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Early versus Delayed Human Milk Fortification in Very Low Birth Weight Infants–A Randomized Controlled Trial
Early versus Delayed Human Milk Fortification in Very Low Birth Weight Infants–A Randomized Controlled Trial Sanket D. Shah, MD1, Narendra Dereddy, MD2, Tamekia L. Jones, PhD2,3, Ramasubbareddy Dhanireddy, MD2,4, and Ajay J. Talati, MD2,4 Objective To compare the effect of initiating human milk fortification at 2 different feeding volumes on feeding intolerance and the time to reach full feeding volume.
Study design Very low birth weight infants (n = 100) were prospectively randomized to early fortification (EF) (beginning at a feeding volume of 20 mL/kg/d) or delayed fortification (at a feeding volume of 100 mL/kg/d). We employed a standardized feeding protocol and parenteral nutrition guidelines for the nutritional management of all study infants. Results The median days to reach full feeding volumes were equivalent in the 2 groups (20 vs 20, P = .45). No significant difference was observed in the total number of episodes of feeding intolerance (58 vs 57). Two cases of necrotizing enterocolitis (Bell stage $2) and deaths occurred in each group. Median daily protein intake (g/kg/d) was higher in EF group in week 1 (3.3 [3.2, 3.5] vs 3.1 [2.9, 3.3], P < .001), week 2 (3.6 [3.5, 3.8] vs 3.2 [2.9, 3.4], P < .001), and week 3 (3.7 [3.4, 3.9] vs 3.5 [2.8, 3.8], P = .006). Cumulative protein intake (g/kg) in the first 4 weeks of life was higher in EF group (98.6 [93.8, 104] vs 89.6 [84.2, 96.4], P < .001). Conclusions Very early human milk fortification may improve early protein intake in very low birth weight infants without increasing frequencies of adverse events. (J Pediatr 2016;-:---). Trial registration ClinicalTrials.gov: NCT01988792.
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chieving adequate extra-uterine growth of very low birth weight (VLBW) infants remains a significant challenge.1 Attention to nutritional management is crucial in premature infants during this critical period of growth. The primary goal of nutrition in VLBW infants is to simulate in utero growth; however, extra-uterine growth restriction is a significant problem.2 The policy statement of the American Academy of Pediatrics regarding breastfeeding supports the use of human milk for all term and preterm infants, with pasteurized donor breast milk (DBM) recommended for VLBW infants if mother’s milk is unavailable.3 The use of human milk in premature infants provides many nutritional, immunologic, and developmental benefits, including long-term neurodevelopmental improvements.4 However, the composition of human milk varies throughout the course of lactation,5 and the amounts of protein, calcium, and phosphorus necessary to achieve adequate growth of preterm infants are insufficient.6,7 Hence, the long-term use of unsupplemented human milk may lead to metabolic complications such as hypoproteinemia8 and osteopenia.9 Adding human milk fortifiers (HMFs) to human milk is necessary to provide additional calories, protein, minerals, and vitamins to premature infants.3 The practice of timing of the fortification of human milk varies because of concerns about immature gut mucosa and motility in VLBW infants. Clinicians are sometimes concerned that addition of fortifiers may induce feeding intolerance and delay achieving full volume enteral feeds and optimal nutrition. Early fortification (EF) provides several benefits to infants such as provision of adequate calories, protein, and other nutrients compared with delayed fortification (DF). In 2004, Berseth et al10 showed that human milk fortification was safely tolerated when enteral intake reaches at least 100 mL/kg/d feeding volume. Sullivan et al11 showed that fortification with human milk-based fortifier was safe if initiated at 40 mL/kg/d feeding volume. In a retrospective study, Tillman et al12 showed that From the Department of Pediatrics, University of Florida, Jacksonville, FL; Department of Pediatrics, University of fortification of human milk from the first feeding was safe and did not cause feeding Tennessee Health Science Center; Children’s intolerance. To our knowledge, a prospective randomized study has not been pubFoundation Research Institute at Le Bonheur Children’s Hospital; and Department of Obstetrics and lished that compares the tolerance of EF vs DF with bovine-based HMF. We hyGynecology, University of Tennessee Health Science Center, Memphis, TN pothesized that early human milk fortification will be as well tolerated as delayed 1
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BW DBM DF DOL EF HMF NEC VLBW
Birth weight Donor breast milk Delayed fortification Day of life Early fortification Human milk fortifier Necrotizing enterocolitis Very low birth weight
Supported by funding from Mead Johnson Nutrition, which had no role in study design, data collection, or data analysis; and University of Tennessee Health Science Center (R07-3223-563) for support research nurse and administrative expenses. S.S. received travel funds from Mead Johnson Nutrition to present some of the data at the Pediatric Academic Societies Annual Meeting. The other authors declare no conflicts of interest. Portions of the study were presented at the meeting of the Pediatric Academic Societies, April 27, 2015, San Diego, CA. 0022-3476/$ - see front matter. Copyright ª 2016 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.jpeds.2016.03.056
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human milk fortification and, hence, will not prolong the days to reach full feeding volume.
Methods This prospective, randomized, controlled, clinical study was conducted in tertiary neonatal intensive care units at Regional One Health and Le Bonheur Children’s Hospital, Memphis, Tennessee (ClinicalTrials.gov: NCT01988792). Infants with birth weight (BW) <1500 g were considered eligible for the study. Infants were excluded if: (1) they died or were expected to die within 72 hours; (2) they were diagnosed with major congenital or chromosomal abnormalities; or (3) mother could not provide her own milk and refused the use of DBM. The University of Tennessee Health Science Center Institutional Review Board approved the study. Informed written consent was obtained from parents prior to their enrollment. Infants were randomized to either EF (fortification beginning at 20 mL/kg/d of human milk feeds) or DF (fortification beginning at 100 mL/kg/d of human milk feeds). Fortification was done with a commercially available acidified liquid HMF (Enfamil; Mead Johnson, LLC, Evansville, Indiana). Five mL of liquid HMF was added to 25 mL of human milk to increase caloric density to 24 Kcal/oz. Parenteral nutrition was initiated on the day of life (DOL) 1. Enteral feedings were initiated at the attending physician’s discretion, followed by a standardized feeding protocol that guided the method of feeding and increments of advancement. Infants with less than 800 g BW received trophic feedings (10 mL/kg/d) for 3 days and advanced by 10 mL/ kg/d every other day. Infants between 800 and 1000 g BW received trophic feedings for 2 days and advanced by 10 mL/ kg/d every day. Infants between 1001 and 1250 g BW received trophic feedings for 2 days and advanced by 10-20 mL/kg/ d every day. Infants between 1251 and 1499 g BW received trophic feedings for 1-2 days and advanced by 20 mL/kg/d every day. Parenteral nutrition was decreased as enteral feeding volumes were advanced. Nursing staff fortified human milk at the bedside. Fortified human milk was delivered continuously (3 hours on and 1 hour off) through a nasogastric tube. DBM was used if mother was unable to provide her own breast milk. DBM was weaned to preterm formula when an infant reached 1500 g weight or 34 weeks postmenstrual age. The primary outcome was the number of days to reach full feeding volume (greater than 140 mL/kg/d enteral volume13). Secondary outcomes included frequency of feeding intolerance, necrotizing enterocolitis (NEC), weight velocity at 4 weeks after birth and at 36 weeks postmenstrual age, parenteral nutrition days, and length of stay. We also collected data on daily weight, protein and caloric intake for the first 4 weeks of life, metabolic acidosis (base deficit $10 mEq/L on blood gas measurement), late-onset sepsis, ventilator days, postnatal steroid treatment, chronic lung disease, patent ductus arteriosus, severe intraventricular hemorrhage (grade III and IV), periventricular leukomalacia, and retinopathy of prematurity. 2
Volume The day when the infant regained BW for the first time was considered as date of regained BW. Gestational age was determined by the best obstetrical estimate using last menstrual period and/or dating ultrasound. Feeding intolerance was defined as enteral feedings being held for at least 24 hours secondary to emesis/aspirates or abdominal distension. We defined NEC as stage II or greater using modified Bell criteria.14 Late-onset sepsis was defined as clinical signs of sepsis associated with positive blood culture after 3 days of age. The duration of total parenteral nutrition days was also recorded. The duration of endotracheal ventilation was defined as total number days infant remained on a ventilator with endotracheal tube. Bronchopulmonary dysplasia was defined as an oxygen requirement at 36 weeks postmenstrual age. A pediatric radiologist evaluated head ultrasounds to identify periventricular leukomalacia and intraventricular hemorrhage. Severe intraventricular hemorrhage on head ultrasound was defined as grade III or grade IV per Papile classification.15 A pediatric ophthalmologist evaluated eyes to diagnose retinopathy of prematurity. Daily weight was obtained unclothed and without diaper at a standard time each day using an electronically calibrated scale. Recumbent length and head circumference were measured weekly by nursing staff per unit practice. Weight gain velocity for first 4 weeks (g/kg/d) was calculated using the exponential method16 and at 36 weeks was calculated by 2-point BW model.16 The 2013 Fenton growth charts were used to obtain z-scores.17 We also calculated daily caloric and protein intake for the first 4-week period and also the cumulative protein and caloric intake for first 4 weeks. Protein and caloric calculations were made by assuming human milk’s contents.18 We collected data regarding serum indices of protein, albumin, blood urea nitrogen, alkaline phosphatase, phosphorous, and calcium that were measured weekly as a standard practice in our unit. A total of 96 infants (48 per group) were required to detect a difference of 7 days to reach full enteral feeding volume to obtain 80% power with a type I error rate of 5% using a 2sided t test. In our unit, mean SD days to reach full enteral feeding volume in VLBW infants was 24 12 days. Subjects were randomly assigned 1:1 to EF or DF using a blocked stratified randomization approach with block size 4 and stratification by BW (<1000 g, 1000-1499 g). Randomization was performed by computerized software after verification of eligibility and signed consent status. The research coordinator and principal investigators enrolled and assigned the patient after randomization. The proper handling of mother’s own milk and appropriate fortification prevented masking of the infants’ caregivers and research investigators. Data were analyzed using an intent-to-treat approach. Data are presented as mean SD and compared using a 2-sided t test when normally distributed. Otherwise, median (IQR) was compared using the Wilcoxon rank sum test. For categorical data, Fisher exact test was conducted. To adjust for the study design, a linear mixed model,19 which is a linear model that contains both fixed and random effects, was performed to Shah et al
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test differences in the primary outcome, days to reach full feeding volume. The linear mixed model included treatment and BW as fixed effects and the blocking factor as the random effect. A P value of less than .05 was considered statistically significant. All analyses were performed using SAS v 9.3 (SAS Institute Inc, Cary, North Carolina).
Results A total of 177 infants were eligible for study enrollment between November 2013 and March 2015 (Figure 1; available at www.jpeds.com). Of these, 100 infants meeting inclusion criteria were randomized in this study. The 2 groups had similar demographics and enrolled predominantly African American babies reflecting the demographics of our population (Table I). The median (IQR) days to reach full feeding volume was 20 (16, 31.5) in the EF group vs 20 (15, 29) in the DF group (Table II). There was no difference in the adjusted mean days to reach full feeds between EF (22 days) and DF (21 days) group based on the linear mixed model results (P = .41). The cases of NEC and deaths were similar between groups (Table II). In the 4 NEC cases, 2 infants developed NEC at about 2 weeks of life (n = 1 EF, n = 1 DF), and 2 infants developed NEC after 5 weeks (n = 1 EF, n = 1 DF). Two infants had medically treated NEC (DOL 11 in EF group and DOL 15 for an infant receiving unfortified mother’s own milk in DF group). Two infants required surgery; 1 in EF group (DOL 36) and 1 in DF group (DOL 58). There was no significant difference in the episodes of feeding intolerance between groups (Table II). Three infants (6%) in the EF group and 6 infants (12%) in
the DF group developed late-onset sepsis. Two infants (4%) in the EF group (DOL 20 and 26) and 5 infants (10%) in the DF group developed metabolic acidosis (base deficit >10 mEq/L on blood gas measurement) (DOL 26, 28, 26, 36, and 52). Four infants in each group developed retinopathy of prematurity $stage 3 and 2 infants in each group developed severe intraventricular hemorrhage. Periventricular leukomalacia occurred in three infants (n = 1 EF, n = 2 DF). There were 2 deaths in each group. Other secondary outcomes such as chronic lung disease, patent ductus arteriosus, postnatal steroid use, and growth variables are shown in Table II. As shown in Figure 2, A, median (IQR) daily protein intake (g/kg/d) was higher in EF group compared with the DF group in week 1 (3.3 [3.2, 3.5] vs 3.1 [2.9, 3.3], P < .001), week 2 (3.6 [3.5, 3.8] vs 3.2 [2.9, 3.4], P < .001), and week 3 (3.7 [3.4, 3.9] vs 3.5 [2.8, 3.8], P = .006). Median (IQR) cumulative protein intake (g/kg) in first 4 weeks in EF group was 98.6 (93.8, 104) compared with DF group protein intake of 89.6 (84.2, 96.4), P < .001 (Table II). Figure 2, B shows the daily comparison of caloric intake. Infants in EF group received 54% of their total human milk as DBM; infants in DF group received 67% as DBM. There were no significant differences in serum levels of total protein, albumin, alkaline phosphatase, phosphorus, calcium, and blood urea nitrogen between groups during the first 6 weeks of life.
Discussion Human milk fortification for preterm and VLBW infants improves growth. The American Academy of Pediatrics
Table I. Demographic characteristics Demographics Maternal characteristics Maternal age, y, median (IQR) Cesarean delivery, n (%) Preeclampsia, n (%) PPROM, n (%) Body mass index $30, n (%) Antenatal steroid, (any) n (%) Race, n (%) African American White Other Neonatal characteristics BW, g, median (IQR) <800 g, n (%) 800-1000 g, n (%) 1001-1250 g, n (%) 1251-1500 g, n (%) Gestational age, wk, median (IQR) Male, n (%) 1-min Apgar score, median (IQR) 5-min Apgar score, median (IQR) Surfactant therapy, n (%) Small for gestational age (<10th percentile) at birth, n (%) Days to start feeds, median (IQR)
EF, n = 50 24 (20, 29) 36 (72) 21 (42) 10 (20) 12 (24) 45 (90) 46 (92) 2 (4) 2 (4) 990 (780, 1200) 14 (28) 11 (22) 14 (28) 11 (22) 27.5 (26, 30) 24 (48) 4 (3, 6) 6 (6, 7) 32 (64) 13 (26) 3 (2, 4)
DF, n = 50 24.5 (22, 30) 36 (72) 14 (28) 14 (28) 14 (28) 43 (86) 44 (88) 4 (8) 2 (4) 990 (840, 1250) 12 (24) 13 (26) 12 (24) 13 (26) 28 (26, 30) 31 (62) 3 (2, 5) 6 (5, 8) 36 (72) 6 (12) 3 (3, 4)
P value .35 1.0 .21 .48 .82 .52 .88
.83 .91 .99 .23 .12 .30 .52 .12 .42
PPROM, preterm premature rupture of membrane. IQR (25th, 75th percentiles).
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Table II. Study outcomes Outcomes Primary outcomes Days to full feeds, (from birth), median (IQR) Days to full feeds, (from feeds initiation), median (IQR) Secondary outcomes Parenteral nutrition, d, median (IQR) Days to regain BW, median (IQR) Infants with feeding intolerance, n (%) NEC (Bell stage $2), n (%) Late-onset sepsis, n (%) Cumulative protein intake in first 4 wk, g/k, median (IQR) Ventilator, d, median (IQR) Chronic lung disease, n (%) Postnatal steroid, n (%) Patent ductus arteriosus, n (%) Medical Surgical Hospital stay, d, median (IQR)* HC change (D z-score), mean (SD) 4 wk of life 36 wk PMA Length change (D z-score), mean (SD) 4 wk of life 36 wk PMA Weight change (D z-score), mean (SD) 4 wk of life 36 wk PMA Weight velocity (g/k/d), median (IQR) 4 wk of life 36 wk PMA Small for gestational age (<10th percentile) at discharge, n (%)
EF, n = 49
DF, n = 50
P value
20 (16, 31.5) 19 (14, 28)
20 (15, 29) 18 (13, 27)
.45 .34
18 (14, 27) 9 (7, 12.5) 15 (31) 2 (4) 3 (6) 98.6 (93.8, 104) 2 (0, 16) 12 (24) 4 (8) 9 (18) 2 (4) 68 (41, 101)
18.5 (14, 26) 10 (8, 12.5) 15 (30) 2 (4) 6 (12) 89.6 (84.2, 96.4) 2 (1, 8) 10 (20) 6 (12) 12 (24) 1 (2) 63 (50, 83)
.76 .32 1.0 1.0 .49 <.001 .83 .64 .74 .62 .49 .88
0.97 (0.91) 0.71 (1.08)
0.95 (1.0) 0.65 (1.07)
.90 .80
1.0 (0.57) 1.58 (0.93)
0.97 (0.69) 1.59 (0.89)
.81 .93
0.96 (0.44) 1.28 (0.57)
1.1 (0.39) 1.41 (0.47)
.08 .22
8.7 (6.4, 12.2) 18.3 (14.9, 20.7) 36 (72)
7.7 (5.1, 10.6) 16.7 (13.9, 22) 34 (68)
.08 .30 .65
HC, head circumference; PMA, postmenstrual age. IQR (25th, 75th percentiles). D indicates difference in z-scores between birth to 4 weeks of life or 36 weeks PMA. Weight velocity at 4 and 36 weeks was calculated by exponential method and 2-point BW model, respectively.16 *Two infants are still hospitalized (one in each group).
recommends human milk as the best source of enteral nutrition for VLBW infants but also recommends fortification.3 Some studies have reported the tolerance of early fortified human milk in VLBW infants, but the timing of fortification for optimal benefits remains uncertain.11,12 In our study, we compared the clinical outcomes of infants who were started on human milk fortification at 2 different feeding volumes. We demonstrated that infants randomized to EF vs DF achieved full feeding volume at the same time with no difference in feeding tolerance or number of episodes when feeds were held for over 24 hours. Concerns have been raised about the potential relationship between milk hyperosmolality and the risk of NEC,20-22 although a study by Pearson et al23 found no association between hyperosmolar feeds and intestinal injury in VLBW infants. Moreover, the incidence of NEC was the same in the EF and DF groups, although our study was not powered to evaluate the difference in incidence of NEC with EF vs DF. Early introduction of bovine-based fortifiers could also raise concerns about early exposure to cow milk protein in VLBW infants. The American Academy of Pediatrics Committee on Nutrition recommends providing sufficient energy and nutrients to preterm infants including 3.0-4.0 g/kg/d protein intake.5 The European Society for Pediatric Gastroenterology, Hepatology, and Nutrition recommends 4
4-4.5 g/kg/d protein intake in <1000 g and 3.5-4.0 g/kg/d protein intake in 1000-1800 g infants to achieve postuterine catch-up growth.13 Despite efforts to improve early nutrition in VLBW infants, growth restriction is frequently observed during the first few months of life.2,24 Nutritional deficits are greatest in the first week of life but continue to accumulate through the first month. We showed that daily protein intake was significantly higher in EF group during the first 3 weeks of life and that cumulative protein intake over 4 weeks was significantly higher in the same group. Senterre et al25 showed that cumulative protein intake in the first week of life played a significant role in postnatal growth during the first 6 weeks of life. Several studies indicated better neurodevelopmental and growth outcomes at 18-22 months of age after improved growth velocity and first week’s protein intake.26,27 By providing more protein in the first 4 weeks, we showed a trend toward improved weight gain. Despite receiving higher average daily and cumulative protein intake over 4 weeks in EF group, their serum protein and albumin level was not different than DF group. This could be explained by the variable protein content in human milk. In our unit, we used a single liquid bovine-based HMF as standard care throughout our study and demonstrated tolerance of EF in VLBW infants. Although we did not use other types of available HMF, these may also be tolerated in VLBW Shah et al
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Figure 2. Median daily A, protein and B, caloric intake in first 4 weeks of life. Data are shown as median (IQR). *P < .005.
infants as shown in other studies. Hair et al28 and Sullivan et al11 reported that EF (40-60 mL/kg/d feeding volume) was well tolerated when using human milk-based HMF. Our study had several limitations. First, we did not analyze the caloric and protein content of individual mother’s own milk. Caloric and protein contents in mother’s milk differ for each infant as shown by Rochow et al.29 Second, the intervention was not blinded to allow proper handling of mother’s own milk and appropriate fortification. Third, although registered staff nurses measured the head circumference and length by a standard technique, there could be some subjective bias and variations while measuring. Our results demonstrated that early initiation of liquid bovine-based HMF at a feeding volume of 20 mL/kg/d was tolerated as well as later initiation at 100 mL/kg/d, and had no effect on the time at which full feeding volumes were achieved. EF provided more protein intake over the first 4 weeks of life and reduced cumulative protein deficit, but did not significantly improve weight gain or biochemical markers of nutritional status. Long-term follow-up is necessary to compare neurodevelopmental outcomes. Our results support early initiation of breast milk fortification to increase protein and caloric intake. However, a larger multicenter, randomized controlled trial will be needed to compare the effect of EF vs DF on safety outcomes such as NEC and lateonset sepsis. n We thank Mark R. Corkins, MD, and Mark L. Hudak, MD, for their suggestions and criticisms during editing of the manuscript; Amanda Preston, PhD, scientific editor at the Children’s Foundation Research Institute at Le Bonheur for editorial assistance in the preparation of
the manuscript; and Sandra Grimes, RN, for obtaining research consents. Submitted for publication Dec 9, 2015; last revision received Feb 15, 2016; accepted Mar 22, 2016. Reprint requests: Sanket D. Shah, MD, Department of Pediatrics, University of Florida, 653-1 West 8th St, Jacksonville, FL 32209. E-mail: sdshah_5@yahoo. com
References 1. Nzegwu NI, Ehrenkranz RA. Post-discharge nutrition and the VLBW infant: to supplement or not supplement?: a review of the current evidence. Clin Perinatol 2014;41:463-74. 2. Martin CR, Brown YF, Ehrenkranz RA, O’Shea TM, Allred EN, Belfort MB, et al. Nutritional practices and growth velocity in the first month of life in extremely premature infants. Pediatrics 2009;124:64957. 3. Section on Breastfeeding. Breastfeeding and the use of human milk. Pediatrics 2012;129:e827-41. 4. Menon G, Williams TC. Human milk for preterm infants: why, what, when and how? Arch Dis Child Fetal Neonatal Ed 2013;98:F559-62. 5. Nutritional needs of the preterm infant. In: Kleinman R, ed. Pediatric nutrition handbook. Elk Grove, IL: American Academy of Pediatrics; 2013. p. 83-110. 6. Nutrition EC, Arslanoglu S, Corpeleijn W, Moro G, Braegger C, Campoy C, et al. Donor human milk for preterm infants: current evidence and research directions. J Pediatr Gastroenterol Nutr 2013;57: 535-42. 7. Heiman H, Schanler RJ. Benefits of maternal and donor human milk for premature infants. Early Hum Dev 2006;82:781-7. 8. Ronnholm KA, Sipila I, Siimes MA. Human milk protein supplementation for the prevention of hypoproteinemia without metabolic imbalance in breast milk-fed, very low-birth-weight infants. J Pediatr 1982; 101:243-7.
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9. Greer FR, Steichen JJ, Tsang RC. Calcium and phosphate supplements in breast milk-related rickets. Results in a very-low-birth-weight infant. Am J Dis Child 1982;136:581-3. 10. Berseth CL, Van Aerde JE, Gross S, Stolz SI, Harris CL, Hansen JW. Growth, efficacy, and safety of feeding an iron-fortified human milk fortifier. Pediatrics 2004;114:e699-706. 11. Sullivan S, Schanler RJ, Kim JH, Patel AL, Trawoger R, KiechlKohlendorfer U, et al. An exclusively human milk-based diet is associated with a lower rate of necrotizing enterocolitis than a diet of human milk and bovine milk-based products. J Pediatr 2010;156: 562-7.e1. 12. Tillman S, Brandon DH, Silva SG. Evaluation of human milk fortification from the time of the first feeding: effects on infants of less than 31 weeks gestational age. J Perinatol 2012;32:525-31. 13. Agostoni C, Buonocore G, Carnielli VP, De Curtis M, Darmaun D, Decsi T, 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. 14. Walsh MC, Kliegman RM. Necrotizing enterocolitis: treatment based on staging criteria. Pediatr Clin North Am 1986;33:179-201. 15. Papile LA, Burstein J, Burstein R, Koffler H. Incidence and evolution of subependymal and intraventricular hemorrhage: a study of infants with birth weights less than 1500 gm. J Pediatr 1978;92:529-34. 16. Patel AL, Engstrom JL, Meier PP, Kimura RE. Accuracy of methods for calculating postnatal growth velocity for extremely low birth weight infants. Pediatrics 2005;116:1466-73. 17. Fenton TR, Kim JH. A systematic review and meta-analysis to revise the Fenton growth chart for preterm infants. BMC Pediatr 2013;13:59. 18. Picciano MF. Representative values for constituents of human milk. Pediatr Clin North Am 2001;48:263-4. 19. Gurka MJ, Edwards LJ. Handbook of statistics 27. In: Rao CR, Miller JP, Rao DC, eds. Handbook of statistics 27—epidemiology
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and medical statistics. 1st ed. Amsterdam, The Netherlands: Elsevier; 2008. p. 253-80. Book LS, Herbst JJ, Atherton SO, Jung AL. Necrotizing enterocolitis in low-birth-weight infants fed an elemental formula. J Pediatr 1975;87: 602-5. De Curtis M, Candusso M, Pieltain C, Rigo J. Effect of fortification on the osmolality of human milk. Arch Dis Child Fetal Neonatal Ed 1999; 81:F141-3. Santulli TV, Schullinger JN, Heird WC, Gongaware RD, Wigger J, Barlow B, et al. Acute necrotizing enterocolitis in infancy: a review of 64 cases. Pediatrics 1975;55:376-87. Pearson F, Johnson MJ, Leaf AA. Milk osmolality: does it matter? Arch Dis Child Fetal Neonatal Ed 2013;98:F166-9. Ehrenkranz RA, Younes N, Lemons JA, Fanaroff AA, Donovan EF, Wright LL, et al. Longitudinal growth of hospitalized very low birth weight infants. Pediatrics 1999;104:280-9. Senterre T, Rigo J. Reduction in postnatal cumulative nutritional deficit and improvement of growth in extremely preterm infants. Acta Paediatr 2012;101:e64-70. Ehrenkranz RA, Dusick AM, Vohr BR, Wright LL, Wrage LA, Poole WK. Growth in the neonatal intensive care unit influences neurodevelopmental and growth outcomes of extremely low birth weight infants. Pediatrics 2006;117:1253-61. Stephens BE, Walden RV, Gargus RA, Tucker R, McKinley L, Mance M, et al. First-week protein and energy intakes are associated with 18-month developmental outcomes in extremely low birth weight infants. Pediatrics 2009;123:1337-43. Hair AB, Hawthorne KM, Chetta KE, Abrams SA. Human milk feeding supports adequate growth in infants
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Figure 1. CONSORT flow diagram.
Early versus Delayed Human Milk Fortification in Very Low Birth Weight Infants–A Randomized Controlled Trial
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Study design Very low birth weight infants (n = 100) were prospectively randomized to early fortification (EF) (beginning at a feeding volume of 20 mL/kg/d) or delayed fortification (at a feeding volume of 100 mL/kg/d). We employed a standardized feeding protocol and parenteral nutrition guidelines for the nutritional management of all study infants. Results The median days to reach full feeding volumes were equivalent in the 2 groups (20 vs 20, P = .45). No significant difference was observed in the total number of episodes of feeding intolerance (58 vs 57). Two cases of necrotizing enterocolitis (Bell stage $2) and deaths occurred in each group. Median daily protein intake (g/kg/d) was higher in EF group in week 1 (3.3 [3.2, 3.5] vs 3.1 [2.9, 3.3], P < .001), week 2 (3.6 [3.5, 3.8] vs 3.2 [2.9, 3.4], P < .001), and week 3 (3.7 [3.4, 3.9] vs 3.5 [2.8, 3.8], P = .006). Cumulative protein intake (g/kg) in the first 4 weeks of life was higher in EF group (98.6 [93.8, 104] vs 89.6 [84.2, 96.4], P < .001). Conclusions Very early human milk fortification may improve early protein intake in very low birth weight infants without increasing frequencies of adverse events. (J Pediatr 2016;-:---). Trial registration ClinicalTrials.gov: NCT01988792.
A
chieving adequate extra-uterine growth of very low birth weight (VLBW) infants remains a significant challenge.1 Attention to nutritional management is crucial in premature infants during this critical period of growth. The primary goal of nutrition in VLBW infants is to simulate in utero growth; however, extra-uterine growth restriction is a significant problem.2 The policy statement of the American Academy of Pediatrics regarding breastfeeding supports the use of human milk for all term and preterm infants, with pasteurized donor breast milk (DBM) recommended for VLBW infants if mother’s milk is unavailable.3 The use of human milk in premature infants provides many nutritional, immunologic, and developmental benefits, including long-term neurodevelopmental improvements.4 However, the composition of human milk varies throughout the course of lactation,5 and the amounts of protein, calcium, and phosphorus necessary to achieve adequate growth of preterm infants are insufficient.6,7 Hence, the long-term use of unsupplemented human milk may lead to metabolic complications such as hypoproteinemia8 and osteopenia.9 Adding human milk fortifiers (HMFs) to human milk is necessary to provide additional calories, protein, minerals, and vitamins to premature infants.3 The practice of timing of the fortification of human milk varies because of concerns about immature gut mucosa and motility in VLBW infants. Clinicians are sometimes concerned that addition of fortifiers may induce feeding intolerance and delay achieving full volume enteral feeds and optimal nutrition. Early fortification (EF) provides several benefits to infants such as provision of adequate calories, protein, and other nutrients compared with delayed fortification (DF). In 2004, Berseth et al10 showed that human milk fortification was safely tolerated when enteral intake reaches at least 100 mL/kg/d feeding volume. Sullivan et al11 showed that fortification with human milk-based fortifier was safe if initiated at 40 mL/kg/d feeding volume. In a retrospective study, Tillman et al12 showed that From the Department of Pediatrics, University of Florida, Jacksonville, FL; Department of Pediatrics, University of fortification of human milk from the first feeding was safe and did not cause feeding Tennessee Health Science Center; Children’s intolerance. To our knowledge, a prospective randomized study has not been pubFoundation Research Institute at Le Bonheur Children’s Hospital; and Department of Obstetrics and lished that compares the tolerance of EF vs DF with bovine-based HMF. We hyGynecology, University of Tennessee Health Science Center, Memphis, TN pothesized that early human milk fortification will be as well tolerated as delayed 1
2
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BW DBM DF DOL EF HMF NEC VLBW
Birth weight Donor breast milk Delayed fortification Day of life Early fortification Human milk fortifier Necrotizing enterocolitis Very low birth weight
Supported by funding from Mead Johnson Nutrition, which had no role in study design, data collection, or data analysis; and University of Tennessee Health Science Center (R07-3223-563) for support research nurse and administrative expenses. S.S. received travel funds from Mead Johnson Nutrition to present some of the data at the Pediatric Academic Societies Annual Meeting. The other authors declare no conflicts of interest. Portions of the study were presented at the meeting of the Pediatric Academic Societies, April 27, 2015, San Diego, CA. 0022-3476/$ - see front matter. Copyright ª 2016 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.jpeds.2016.03.056
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human milk fortification and, hence, will not prolong the days to reach full feeding volume.
Methods This prospective, randomized, controlled, clinical study was conducted in tertiary neonatal intensive care units at Regional One Health and Le Bonheur Children’s Hospital, Memphis, Tennessee (ClinicalTrials.gov: NCT01988792). Infants with birth weight (BW) <1500 g were considered eligible for the study. Infants were excluded if: (1) they died or were expected to die within 72 hours; (2) they were diagnosed with major congenital or chromosomal abnormalities; or (3) mother could not provide her own milk and refused the use of DBM. The University of Tennessee Health Science Center Institutional Review Board approved the study. Informed written consent was obtained from parents prior to their enrollment. Infants were randomized to either EF (fortification beginning at 20 mL/kg/d of human milk feeds) or DF (fortification beginning at 100 mL/kg/d of human milk feeds). Fortification was done with a commercially available acidified liquid HMF (Enfamil; Mead Johnson, LLC, Evansville, Indiana). Five mL of liquid HMF was added to 25 mL of human milk to increase caloric density to 24 Kcal/oz. Parenteral nutrition was initiated on the day of life (DOL) 1. Enteral feedings were initiated at the attending physician’s discretion, followed by a standardized feeding protocol that guided the method of feeding and increments of advancement. Infants with less than 800 g BW received trophic feedings (10 mL/kg/d) for 3 days and advanced by 10 mL/ kg/d every other day. Infants between 800 and 1000 g BW received trophic feedings for 2 days and advanced by 10 mL/ kg/d every day. Infants between 1001 and 1250 g BW received trophic feedings for 2 days and advanced by 10-20 mL/kg/ d every day. Infants between 1251 and 1499 g BW received trophic feedings for 1-2 days and advanced by 20 mL/kg/d every day. Parenteral nutrition was decreased as enteral feeding volumes were advanced. Nursing staff fortified human milk at the bedside. Fortified human milk was delivered continuously (3 hours on and 1 hour off) through a nasogastric tube. DBM was used if mother was unable to provide her own breast milk. DBM was weaned to preterm formula when an infant reached 1500 g weight or 34 weeks postmenstrual age. The primary outcome was the number of days to reach full feeding volume (greater than 140 mL/kg/d enteral volume13). Secondary outcomes included frequency of feeding intolerance, necrotizing enterocolitis (NEC), weight velocity at 4 weeks after birth and at 36 weeks postmenstrual age, parenteral nutrition days, and length of stay. We also collected data on daily weight, protein and caloric intake for the first 4 weeks of life, metabolic acidosis (base deficit $10 mEq/L on blood gas measurement), late-onset sepsis, ventilator days, postnatal steroid treatment, chronic lung disease, patent ductus arteriosus, severe intraventricular hemorrhage (grade III and IV), periventricular leukomalacia, and retinopathy of prematurity. 2
Volume The day when the infant regained BW for the first time was considered as date of regained BW. Gestational age was determined by the best obstetrical estimate using last menstrual period and/or dating ultrasound. Feeding intolerance was defined as enteral feedings being held for at least 24 hours secondary to emesis/aspirates or abdominal distension. We defined NEC as stage II or greater using modified Bell criteria.14 Late-onset sepsis was defined as clinical signs of sepsis associated with positive blood culture after 3 days of age. The duration of total parenteral nutrition days was also recorded. The duration of endotracheal ventilation was defined as total number days infant remained on a ventilator with endotracheal tube. Bronchopulmonary dysplasia was defined as an oxygen requirement at 36 weeks postmenstrual age. A pediatric radiologist evaluated head ultrasounds to identify periventricular leukomalacia and intraventricular hemorrhage. Severe intraventricular hemorrhage on head ultrasound was defined as grade III or grade IV per Papile classification.15 A pediatric ophthalmologist evaluated eyes to diagnose retinopathy of prematurity. Daily weight was obtained unclothed and without diaper at a standard time each day using an electronically calibrated scale. Recumbent length and head circumference were measured weekly by nursing staff per unit practice. Weight gain velocity for first 4 weeks (g/kg/d) was calculated using the exponential method16 and at 36 weeks was calculated by 2-point BW model.16 The 2013 Fenton growth charts were used to obtain z-scores.17 We also calculated daily caloric and protein intake for the first 4-week period and also the cumulative protein and caloric intake for first 4 weeks. Protein and caloric calculations were made by assuming human milk’s contents.18 We collected data regarding serum indices of protein, albumin, blood urea nitrogen, alkaline phosphatase, phosphorous, and calcium that were measured weekly as a standard practice in our unit. A total of 96 infants (48 per group) were required to detect a difference of 7 days to reach full enteral feeding volume to obtain 80% power with a type I error rate of 5% using a 2sided t test. In our unit, mean SD days to reach full enteral feeding volume in VLBW infants was 24 12 days. Subjects were randomly assigned 1:1 to EF or DF using a blocked stratified randomization approach with block size 4 and stratification by BW (<1000 g, 1000-1499 g). Randomization was performed by computerized software after verification of eligibility and signed consent status. The research coordinator and principal investigators enrolled and assigned the patient after randomization. The proper handling of mother’s own milk and appropriate fortification prevented masking of the infants’ caregivers and research investigators. Data were analyzed using an intent-to-treat approach. Data are presented as mean SD and compared using a 2-sided t test when normally distributed. Otherwise, median (IQR) was compared using the Wilcoxon rank sum test. For categorical data, Fisher exact test was conducted. To adjust for the study design, a linear mixed model,19 which is a linear model that contains both fixed and random effects, was performed to Shah et al
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test differences in the primary outcome, days to reach full feeding volume. The linear mixed model included treatment and BW as fixed effects and the blocking factor as the random effect. A P value of less than .05 was considered statistically significant. All analyses were performed using SAS v 9.3 (SAS Institute Inc, Cary, North Carolina).
Results A total of 177 infants were eligible for study enrollment between November 2013 and March 2015 (Figure 1; available at www.jpeds.com). Of these, 100 infants meeting inclusion criteria were randomized in this study. The 2 groups had similar demographics and enrolled predominantly African American babies reflecting the demographics of our population (Table I). The median (IQR) days to reach full feeding volume was 20 (16, 31.5) in the EF group vs 20 (15, 29) in the DF group (Table II). There was no difference in the adjusted mean days to reach full feeds between EF (22 days) and DF (21 days) group based on the linear mixed model results (P = .41). The cases of NEC and deaths were similar between groups (Table II). In the 4 NEC cases, 2 infants developed NEC at about 2 weeks of life (n = 1 EF, n = 1 DF), and 2 infants developed NEC after 5 weeks (n = 1 EF, n = 1 DF). Two infants had medically treated NEC (DOL 11 in EF group and DOL 15 for an infant receiving unfortified mother’s own milk in DF group). Two infants required surgery; 1 in EF group (DOL 36) and 1 in DF group (DOL 58). There was no significant difference in the episodes of feeding intolerance between groups (Table II). Three infants (6%) in the EF group and 6 infants (12%) in
the DF group developed late-onset sepsis. Two infants (4%) in the EF group (DOL 20 and 26) and 5 infants (10%) in the DF group developed metabolic acidosis (base deficit >10 mEq/L on blood gas measurement) (DOL 26, 28, 26, 36, and 52). Four infants in each group developed retinopathy of prematurity $stage 3 and 2 infants in each group developed severe intraventricular hemorrhage. Periventricular leukomalacia occurred in three infants (n = 1 EF, n = 2 DF). There were 2 deaths in each group. Other secondary outcomes such as chronic lung disease, patent ductus arteriosus, postnatal steroid use, and growth variables are shown in Table II. As shown in Figure 2, A, median (IQR) daily protein intake (g/kg/d) was higher in EF group compared with the DF group in week 1 (3.3 [3.2, 3.5] vs 3.1 [2.9, 3.3], P < .001), week 2 (3.6 [3.5, 3.8] vs 3.2 [2.9, 3.4], P < .001), and week 3 (3.7 [3.4, 3.9] vs 3.5 [2.8, 3.8], P = .006). Median (IQR) cumulative protein intake (g/kg) in first 4 weeks in EF group was 98.6 (93.8, 104) compared with DF group protein intake of 89.6 (84.2, 96.4), P < .001 (Table II). Figure 2, B shows the daily comparison of caloric intake. Infants in EF group received 54% of their total human milk as DBM; infants in DF group received 67% as DBM. There were no significant differences in serum levels of total protein, albumin, alkaline phosphatase, phosphorus, calcium, and blood urea nitrogen between groups during the first 6 weeks of life.
Discussion Human milk fortification for preterm and VLBW infants improves growth. The American Academy of Pediatrics
Table I. Demographic characteristics Demographics Maternal characteristics Maternal age, y, median (IQR) Cesarean delivery, n (%) Preeclampsia, n (%) PPROM, n (%) Body mass index $30, n (%) Antenatal steroid, (any) n (%) Race, n (%) African American White Other Neonatal characteristics BW, g, median (IQR) <800 g, n (%) 800-1000 g, n (%) 1001-1250 g, n (%) 1251-1500 g, n (%) Gestational age, wk, median (IQR) Male, n (%) 1-min Apgar score, median (IQR) 5-min Apgar score, median (IQR) Surfactant therapy, n (%) Small for gestational age (<10th percentile) at birth, n (%) Days to start feeds, median (IQR)
EF, n = 50 24 (20, 29) 36 (72) 21 (42) 10 (20) 12 (24) 45 (90) 46 (92) 2 (4) 2 (4) 990 (780, 1200) 14 (28) 11 (22) 14 (28) 11 (22) 27.5 (26, 30) 24 (48) 4 (3, 6) 6 (6, 7) 32 (64) 13 (26) 3 (2, 4)
DF, n = 50 24.5 (22, 30) 36 (72) 14 (28) 14 (28) 14 (28) 43 (86) 44 (88) 4 (8) 2 (4) 990 (840, 1250) 12 (24) 13 (26) 12 (24) 13 (26) 28 (26, 30) 31 (62) 3 (2, 5) 6 (5, 8) 36 (72) 6 (12) 3 (3, 4)
P value .35 1.0 .21 .48 .82 .52 .88
.83 .91 .99 .23 .12 .30 .52 .12 .42
PPROM, preterm premature rupture of membrane. IQR (25th, 75th percentiles).
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Table II. Study outcomes Outcomes Primary outcomes Days to full feeds, (from birth), median (IQR) Days to full feeds, (from feeds initiation), median (IQR) Secondary outcomes Parenteral nutrition, d, median (IQR) Days to regain BW, median (IQR) Infants with feeding intolerance, n (%) NEC (Bell stage $2), n (%) Late-onset sepsis, n (%) Cumulative protein intake in first 4 wk, g/k, median (IQR) Ventilator, d, median (IQR) Chronic lung disease, n (%) Postnatal steroid, n (%) Patent ductus arteriosus, n (%) Medical Surgical Hospital stay, d, median (IQR)* HC change (D z-score), mean (SD) 4 wk of life 36 wk PMA Length change (D z-score), mean (SD) 4 wk of life 36 wk PMA Weight change (D z-score), mean (SD) 4 wk of life 36 wk PMA Weight velocity (g/k/d), median (IQR) 4 wk of life 36 wk PMA Small for gestational age (<10th percentile) at discharge, n (%)
EF, n = 49
DF, n = 50
P value
20 (16, 31.5) 19 (14, 28)
20 (15, 29) 18 (13, 27)
.45 .34
18 (14, 27) 9 (7, 12.5) 15 (31) 2 (4) 3 (6) 98.6 (93.8, 104) 2 (0, 16) 12 (24) 4 (8) 9 (18) 2 (4) 68 (41, 101)
18.5 (14, 26) 10 (8, 12.5) 15 (30) 2 (4) 6 (12) 89.6 (84.2, 96.4) 2 (1, 8) 10 (20) 6 (12) 12 (24) 1 (2) 63 (50, 83)
.76 .32 1.0 1.0 .49 <.001 .83 .64 .74 .62 .49 .88
0.97 (0.91) 0.71 (1.08)
0.95 (1.0) 0.65 (1.07)
.90 .80
1.0 (0.57) 1.58 (0.93)
0.97 (0.69) 1.59 (0.89)
.81 .93
0.96 (0.44) 1.28 (0.57)
1.1 (0.39) 1.41 (0.47)
.08 .22
8.7 (6.4, 12.2) 18.3 (14.9, 20.7) 36 (72)
7.7 (5.1, 10.6) 16.7 (13.9, 22) 34 (68)
.08 .30 .65
HC, head circumference; PMA, postmenstrual age. IQR (25th, 75th percentiles). D indicates difference in z-scores between birth to 4 weeks of life or 36 weeks PMA. Weight velocity at 4 and 36 weeks was calculated by exponential method and 2-point BW model, respectively.16 *Two infants are still hospitalized (one in each group).
recommends human milk as the best source of enteral nutrition for VLBW infants but also recommends fortification.3 Some studies have reported the tolerance of early fortified human milk in VLBW infants, but the timing of fortification for optimal benefits remains uncertain.11,12 In our study, we compared the clinical outcomes of infants who were started on human milk fortification at 2 different feeding volumes. We demonstrated that infants randomized to EF vs DF achieved full feeding volume at the same time with no difference in feeding tolerance or number of episodes when feeds were held for over 24 hours. Concerns have been raised about the potential relationship between milk hyperosmolality and the risk of NEC,20-22 although a study by Pearson et al23 found no association between hyperosmolar feeds and intestinal injury in VLBW infants. Moreover, the incidence of NEC was the same in the EF and DF groups, although our study was not powered to evaluate the difference in incidence of NEC with EF vs DF. Early introduction of bovine-based fortifiers could also raise concerns about early exposure to cow milk protein in VLBW infants. The American Academy of Pediatrics Committee on Nutrition recommends providing sufficient energy and nutrients to preterm infants including 3.0-4.0 g/kg/d protein intake.5 The European Society for Pediatric Gastroenterology, Hepatology, and Nutrition recommends 4
4-4.5 g/kg/d protein intake in <1000 g and 3.5-4.0 g/kg/d protein intake in 1000-1800 g infants to achieve postuterine catch-up growth.13 Despite efforts to improve early nutrition in VLBW infants, growth restriction is frequently observed during the first few months of life.2,24 Nutritional deficits are greatest in the first week of life but continue to accumulate through the first month. We showed that daily protein intake was significantly higher in EF group during the first 3 weeks of life and that cumulative protein intake over 4 weeks was significantly higher in the same group. Senterre et al25 showed that cumulative protein intake in the first week of life played a significant role in postnatal growth during the first 6 weeks of life. Several studies indicated better neurodevelopmental and growth outcomes at 18-22 months of age after improved growth velocity and first week’s protein intake.26,27 By providing more protein in the first 4 weeks, we showed a trend toward improved weight gain. Despite receiving higher average daily and cumulative protein intake over 4 weeks in EF group, their serum protein and albumin level was not different than DF group. This could be explained by the variable protein content in human milk. In our unit, we used a single liquid bovine-based HMF as standard care throughout our study and demonstrated tolerance of EF in VLBW infants. Although we did not use other types of available HMF, these may also be tolerated in VLBW Shah et al
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Figure 2. Median daily A, protein and B, caloric intake in first 4 weeks of life. Data are shown as median (IQR). *P < .005.
infants as shown in other studies. Hair et al28 and Sullivan et al11 reported that EF (40-60 mL/kg/d feeding volume) was well tolerated when using human milk-based HMF. Our study had several limitations. First, we did not analyze the caloric and protein content of individual mother’s own milk. Caloric and protein contents in mother’s milk differ for each infant as shown by Rochow et al.29 Second, the intervention was not blinded to allow proper handling of mother’s own milk and appropriate fortification. Third, although registered staff nurses measured the head circumference and length by a standard technique, there could be some subjective bias and variations while measuring. Our results demonstrated that early initiation of liquid bovine-based HMF at a feeding volume of 20 mL/kg/d was tolerated as well as later initiation at 100 mL/kg/d, and had no effect on the time at which full feeding volumes were achieved. EF provided more protein intake over the first 4 weeks of life and reduced cumulative protein deficit, but did not significantly improve weight gain or biochemical markers of nutritional status. Long-term follow-up is necessary to compare neurodevelopmental outcomes. Our results support early initiation of breast milk fortification to increase protein and caloric intake. However, a larger multicenter, randomized controlled trial will be needed to compare the effect of EF vs DF on safety outcomes such as NEC and lateonset sepsis. n We thank Mark R. Corkins, MD, and Mark L. Hudak, MD, for their suggestions and criticisms during editing of the manuscript; Amanda Preston, PhD, scientific editor at the Children’s Foundation Research Institute at Le Bonheur for editorial assistance in the preparation of
the manuscript; and Sandra Grimes, RN, for obtaining research consents. Submitted for publication Dec 9, 2015; last revision received Feb 15, 2016; accepted Mar 22, 2016. Reprint requests: Sanket D. Shah, MD, Department of Pediatrics, University of Florida, 653-1 West 8th St, Jacksonville, FL 32209. E-mail: sdshah_5@yahoo. com
References 1. Nzegwu NI, Ehrenkranz RA. Post-discharge nutrition and the VLBW infant: to supplement or not supplement?: a review of the current evidence. Clin Perinatol 2014;41:463-74. 2. Martin CR, Brown YF, Ehrenkranz RA, O’Shea TM, Allred EN, Belfort MB, et al. Nutritional practices and growth velocity in the first month of life in extremely premature infants. Pediatrics 2009;124:64957. 3. Section on Breastfeeding. Breastfeeding and the use of human milk. Pediatrics 2012;129:e827-41. 4. Menon G, Williams TC. Human milk for preterm infants: why, what, when and how? Arch Dis Child Fetal Neonatal Ed 2013;98:F559-62. 5. Nutritional needs of the preterm infant. In: Kleinman R, ed. Pediatric nutrition handbook. Elk Grove, IL: American Academy of Pediatrics; 2013. p. 83-110. 6. Nutrition EC, Arslanoglu S, Corpeleijn W, Moro G, Braegger C, Campoy C, et al. Donor human milk for preterm infants: current evidence and research directions. J Pediatr Gastroenterol Nutr 2013;57: 535-42. 7. Heiman H, Schanler RJ. Benefits of maternal and donor human milk for premature infants. Early Hum Dev 2006;82:781-7. 8. Ronnholm KA, Sipila I, Siimes MA. Human milk protein supplementation for the prevention of hypoproteinemia without metabolic imbalance in breast milk-fed, very low-birth-weight infants. J Pediatr 1982; 101:243-7.
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9. Greer FR, Steichen JJ, Tsang RC. Calcium and phosphate supplements in breast milk-related rickets. Results in a very-low-birth-weight infant. Am J Dis Child 1982;136:581-3. 10. Berseth CL, Van Aerde JE, Gross S, Stolz SI, Harris CL, Hansen JW. Growth, efficacy, and safety of feeding an iron-fortified human milk fortifier. Pediatrics 2004;114:e699-706. 11. Sullivan S, Schanler RJ, Kim JH, Patel AL, Trawoger R, KiechlKohlendorfer U, et al. An exclusively human milk-based diet is associated with a lower rate of necrotizing enterocolitis than a diet of human milk and bovine milk-based products. J Pediatr 2010;156: 562-7.e1. 12. Tillman S, Brandon DH, Silva SG. Evaluation of human milk fortification from the time of the first feeding: effects on infants of less than 31 weeks gestational age. J Perinatol 2012;32:525-31. 13. Agostoni C, Buonocore G, Carnielli VP, De Curtis M, Darmaun D, Decsi T, 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. 14. Walsh MC, Kliegman RM. Necrotizing enterocolitis: treatment based on staging criteria. Pediatr Clin North Am 1986;33:179-201. 15. Papile LA, Burstein J, Burstein R, Koffler H. Incidence and evolution of subependymal and intraventricular hemorrhage: a study of infants with birth weights less than 1500 gm. J Pediatr 1978;92:529-34. 16. Patel AL, Engstrom JL, Meier PP, Kimura RE. Accuracy of methods for calculating postnatal growth velocity for extremely low birth weight infants. Pediatrics 2005;116:1466-73. 17. Fenton TR, Kim JH. A systematic review and meta-analysis to revise the Fenton growth chart for preterm infants. BMC Pediatr 2013;13:59. 18. Picciano MF. Representative values for constituents of human milk. Pediatr Clin North Am 2001;48:263-4. 19. Gurka MJ, Edwards LJ. Handbook of statistics 27. In: Rao CR, Miller JP, Rao DC, eds. Handbook of statistics 27—epidemiology
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and medical statistics. 1st ed. Amsterdam, The Netherlands: Elsevier; 2008. p. 253-80. Book LS, Herbst JJ, Atherton SO, Jung AL. Necrotizing enterocolitis in low-birth-weight infants fed an elemental formula. J Pediatr 1975;87: 602-5. De Curtis M, Candusso M, Pieltain C, Rigo J. Effect of fortification on the osmolality of human milk. Arch Dis Child Fetal Neonatal Ed 1999; 81:F141-3. Santulli TV, Schullinger JN, Heird WC, Gongaware RD, Wigger J, Barlow B, et al. Acute necrotizing enterocolitis in infancy: a review of 64 cases. Pediatrics 1975;55:376-87. Pearson F, Johnson MJ, Leaf AA. Milk osmolality: does it matter? Arch Dis Child Fetal Neonatal Ed 2013;98:F166-9. Ehrenkranz RA, Younes N, Lemons JA, Fanaroff AA, Donovan EF, Wright LL, et al. Longitudinal growth of hospitalized very low birth weight infants. Pediatrics 1999;104:280-9. Senterre T, Rigo J. Reduction in postnatal cumulative nutritional deficit and improvement of growth in extremely preterm infants. Acta Paediatr 2012;101:e64-70. Ehrenkranz RA, Dusick AM, Vohr BR, Wright LL, Wrage LA, Poole WK. Growth in the neonatal intensive care unit influences neurodevelopmental and growth outcomes of extremely low birth weight infants. Pediatrics 2006;117:1253-61. Stephens BE, Walden RV, Gargus RA, Tucker R, McKinley L, Mance M, et al. First-week protein and energy intakes are associated with 18-month developmental outcomes in extremely low birth weight infants. Pediatrics 2009;123:1337-43. Hair AB, Hawthorne KM, Chetta KE, Abrams SA. Human milk feeding supports adequate growth in infants
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Figure 1. CONSORT flow diagram.
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