. Kuschel CA, Harding JE. Multicomponent fortified human milk for promoting growth in preterm infants. Cochrane Database Syst Rev. 2004;1:CD000343.   3. Polberger S, Räihä NC, Juvonen P, Moro GE, Minoli I, Warm A. Individualized protein fortification of human milk for preterm infants: comparison of ultrafiltrated human milk protein and bovine whey fortifier. J Pediatr Gastroenterol Nutr. 1999; 29:332-338.   4. Reis BB, Hall RT, Schanler RJ, et al. Enhanced growth of preterm infants fed a new powered human milk fortifier: a randomized, controlled trial. Pediatrics. 2000;106:581-588.   5. Srinivasan L, Bokiniec R, King C, Weaver G, Edwards AD. Increased osmolality of breast milk with therapeutic additives. Arch Dis Child. 2004;89:F514-517.   6. Carlson SJ, Ziegler EE. Nutrient intakes and growth of very low birth weight infants. J Perinatol. 1998;18:52-58.   7. Schanler RJ, Shulman RJ, Lau C. Feeding strategies for premature infants: beneficial outcomes of feeding fortified human milk versus preterm formula. Pediatrics. 1999;103:1150-1157.   8. Cormack BE, Bloomfield FH. An audit of feeding practices in babies <1200 g or 30 weeks gestation during the first month of life. J Paediatr Child Health. 2006;42:458-463.   9. Agostoni 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;50:85-91. 10. Arslanoglu S, Moro GE, Ziegler EE. Adjustable fortification of human milk fed to preterm infants: does it make a difference? J Perinatol. 2006;26:614-621. 11. Kashyap S, Schulze KF, Forsyth M, Dell RB, Ramakrishnan R, Heird WC. Growth, nutrient retention, and metabolic response of low-birth-weight infants fed supplemented and unsupplemented preterm human milk. Am J Clin Nutr. 1990;52:254-262. 12. Carlson SJ, Ziegler EE. Nutrient intakes and growth of very low birth weight infants. J Perinatol. 1998;18:252-258. 13. Schanler RJ, Shulman RJ, Lau C. Feeding strategies for premature infants: beneficial outcomes of feeding fortified human milk versus preterm formula. Pediatrics. 1999;103: 1150-1157. 14. Lucas A, Fewtrell MS, Morley R, et al. Randomized outcome trial of human milk fortification and developmental outcome in preterm infants. Am J Clin Nutr. 1996;64:142-151. 15. de Halleux V, Close A, Stalport S, Studzinski F, Habibi F, Rigo J. Advantages of individualized fortification of human milk for preterm infants. Arch Pediatr. 2007;14(Suppl 1):S5-S10. 16. Cooke RJ. Adjustable fortification of human milk fed to preterm infants. J Perinatol. 2006;26:591-592. 17. Boehm G, Teichmann B, Jung K. Development of ureasynthesizing capacity in preterm infants during the first weeks of life. Biol Neonate. 1991;59:1-4. 18. Fomon S. Protein. In: Fomon SJ (ed). Nutrition of Normal Infants. St Louis, MO: Mosby; 1993:121-139. 19. Embleton NE, Pang N, Cooke RJ. Postnatal malnutrition and growth retardation: an inevitable consequence of current recommendations in preterm infants? Pediatrics. 2001;107:270-273. 20. Boehm G, Muller DM, Beyreiss K, Raiha NC. Evidence for functional immaturity of the ornithine-urea cycle in very- lowbirth-weight infants. Biol Neonate. 1988;54:121-125. 21. Guignard J-P. Postnatal development of glomerular filtration rate in neonates. In: Polin RA, Fox WW, Abman SH (eds). Fetal and Neonatal Physiology. Philadelphia, PA: Saunders; 2004:1256-1266. 22. Boehm G, Gedlu E, Muller MD, Beyreiss K, Raiha NC. Postnatal development of urea- and ammonia-excretion in urine of very-low-birth-weight infants small for gestational age. Acta Paediatrica Hungarica. 1991;31:31-45. 23. Bauer J, Gerss J. Longitudinal analysis of macronutrients and minerals in human milk produced by mothers of preterm infants. Clin Nutr. 2011;30:215-220. 24. Faerk J, Peterson S, Pietersen B, et al. Diet and bone mineral content at term in premature infants. Pediatr Res. 2000; 47:148-156. 25. De Schepper J, Cools F, Vandenplas Y, et al. Whole body bone mineral content is similar at discharge from the hospital in premature infants receiving fortified breast milk or preterm formula. J Pediatr Gastroenterol Nutr. 2005;41:230-234. 26. Corvaglia L, Aceti A, Paoletti V, et al. Standard fortification of preterm human milk fails to meet recommended protein intake: bedside evaluation by near-infrared-reflectance analysis. Early Hum Dev. 2010;86:237-240.

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