Clinical Experience with a New, Non-Acidified Liquid Human Milk Fortifier in Very Low Birth Weight Infants.

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Fernando Moya, Jennifer Fowler, Adrian Florens, Kirsten Frank, and 4 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-4331662/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Objective To compare nutritional outcomes among infants receiving a new non-acidified liquid human milk fortifier (NALHMF) or an acidified liquid human milk fortifier (ALHMF). Study Design: Retrospective, multicenter study including 515 VLBW infants. Primary outcome was growth velocity during fortification. Student’s t, ANOVA, Wilcoxon, and Kruskal-Wallis tests were used for numeric variables, or, chi-squared and Fisher’s exact test for categorical variables. Growth velocity between groups was compared with repeated measures regression. Results 242 and 273 infants received ALHMF and NALHMF, respectively, with no demographic differences between the groups. Growth velocity during fortification was significantly higher in the group receiving NALHMF, despite similar total fluid or calorie intake. Metabolic acidosis was diagnosed less frequently with the NALHMF, with marked differences between centers. Conclusion Fortification of human milk using the new NALHMF resulted in faster growth velocity during fortification and less metabolic acidosis compared with feeding human milk fortified with an ALHMF. Health sciences/Medical research/Outcomes research Health sciences/Health care/Paediatrics Figures Figure 1 Figure 2 Introduction Human milk is the preferred source of nutrition to feed all infants (1). Nowadays, most preterm infants receive their mother’s own milk (MOM) or donor human milk (DHM) as their main source of feeding (2). It has been shown that the protein content of human milk as well as that of other nutrients may not be sufficient to meet the higher nutritional requirements of preterm infants, especially those of VLBW (3). The American Academy of Pediatrics and other organizations, therefore, recommend adding specifically designed fortifiers to either MOM or DHM to promote better growth (4,5). Implementing best feeding practices for VLBW infants may help with reducing short and long-term consequences of poor growth. Currently available fortifiers can be of human or bovine origin and have been in use for several decades. These fortifiers have been studied extensively, and there is insufficient evidence to support the choice of human milk-based fortifiers over bovine milk-derived products (6–9). For about a decade, bovine derived fortifiers have come in liquid form and their composition has been adjusted to increase their protein content and add long-chain polyunsaturated fatty acids (10,11). A better understanding of many of the macro- and micronutrients found in human milk has also resulted in other modifications of these fortifiers to improve their ability to support nutrition and growth of preterm infants (3,12). Recently, a new, non-acidified liquid human milk fortifier became available (NALHMF, Reckitt-Mead Johnson Nutrition, Evansville, IN). This new fortifier differs from its previous formulation in some of its components and comes in two preparations with different protein content, namely High Protein or Standard Protein (Table 1 ). However, one of the most important changes is the utilization of a process to maintain sterility that does not involve acidifying its content as it was previously done. To date there are no reports of clinical experiences with this fortifier compared with a population of VLBW infants who received the previous acidified liquid human milk fortifier from the same manufacturer (ALHMF). Therefore, we decided to compare relevant nutritional outcomes in a population of VLBW infants receiving these fortifiers. Table 1 Macro and micro-nutrient composition of the fortifiers under study* ALHMF NALHMF High Protein and (Standard) Total Calories 100 100 Protein, g 4 4 (3.4) Carbohydrate 8.1 7.9 (8.7) Fat, g 6 6 DHA, mg 24 24 ARA, mg 38 38 Calcium, mg 145 145 Phosphorus, mg 80 80 Sodium, mg 57 57 Iron, mg 1.91 1.9 Zinc, mg 1.37 1.37 Vitamin A, IU 1250 1240 Vitamin D, IU 210 210 Vitamin E, IU 6.2 6.2 Potassium, mg 98 98 Magnesium, mg 5.3 5.3 Osmolality, mOsm/kg H2O 336 350 (330) pH 4.7 6 *Per 100 Kcal of fortified preterm human milk fortified to 24 Kcal/ounce. Values in parenthesis reflect those in the Standard fortifier preparation. Abbreviations, HMF: human milk fortifier, DHA: docosahexaenoic acid, ARA: arachidonic acid. Methods We conducted a retrospective study in three Neonatal Intensive Care Units (NICU’s), two in North Carolina and one in Florida. The institutional review boards at each institution approved the study and exempted it from acquiring informed consent. All three NICU’s initiated the use of the new NALHMF during 2020 or 2021. Previously, all NICU’s had utilized the ALHMF of the same manufacturer. These fortifiers were used per manufacturer’s recommendations. One center’s feeding protocol (in FL) included using initially in infants below 32 weeks’ gestation Prolacta human donor milk (20 Kcal/oz, Prolacta Bioscience, Duarte, CA), if mother’s own milk was unavailable. In this center, fortification was done at first with Prolacta human milk fortifier and progressed to the bovine fortifier past 30–32 weeks of corrected gestational age. We used a convenience sample of infants who received the NALHMF during one full year after its initiation at each center. For comparison, we collected data from infants who received the ALHMF for a similar period of time before switching to the new preparation. We allowed a period of three months between the change from the ALHMF to the NALHMF to avoid collecting data from infants who may have received both. The entry criteria for the study were as follows: 1) gestational age ≤ 32 weeks, 2) birth weight ≤ 1500 g, 3) receiving mother’s own or donor milk (no formula), 4) enteral intake > 80 ml/kg/d. Exclusion criteria were: a) intake of any formula or fortified breast milk using a bovine derived fortifier prior to study entry, b) diagnosis of a significant chromosomal abnormality or a condition incompatible with progressive enteral feeding, c) significant depression after delivery (Apgar score < 4 at 5 minutes), d) use of pharmacologic doses of corticosteroids within 3 days prior to starting fortification, e) undergoing fluid restriction (fluid intake < 120 ml/kg/d) at start of fortification, f) use of probiotics. These entry and exclusion criteria were chosen since they were used in previous controlled trials of fortifiers that recruited a relatively similar population (10,11,13). Moreover, by choosing a population of VLBW infants, there would be a period of fortification long enough to potentially identify differences in clinical outcomes between the fortifiers under study. Data were abstracted from medical records into deidentified case report forms. Total fluid intake, concomitant medications and laboratory values were recorded. Total calories and protein intake were estimated by adding the actual intake in parenteral nutrition (if still receiving it) plus the estimated intake in MOM or DHM, including anything added by the fortifiers. Whereas the exact proportion of MOM versus DHM used daily was not consistently documented, whenever DHM was listed as being fed, calculations used an estimated protein intake of 0.9 g/dL if DHM was given, or 1.1 g/dL if MOM was fed. When both were used, estimations assumed that they were mixed in approximately equal proportions. The Z scores for weight, length and head circumference were determined using the Fenton growth curves (14). Feeding intolerance was defined as stopping feeding for more than 8 hours on any given day (10). This was assessed and reported by week of fortification and any one infant could have experienced feeding intolerance in different weeks of fortification. Metabolic acidosis was diagnosed when there was a serum bicarbonate < 18 mEq/L or a base deficit below − 6 in an electrolyte or blood gas determination obtained during fortification (10,13). Also, whether this was addressed by stopping/modifying fortification or with the use of a therapeutic agent was consigned. Late onset sepsis was diagnosed if the infant had positive blood cultures that were not deemed a contaminant and the infant received antibiotic treatment for more than 2 days. Necrotizing enterocolitis was recorded when infants had a confirmed stage II or higher using Bell’s criteria (15). All three centers used their own feeding guidelines/protocols. In brief, all of them began with a variable period of “trophic feeds” between 10–30 ml/kg/d of either MOM or DHM. In one center (in FL), Prolacta (20 cal/oz) was used to begin “trophic feeds”. These were subsequently advanced after 2–3 days by 20–30 ml/kg/d and fortification was started when an enteral intake of 80–100 ml/kg/d was reached. If Prolacta had been supplied, this was switched to either ALHMF or NALHMF after about 7 days of use or at 32 weeks corrected gestational age. Administration of parenteral nutrition and lipid emulsions was generally stopped in all three centers when infants reached an enteral intake of about 100–120 ml/kg/d. Demographic characteristics are reported as median and 25th -75th interquartile ranges. Other data are reported as indicated. Comparison between groups were done using Student’s t, ANOVA, Wilcoxon, and Kruskal-Wallis tests where applicable for numeric variables; chi-squared and Fisher’s exact test were used where appropriate for categorical variables. A repeated measures regression (using lme4 in R) was used to compare growth velocity between groups only including infants who received either fortifier throughout the first 4 weeks of treatment (N = 308). Gestational age, fortifier group, location, and gender were incorporated into the model. Results A total of 515 infants were included. There were significant differences in multiple demographic variables between infants from each center as shown in Table 2 . However, when infants from all centers were combined into those receiving the ALHMF or NALHMF, there were no significant differences between groups (Table 3 ). Infants in the study were on average about 28–29 weeks of gestational age and between 1100–1200 grams birth weight. About 12% in either group were growth restricted. On average, infants included in the study received about 6–8 days of parenteral nutrition (PN), enteral feeds began at around 3 days after birth and fortification was generally started 7 or more days after birth, although in one center feedings and fortification were started much sooner (Table 2 ). Donor human milk was used in about 2/3 of the infants in either group. In one of the NICU’s (Florida site) 53% and 56% of infants from the ALHMF and NALHMF groups, respectively, received Prolacta before switching to the bovine-derived fortifiers under study as described in Methods. Table 2 Demographic characteristics of infants from each center Betty Cameron Palm Beach East Carolina p N 179 92 244 Sex (%) Female 86 (48.0) 44 (47.8) 141 (57.8) 0.076 Male 93 (52.0) 48 (52.2) 103 (42.2) Birth Weight, g (median [IQR]) 1108 [910, 1290] 1152 [970, 1320] 1004 [814, 1253] 0.002 Birth Length, cm (median [IQR]) 37.00 [33.00, 38.50] 37.00 [35.00, 39.00] 36.00 [32.50, 38.00] 0.01 Birth FOC, cm (median [IQR]) 25.70 [24.00, 27.35] 26.25 [25.00, 27.12] 25.00 [23.00, 26.50] < 0.001 Gest. Age, weeks (median [IQR]) 28.5 [26.4, 30.2] 29.0 [27.5, 30.0] 28.3 [26.4, 30.0] 0.056 Birth Type (%) Single 143 (79.9) 62 (67.4) 195 (79.9) 0.033 Twin 36 (20.1) 30 (32.6) 49 (20.1) APGAR at 5 min (median [IQR]) 8.00 [7.00, 9.00] 8.00 [8.00, 9.00] 7.00 [6.00, 8.00] < 0.001 Delivery Type (%) C-Section 136 (76.0) 74 (80.4) 196 (80.3) 0.511 Donor Milk Used (%) No 59 (33.0) 31 (33.7) 97 (39.8) 0.302 Yes 120 (67.0) 61 (66.3) 147 (60.2) Day when birth weight regained (median [IQR]) 8.0 [6.0, 10.0] 8.0 [6.0, 10.5] 9.0 [7.0, 13.0] 0.002 Day when nutritive* enteral feeds started (median [IQR]) 7.0 [5.0, 9.0] 4.0 [3.0, 5.0] 1.0 [1.0, 2.0] < 0.001 Days of PN received before study day 0 (median [IQR]) 8.5 [7.0, 12.7] 9.0 [7.0, 11.0] 5.0 [5.0, 6.0] < 0.001 Days of age at start of bovine fortification** (median [IQR]) 10.0 [7.0, 14.0] 14.0 [10.75, 23.00] 6.00 [5.00, 7.00] < 0.001 *Enteral feeds after “trophic feeds”. Table 3 Demographic characteristics of infants receiving either fortifier ALHMF NALHMF p N 242 273 Sex (%) Female 116 (47.9) 154 (56.4) 0.06 Male 126 (52.1) 119 (43.6) Birth Weight, g (median [IQR]) 1100 [870, 1280] 1070 [870, 1270] 0.65 Birth Length, cm (median [IQR]) 36.0 [33.0, 38.5] 36.5 [33.5, 38.5] 0.54 Birth FOC, cm (median [IQR]) 25.5 [23.5, 27.0] 25.5 [24.0, 27.0] 0.79 Gestational Age, weeks (median [IQR]) 28.6 [26.4, 30.2] 28.5 [27.0, 30.0] 0.91 Birth Type (%) Single 182 (75.2) 218 (79.9) 0.24 Twin 60 (24.8) 55 (20.1) APGAR at 5 min (median [IQR]) 8.0 [7.0, 8.0] 8.0 [7.0, 8.0] 0.30 Delivery Type N (%) C-Section 185 (76.4) 221 (81.0) 0.25 Vaginal 57 (23.6) 52 (19.0) Donor Milk Used N (%) No 81 (33.5) 106 (38.8) 0.24 Yes 161 (66.5) 167 (61.2) Day when nutritive enteral feeds started (median [IQR]) 3.0 [1.0, 6.0] 3.0 [1.0, 6.0] 0.96 Days of PN received before study day 0 (median [IQR]) 6.0 [5.0, 9.0] 6.0 [5.0, 9.0] 0.32 Days of age at fortification (median [IQR]) 7.0 [6.0, 12.0] 7.0 [6.0, 12.0] 0.58 The proportion of infants receiving fortification decreased progressively over time and was not different between groups. About 93–96% of infants were getting fortified milk two weeks after starting this process; this proportion decreased to between 78–88% at three weeks and between 55–68% at four weeks. Thereafter, fewer infants in either group received fortified human milk (one center stopped using DHM after 30 days). Total fluid intake did not differ between groups at the start or during the several weeks of fortification (Fig. 1 A). The median protein intake before fortification started was about 2.7 g/kg/d in both groups and increased afterwards. Subsequently, there were small but significant differences in total protein intake favoring the ALHMF group at 1, 2 and 3 weeks of fortification (Fig. 1 B). A few infants had markedly high protein intakes primarily due to large intake volumes, especially after getting fortification for more than two weeks. There was only a marginal significant difference in overall caloric intake between groups before fortification started (Fig. 1 C). Growth velocity at 2, 3 and 4 weeks of fortification was significantly higher in the group receiving NALHMF (Fig. 2 A). This group also exhibited a higher growth velocity at 5 weeks of fortification, but the proportion of infants in either group getting fortified human milk had dropped markedly. When growth velocity was compared among infants that received either fortifier for all 4 weeks (N = 308) using a regression model including gestational age, fortifier group, location, and gender, the effect of NALHMF was still significant (2.15, CI 0.89–3.42 g/kg/d). Z scores for weight, length and head circumference decreased comparably over time in both groups, although at 4 weeks of fortification the decrease in weight Z scores was slightly more pronounced in the ALHMF group (Fig. 2 B). Feeding intolerance was relatively uncommon and occurred in equal proportion within each week of fortification using either product (week 1 ALHMF = 3%, NALHMF = 4%; week 2 ALHMF = 8%, NALHMF = 6%; week 3 ALHMF = 5%, NALHMF = 5% and week 4 ALHMF = 2%, NALHMF = 3%). Overall, metabolic acidosis was diagnosed less frequently in the group receiving the NALHMF. The diagnosis of metabolic acidosis decreased in all centers; however, there were marked discrepancies within centers in the proportion of infants with this abnormality (Table 4 ). Most of those infants diagnosed with metabolic acidosis were treated with either discontinuation of fortification or administering sodium citrate with rapid resolution. Table 4 Metabolic acidosis (serum bicarb. <18 mEq/L or base deficit below − 6) Betty Cameron Children’s Hospital ALHMF NALHMF p N 88 91 Acidosis Diagnosed (%) No 67 (76.1) 77 (84.6) 0.21 Yes 21 (23.9) 14 (15.4) Palm Beach Children’s Hospital N 42 50 Acidosis Diagnosed (%) No 33 (78.6) 49 (98.0) 0.008 Yes 9 (21.4) 1 (2.0) East Carolina Health N 113 131 Acidosis Diagnosed (%) No 32 (28.3) 53 (40.5) 0.064 Yes 81 (71.7) 78 (59.5) Total No 132 (54.3) 179 (65.8) Yes 111 (45.7) 93 (34.2) 0.010 Although all values favored the NALHMF group, there were no significant differences in median [25–75% IQ] length of stay (ALHMF 68 [48, 91] days, NALHMF 66 [48, 54] days) or corrected gestational age at discharge (ALHMF 38.5 [37.0, 40.6] weeks, NALHMF 38.1 [36.4, 40.5] weeks). Likewise, discharge median [25–75% IQ] for weight, length and head circumference were similar between groups (2670 [2286, 3173] grams vs. 2635 [2302, 3170] grams; 45.6 [43.5, 47.5] cm vs. 45.1 [43.5, 47.0] cm; 33.0 [31.5, 34.5] cm vs. 33.0 [31.5, 34.5] cm, for the ALHMF and NALHMF groups, respectively). Culture proven sepsis was diagnosed in 9.8% and 8.7% of infants in the ALHMF and NALHMF groups, respectively. Also, confirmed NEC was uncommon in both groups (ALHMF 5.7%, NALHMF 4.7%). Discussion Fortification of human milk is critical to ensure that VLBW infants receive an appropriate intake of protein and other nutrients needed for optimal growth (3–5). Currently, there are several commercially available fortifiers of human or bovine milk origin in liquid or powder form, which vary in their nutrient composition (8). At present, the evidence does not support better outcomes with human milk-derived fortifiers over bovine products (9,19). This notwithstanding, it is very important to examine clinical outcomes, particularly growth, among populations of infants receiving these fortifiers. In this study we report growth outcomes in a large population of VLBW infants exposed to a new bovine-derived fortifier and compared them to those observed among infants receiving a previous formulation of this fortifier. For this retrospective evaluation we used entry criteria that were quite similar to previous controlled trials of bovine-derived fortifiers (10,11,13). Also, we examined these outcomes in three NICU’s from separate regions, managed by different providers. This real-world approach could enhance the generalizability of our findings. There were significant albeit small differences in many demographic characteristics between infants enrolled at the three participating centers; perhaps the most striking being the median days of age when fortification was initiated where one center added fortification many days before the other two NICUs (Table 2 ). This is probably a reflection of each NICU’s feeding guidelines and the lack of a widely accepted approach to nutritional support. However, when infants from all three NICUs were grouped according to which fortifier they received, the groups were comparable. Only gender approximated significance, and therefore, this variable was incorporated into regression models. As anticipated and reflecting current practice, the majority of VLBW infants received fortified MOM or DHM for several weeks (2). Whereas we could not consistently retrieve the exact amount of DHM used each day, the proportion of infants receiving DHM was similar between groups when all three NICUs were compared separately, or once grouped according to the fortifier received. Likewise, in the NICU that utilized Prolacta to initiate feedings, the proportion of infants in the ALHMF and NALHMF groups that received Prolacta was similar. Donor milk use in infants in our study is well within what has been reported in other recent studies (7,13,17). Moreover, the proportion of infants that received fortification for 4 weeks is quite similar to what has been reported previously in clinical trials of bovine-derived fortifiers (10,13). Growth velocity was higher among infants receiving the new NALHMF during the first several weeks of fortification. This benefit seemed to persist beyond 4 weeks of fortification; however, there was considerable attrition in the number of infants still receiving either fortifier past this time. In addition, when growth velocity was compared only among those infants that received either fortifier for 4 weeks, an outcome reported in several previous fortifier studies (10,11,13), the group receiving NALHMF still had a greater growth velocity in weight. This advantage in weight gain was also suggested by comparing Z scores, since the usual decrease in weight Z scores observed in VLBW infants during their NICU stay was less pronounced in those fed the new fortifier. Better weight gain was seen despite similar intakes of total fluids and calories between both groups, although overall protein intake was higher among infants fed the ALHMF. We focused mainly on weight gain because measurements of length can be variable if not using length boards. This was the case in one of our NICUs. Growth velocity in both groups, but particularly in the NALHMF group approximated that reported in recent controlled trials of bovine-based fortifiers and appears to be higher than growth velocity seen when human milk-derived fortifiers are used (10,11, 13, 17, 18). The reasons why growth velocity was higher among infants receiving the NALHMF are unclear. This could not be attributed to a different intake of volume or energy since these did not differ between groups during fortification. However, there was a higher protein intake in the group receiving the ALHMF whereby excess protein may have led to slower growth and more metabolic acidosis (see below). Also, feeding intolerance was not a factor since it was reported with similar frequency in either group. A potential explanation may also relate to the occurrence of metabolic acidosis. We chose a threshold to diagnose this abnormality that has been used before, although the clinical significance of it remains unclear since other studies have utilized a much lower threshold of bicarbonate or base deficit to diagnose metabolic acidosis, or have not reported it at all (7,11,13,17,20). Nonetheless, the presence of metabolic acidosis has been associated with slower growth and a longer length of stay (13,21,22). In our study, there were marked differences in the diagnosis of metabolic acidosis, with one center reporting it between 3 to 7 times more frequently than the other two NICUs. Infants from this NICU were on average a few days less mature and weighed a fraction less at birth than the other groups. Even though this could be a contributing factor, it is unlikely to have played a major role in the pathogenesis of metabolic acidosis. Perhaps the most meaningful differences identified in this center were a shorter interval of exposure to parenteral nutrition and a much earlier initiation of enteral feeds and fortification. Metabolic acidosis is common among preterm infants and relates, in part, to protein intake and renal maturation (21,24). Neonatologists often add early in the NICU course acetate salts to parenteral nutrition or umbilical arterial solutions to buffer any decrease in pH and base deficit observed in preterm infants. Therefore, it is possible that attempts to aggressively nourish these infants enterally early on and shortening the days of parenteral nutrition may have translated into more metabolic acidosis or a serum bicarbonate level below 18 mEq/L. Several reports have associated the use of the ALHMF with metabolic acidosis (25–28), which may also be associated to a higher protein intake as seen in the ALHMF group in our study. This notwithstanding, the frequency of metabolic acidosis was significantly lower with the NALHMF than the ALHMF and decreased in all three centers. This decreased to about 10% of infants in two of the three centers with use of the NALHMF, which is a frequency of metabolic acidosis commonly reported among infants getting human milk fortifiers (13,20,29). A recent experimental study demonstrated that there are minimal drops in the pH of human milk with the addition of the NALHMF, which is unlikely to be a contributing factor to the pathogenesis of metabolic acidosis among infants receiving this fortifier (30). Even though there was a trend towards a shorter length of stay and earlier corrected gestational age at discharge, these differences were not significant. Several other studies have failed to show advantages in these outcomes with fortification. This is not surprising given that the decision to discharge an infant depends on many factors and not only on their nutritional/growth status. Furthermore, no differences in anthropometrics at discharge between groups were identified. This suggests that any growth advantage observed during fortification may no longer be observed once this stops or is modified (10,11,29). Likewise, no differences were observed in late onset sepsis or NEC. Both these complications occurred with relatively low frequency as one might expect in a stable population of VLBW infants receiving human milk as their main source of nutrition (7,10,11,13,17,20). In summary, among VLBW infants, fortification of human milk using the new NALHMF resulted in faster growth velocity during fortification, less metabolic acidosis and similar tolerance and other morbidities compared with feeding human milk fortified with an ALHMF. Declarations Conflict of Interest Fernando Moya, Jennifer Fowler, Adrian Florens and Kirsten Frank are part of Reckitt Mead Johnson Nutrition Speaker’s Bureau. Funding This study was funded by an unrestricted research grant from Reckitt Mead Johnson Nutrition. The investigators designed the study, collected, and analyzed all data independently from the funding organization. Reckitt Mead Johnson Nutrition had no input on conducting the study and writing the final manuscript. Author Contributions: FM designed the study, analyzed the data and helped to write the manuscript. JF collected the data and helped to write the manuscript. AF collected the data and helped to write the manuscript. KF collected the data and helped to write the manuscript. JD collected the data and helped to write the manuscript. OD collected the data and helped to write the manuscript. TF collected the data and helped to write the manuscript. AG analyzed the data and helped to write the manuscript. 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Lainwala S, Kosyakova N, Spizzoucco AM, Herson V, Brownell EA. Clinical and nutritional outcomes of two liquid human milk fortifiers for premature infants. J Neonatal Perinatal Med. 2017; 10: 393-401. Cordova EG, Soldateli B, Rosner B, Drouin K, Davitt E, Pepin H et al. Growth and clinical outcomes of very low-birth-weight infants receiving acidified vs nonacidified liquid human milk fortifiers. Nutr Clin Pract. 2021; 36: 1304-1311. Darrow CJ, Bai-Tong SS, Kang EM, Thompson CL, Walsh MC. Use of acidified versus non-acidified liquid human milk fortifier in very low birth weight infants: a retrospective comparison of clinical outcomes. J Neonatal Perinatal Med. 2020; 13: 71-79. Thoene M, Lyden E, Weishaar K, Elliot E, Wu R, White K et al. Comparison of a powdered, acidified liquid, and non-acidified liquid human milk fortifier on clinical outcomes in premature infants. Nutrients. 2016; 8: 451. Salas A, Gunagam E, Nguyen K, Reeves A, Argent V, Finck A et al. Early human milk fortification in infants born extremely preterm: A randomized trial. Pediatrics 2023; 152: e2023061603. Pineda D, Bingham R, Gates A, Thompson AB, Stansfield BK. Acid/base balance in fortified donor human milk: an experimental study. J Parenter Enteral Nutr. 2023; 47: 904-910. Additional Declarations Yes there is potential conflict of interest. Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-4331662","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Article","associatedPublications":[],"authors":[{"id":296973592,"identity":"57f44110-0764-4ca3-b4f1-405f10a85686","order_by":0,"name":"Fernando Moya","email":"data:image/png;base64,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","orcid":"","institution":"Betty Cameron Children's Hospital","correspondingAuthor":true,"prefix":"","firstName":"Fernando","middleName":"","lastName":"Moya","suffix":""},{"id":296973593,"identity":"d0629562-9c68-4803-ad96-800ab26fb433","order_by":1,"name":"Jennifer Fowler","email":"","orcid":"","institution":"ECU Health","correspondingAuthor":false,"prefix":"","firstName":"Jennifer","middleName":"","lastName":"Fowler","suffix":""},{"id":296973594,"identity":"d1d40d6e-8142-49b5-9985-2512eae53a60","order_by":2,"name":"Adrian Florens","email":"","orcid":"","institution":"Palm Beach Children's Hospital","correspondingAuthor":false,"prefix":"","firstName":"Adrian","middleName":"","lastName":"Florens","suffix":""},{"id":296973595,"identity":"c3cbe037-79c7-4953-84f1-aa6df988750a","order_by":3,"name":"Kirsten Frank","email":"","orcid":"","institution":"Novant New Hanover Regional Medical Center","correspondingAuthor":false,"prefix":"","firstName":"Kirsten","middleName":"","lastName":"Frank","suffix":""},{"id":296973596,"identity":"df6a159e-142c-4922-b6ec-d12ec580cda3","order_by":4,"name":"Jennifer Dombrowski","email":"","orcid":"","institution":"Palm Beach Children's Hospital","correspondingAuthor":false,"prefix":"","firstName":"Jennifer","middleName":"","lastName":"Dombrowski","suffix":""},{"id":296973597,"identity":"e089bf9e-fdf2-4ca1-93bc-4b091a106146","order_by":5,"name":"Olivia Davis","email":"","orcid":"","institution":"Palm Beach Children's Hospital","correspondingAuthor":false,"prefix":"","firstName":"Olivia","middleName":"","lastName":"Davis","suffix":""},{"id":296973598,"identity":"87e31e9c-7ef7-4486-82af-58b182f8c420","order_by":6,"name":"Tiffony Blanks","email":"","orcid":"","institution":"Betty Cameron Children's Hospital","correspondingAuthor":false,"prefix":"","firstName":"Tiffony","middleName":"","lastName":"Blanks","suffix":""},{"id":296973599,"identity":"638a7c33-702b-4a92-9fd8-670c9924f07e","order_by":7,"name":"Austin Gratton","email":"","orcid":"","institution":"Novant New Hanover Regional Medical Center","correspondingAuthor":false,"prefix":"","firstName":"Austin","middleName":"","lastName":"Gratton","suffix":""}],"badges":[],"createdAt":"2024-04-26 21:45:36","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-4331662/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-4331662/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":56040431,"identity":"db2c01ee-7f5e-458a-8f70-9acbe81c67bf","added_by":"auto","created_at":"2024-05-07 19:16:04","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":188039,"visible":true,"origin":"","legend":"\u003cp\u003e1A: Total fluid intake over the first four weeks of fortification for the groups receiving ALHMF (blue) or NALHMF (light blue) `shown as median and 25-75 IQR, vertical lines represent the range. The total N per week of fortification is shown in the X axis. There were no significant differences.\u003c/p\u003e\n\u003cp\u003e1B: Total protein intake over the first four weeks of fortification for the groups receiving ALHMF (blue) or NALHMF (light blue) shown as median and 25-75 IQR, vertical lines represent the range. The total N per week of fortification is shown in the X axis. Significant differences in acidified vs. non-acidified (median [IQR]): Week 1, 3.80 [3.53, 4.08] vs. 3.63 [3.38, 3.90], p-value \u0026lt;0.001; Week 2, 4.22 [3.95, 4.43] vs. 4.10 [3.75, 4.40], p-value 0.015; Week 3, 4.30 [4.00, 4.50] vs. 4.16 [3.80, 4.40], p-value 0.006.\u003c/p\u003e\n\u003cp\u003e1C: Total calorie intake over the first four weeks of fortification for the groups receiving ALHMF (blue) or NALHMF (light blue) shown as median and 25-75 IQR, vertical lines represent the range. The total N per week of fortification is shown in the X axis. Significant differences in acidified vs. non-acidified (median [IQR]): Before fortification, 97.0 [89.00, 106.2] vs. 99.05 [92.12, 108.77], p-value 0.017.\u003c/p\u003e","description":"","filename":"1.png","url":"https://assets-eu.researchsquare.com/files/rs-4331662/v1/530b1fb137f5e2aae0098c8b.png"},{"id":56040430,"identity":"8d367bd6-e531-402b-805b-3e2fcdb570b0","added_by":"auto","created_at":"2024-05-07 19:16:04","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":144857,"visible":true,"origin":"","legend":"\u003cp\u003e2A:\u003cstrong\u003e \u003c/strong\u003eGrowth rate over the study period calculated with the exponential method.\u003c/p\u003e\n\u003cp\u003eComparisons of the growth velocity regression lines for the ALHMF (blue) and NALHMF (light blue) groups were done using a repeated measures regression (using lme4 in R) only including infants who received either fortifier throughout the first 4 weeks of treatment (N = 308). Gestational age, fortifier group, location, and gender were incorporated into the model.\u003c/p\u003e\n\u003cp\u003e2B:\u003cstrong\u003e \u003c/strong\u003eChanges in weight Z score over time for the groups receiving ALHMF (blue) or NALHMF (light blue) shown as median and 25-75 IQR, vertical lines represent the range. No significant differences were identified. SOF= Start of fortification\u003c/p\u003e","description":"","filename":"2.png","url":"https://assets-eu.researchsquare.com/files/rs-4331662/v1/6a58f7bf7d91c779c2b252f7.png"},{"id":57489104,"identity":"c2d3a4a1-5885-4b03-9684-02b9df3c1a4e","added_by":"auto","created_at":"2024-05-31 10:59:15","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":860307,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-4331662/v1/f66653d7-e272-45fd-b622-40bc51f63a18.pdf"}],"financialInterests":"\u003cb\u003eYes\u003c/b\u003e there is potential conflict of interest.","formattedTitle":"Clinical Experience with a New, Non-Acidified Liquid Human Milk Fortifier in Very Low Birth Weight Infants.","fulltext":[{"header":"Introduction","content":"\u003cp\u003eHuman milk is the preferred source of nutrition to feed all infants (1). Nowadays, most preterm infants receive their mother\u0026rsquo;s own milk (MOM) or donor human milk (DHM) as their main source of feeding (2). It has been shown that the protein content of human milk as well as that of other nutrients may not be sufficient to meet the higher nutritional requirements of preterm infants, especially those of VLBW (3). The American Academy of Pediatrics and other organizations, therefore, recommend adding specifically designed fortifiers to either MOM or DHM to promote better growth (4,5). Implementing best feeding practices for VLBW infants may help with reducing short and long-term consequences of poor growth. Currently available fortifiers can be of human or bovine origin and have been in use for several decades. These fortifiers have been studied extensively, and there is insufficient evidence to support the choice of human milk-based fortifiers over bovine milk-derived products (6\u0026ndash;9). For about a decade, bovine derived fortifiers have come in liquid form and their composition has been adjusted to increase their protein content and add long-chain polyunsaturated fatty acids (10,11). A better understanding of many of the macro- and micronutrients found in human milk has also resulted in other modifications of these fortifiers to improve their ability to support nutrition and growth of preterm infants (3,12).\u003c/p\u003e \u003cp\u003eRecently, a new, non-acidified liquid human milk fortifier became available (NALHMF, Reckitt-Mead Johnson Nutrition, Evansville, IN). This new fortifier differs from its previous formulation in some of its components and comes in two preparations with different protein content, namely High Protein or Standard Protein (Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e). However, one of the most important changes is the utilization of a process to maintain sterility that does not involve acidifying its content as it was previously done. To date there are no reports of clinical experiences with this fortifier compared with a population of VLBW infants who received the previous acidified liquid human milk fortifier from the same manufacturer (ALHMF). Therefore, we decided to compare relevant nutritional outcomes in a population of VLBW infants receiving these fortifiers.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eMacro and micro-nutrient composition of the fortifiers under study*\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"3\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eALHMF\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eNALHMF\u003c/p\u003e \u003cp\u003eHigh Protein and (Standard)\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTotal Calories\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e100\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e100\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eProtein, g\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e4 (3.4)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCarbohydrate\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e8.1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e7.9 (8.7)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eFat, g\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e6\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDHA, mg\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e24\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e24\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eARA, mg\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e38\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e38\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCalcium, mg\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e145\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e145\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePhosphorus, mg\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e80\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e80\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSodium, mg\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e57\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e57\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eIron, mg\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1.91\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1.9\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eZinc, mg\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1.37\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1.37\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eVitamin A, IU\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1250\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1240\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eVitamin D, IU\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e210\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e210\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eVitamin E, IU\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e6.2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e6.2\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePotassium, mg\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e98\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e98\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMagnesium, mg\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e5.3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e5.3\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eOsmolality, mOsm/kg H2O\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e336\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e350 (330)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003epH\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e4.7\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e6\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"3\"\u003e*Per 100 Kcal of fortified preterm human milk fortified to 24 Kcal/ounce. Values in parenthesis reflect those in the Standard fortifier preparation. Abbreviations, HMF: human milk fortifier, DHA: docosahexaenoic acid, ARA: arachidonic acid.\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e"},{"header":"Methods","content":"\u003cp\u003e We conducted a retrospective study in three Neonatal Intensive Care Units (NICU\u0026rsquo;s), two in North Carolina and one in Florida. The institutional review boards at each institution approved the study and exempted it from acquiring informed consent. All three NICU\u0026rsquo;s initiated the use of the new NALHMF during 2020 or 2021. Previously, all NICU\u0026rsquo;s had utilized the ALHMF of the same manufacturer. These fortifiers were used per manufacturer\u0026rsquo;s recommendations. One center\u0026rsquo;s feeding protocol (in FL) included using initially in infants below 32 weeks\u0026rsquo; gestation Prolacta human donor milk (20 Kcal/oz, Prolacta Bioscience, Duarte, CA), if mother\u0026rsquo;s own milk was unavailable. In this center, fortification was done at first with Prolacta human milk fortifier and progressed to the bovine fortifier past 30\u0026ndash;32 weeks of corrected gestational age. We used a convenience sample of infants who received the NALHMF during one full year after its initiation at each center. For comparison, we collected data from infants who received the ALHMF for a similar period of time before switching to the new preparation. We allowed a period of three months between the change from the ALHMF to the NALHMF to avoid collecting data from infants who may have received both.\u003c/p\u003e \u003cp\u003eThe entry criteria for the study were as follows: 1) gestational age\u0026thinsp;\u003cspan type=\"Underline\" class=\"Underline\" name=\"Emphasis\"\u003e\u0026le;\u003c/span\u003e\u0026thinsp;32 weeks, 2) birth weight\u0026thinsp;\u003cspan type=\"Underline\" class=\"Underline\" name=\"Emphasis\"\u003e\u0026le;\u003c/span\u003e\u0026thinsp;1500 g, 3) receiving mother\u0026rsquo;s own or donor milk (no formula), 4) enteral intake\u0026thinsp;\u0026gt;\u0026thinsp;80 ml/kg/d. Exclusion criteria were: a) intake of any formula or fortified breast milk using a bovine derived fortifier prior to study entry, b) diagnosis of a significant chromosomal abnormality or a condition incompatible with progressive enteral feeding, c) significant depression after delivery (Apgar score\u0026thinsp;\u0026lt;\u0026thinsp;4 at 5 minutes), d) use of pharmacologic doses of corticosteroids within 3 days prior to starting fortification, e) undergoing fluid restriction (fluid intake\u0026thinsp;\u0026lt;\u0026thinsp;120 ml/kg/d) at start of fortification, f) use of probiotics. These entry and exclusion criteria were chosen since they were used in previous controlled trials of fortifiers that recruited a relatively similar population (10,11,13). Moreover, by choosing a population of VLBW infants, there would be a period of fortification long enough to potentially identify differences in clinical outcomes between the fortifiers under study. Data were abstracted from medical records into deidentified case report forms. Total fluid intake, concomitant medications and laboratory values were recorded. Total calories and protein intake were estimated by adding the actual intake in parenteral nutrition (if still receiving it) plus the estimated intake in MOM or DHM, including anything added by the fortifiers. Whereas the exact proportion of MOM versus DHM used daily was not consistently documented, whenever DHM was listed as being fed, calculations used an estimated protein intake of 0.9 g/dL if DHM was given, or 1.1 g/dL if MOM was fed. When both were used, estimations assumed that they were mixed in approximately equal proportions. The Z scores for weight, length and head circumference were determined using the Fenton growth curves (14). Feeding intolerance was defined as stopping feeding for more than 8 hours on any given day (10). This was assessed and reported by week of fortification and any one infant could have experienced feeding intolerance in different weeks of fortification. Metabolic acidosis was diagnosed when there was a serum bicarbonate\u0026thinsp;\u0026lt;\u0026thinsp;18 mEq/L or a base deficit below \u0026minus;\u0026thinsp;6 in an electrolyte or blood gas determination obtained during fortification (10,13). Also, whether this was addressed by stopping/modifying fortification or with the use of a therapeutic agent was consigned. Late onset sepsis was diagnosed if the infant had positive blood cultures that were not deemed a contaminant and the infant received antibiotic treatment for more than 2 days. Necrotizing enterocolitis was recorded when infants had a confirmed stage II or higher using Bell\u0026rsquo;s criteria (15).\u003c/p\u003e \u003cp\u003e All three centers used their own feeding guidelines/protocols. In brief, all of them began with a variable period of \u0026ldquo;trophic feeds\u0026rdquo; between 10\u0026ndash;30 ml/kg/d of either MOM or DHM. In one center (in FL), Prolacta (20 cal/oz) was used to begin \u0026ldquo;trophic feeds\u0026rdquo;. These were subsequently advanced after 2\u0026ndash;3 days by 20\u0026ndash;30 ml/kg/d and fortification was started when an enteral intake of 80\u0026ndash;100 ml/kg/d was reached. If Prolacta had been supplied, this was switched to either ALHMF or NALHMF after about 7 days of use or at 32 weeks corrected gestational age. Administration of parenteral nutrition and lipid emulsions was generally stopped in all three centers when infants reached an enteral intake of about 100\u0026ndash;120 ml/kg/d.\u003c/p\u003e \u003cp\u003eDemographic characteristics are reported as median and 25th -75th interquartile ranges. Other data are reported as indicated. Comparison between groups were done using Student\u0026rsquo;s t, ANOVA, Wilcoxon, and Kruskal-Wallis tests where applicable for numeric variables; chi-squared and Fisher\u0026rsquo;s exact test were used where appropriate for categorical variables. A repeated measures regression (using lme4 in R) was used to compare growth velocity between groups only including infants who received either fortifier throughout the first 4 weeks of treatment (N\u0026thinsp;=\u0026thinsp;308). Gestational age, fortifier group, location, and gender were incorporated into the model.\u003c/p\u003e"},{"header":"Results","content":"\u003cp\u003eA total of 515 infants were included. There were significant differences in multiple demographic variables between infants from each center as shown in Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e. However, when infants from all centers were combined into those receiving the ALHMF or NALHMF, there were no significant differences between groups (Table\u0026nbsp;\u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e3\u003c/span\u003e). Infants in the study were on average about 28\u0026ndash;29 weeks of gestational age and between 1100\u0026ndash;1200 grams birth weight. About 12% in either group were growth restricted. On average, infants included in the study received about 6\u0026ndash;8 days of parenteral nutrition (PN), enteral feeds began at around 3 days after birth and fortification was generally started 7 or more days after birth, although in one center feedings and fortification were started much sooner (Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e). Donor human milk was used in about 2/3 of the infants in either group. In one of the NICU\u0026rsquo;s (Florida site) 53% and 56% of infants from the ALHMF and NALHMF groups, respectively, received Prolacta before switching to the bovine-derived fortifiers under study as described in Methods.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab2\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003e\u003cb\u003eDemographic characteristics of infants from each center\u003c/b\u003e\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"6\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eBetty Cameron\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003ePalm Beach\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003eEast Carolina\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c6\"\u003e \u003cp\u003ep\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eN\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e179\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e92\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e244\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSex (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eFemale\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e86 (48.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e44 (47.8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e141 (57.8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0.076\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eMale\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e93 (52.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e48 (52.2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e103 (42.2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBirth Weight, g (median [IQR])\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1108 [910, 1290]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1152 [970, 1320]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e1004 [814, 1253]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0.002\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBirth Length, cm (median [IQR])\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e37.00 [33.00, 38.50]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e37.00 [35.00, 39.00]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e36.00 [32.50, 38.00]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0.01\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBirth FOC, cm (median [IQR])\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e25.70 [24.00, 27.35]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e26.25 [25.00, 27.12]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e25.00 [23.00, 26.50]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eGest. Age, weeks (median [IQR])\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e28.5 [26.4, 30.2]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e29.0 [27.5, 30.0]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e28.3 [26.4, 30.0]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0.056\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBirth Type (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eSingle\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e143 (79.9)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e62 (67.4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e195 (79.9)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0.033\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eTwin\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e36 (20.1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e30 (32.6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e49 (20.1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAPGAR at 5 min (median [IQR])\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e8.00 [7.00, 9.00]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e8.00 [8.00, 9.00]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e7.00 [6.00, 8.00]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDelivery Type (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eC-Section\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e136 (76.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e74 (80.4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e196 (80.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0.511\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDonor Milk Used (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eNo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e59 (33.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e31 (33.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e97 (39.8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0.302\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eYes\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e120 (67.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e61 (66.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e147 (60.2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDay when birth weight regained (median [IQR])\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e8.0 [6.0, 10.0]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e8.0 [6.0, 10.5]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e9.0 [7.0, 13.0]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0.002\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDay when nutritive* enteral feeds started (median [IQR])\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e7.0 [5.0, 9.0]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e4.0 [3.0, 5.0]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e1.0 [1.0, 2.0]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDays of PN received before study day 0 (median [IQR])\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e8.5 [7.0, 12.7]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e9.0 [7.0, 11.0]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e5.0 [5.0, 6.0]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDays of age at start of bovine fortification** (median [IQR])\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e10.0 [7.0, 14.0]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e14.0 [10.75, 23.00]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e6.00 [5.00, 7.00]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"6\"\u003e*Enteral feeds after \u0026ldquo;trophic feeds\u0026rdquo;.\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab3\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 3\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eDemographic characteristics of infants receiving either fortifier\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"5\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eALHMF\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eNALHMF\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003ep\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eN\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e242\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e273\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSex (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eFemale\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e116 (47.9)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e154 (56.4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.06\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eMale\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e126 (52.1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e119 (43.6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBirth Weight, g (median [IQR])\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1100 [870, 1280]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1070 [870, 1270]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.65\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBirth Length, cm (median [IQR])\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e36.0 [33.0, 38.5]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e36.5 [33.5, 38.5]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.54\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBirth FOC, cm (median [IQR])\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e25.5 [23.5, 27.0]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e25.5 [24.0, 27.0]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.79\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eGestational Age, weeks\u003c/p\u003e \u003cp\u003e(median [IQR])\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e28.6 [26.4, 30.2]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e28.5 [27.0, 30.0]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.91\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBirth Type (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eSingle\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e182 (75.2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e218 (79.9)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.24\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eTwin\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e60 (24.8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e55 (20.1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAPGAR at 5 min\u003c/p\u003e \u003cp\u003e(median [IQR])\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e8.0 [7.0, 8.0]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e8.0 [7.0, 8.0]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.30\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDelivery Type N (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eC-Section\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e185 (76.4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e221 (81.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.25\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eVaginal\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e57 (23.6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e52 (19.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDonor Milk Used N (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eNo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e81 (33.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e106 (38.8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.24\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eYes\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e161 (66.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e167 (61.2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDay when nutritive enteral feeds started (median [IQR])\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e3.0 [1.0, 6.0]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e3.0 [1.0, 6.0]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.96\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDays of PN received before study day 0 (median [IQR])\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e6.0 [5.0, 9.0]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e6.0 [5.0, 9.0]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.32\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDays of age at fortification (median [IQR])\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e7.0 [6.0, 12.0]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e7.0 [6.0, 12.0]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.58\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003eThe proportion of infants receiving fortification decreased progressively over time and was not different between groups. About 93\u0026ndash;96% of infants were getting fortified milk two weeks after starting this process; this proportion decreased to between 78\u0026ndash;88% at three weeks and between 55\u0026ndash;68% at four weeks. Thereafter, fewer infants in either group received fortified human milk (one center stopped using DHM after 30 days). Total fluid intake did not differ between groups at the start or during the several weeks of fortification (Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e1\u003c/span\u003eA). The median protein intake before fortification started was about 2.7 g/kg/d in both groups and increased afterwards. Subsequently, there were small but significant differences in total protein intake favoring the ALHMF group at 1, 2 and 3 weeks of fortification (Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e1\u003c/span\u003eB). A few infants had markedly high protein intakes primarily due to large intake volumes, especially after getting fortification for more than two weeks. There was only a marginal significant difference in overall caloric intake between groups before fortification started (Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e1\u003c/span\u003eC). Growth velocity at 2, 3 and 4 weeks of fortification was significantly higher in the group receiving NALHMF (Fig.\u0026nbsp;\u003cspan refid=\"Fig5\" class=\"InternalRef\"\u003e2\u003c/span\u003eA). This group also exhibited a higher growth velocity at 5 weeks of fortification, but the proportion of infants in either group getting fortified human milk had dropped markedly. When growth velocity was compared among infants that received either fortifier for all 4 weeks (N\u0026thinsp;=\u0026thinsp;308) using a regression model including gestational age, fortifier group, location, and gender, the effect of NALHMF was still significant (2.15, CI 0.89\u0026ndash;3.42 g/kg/d). Z scores for weight, length and head circumference decreased comparably over time in both groups, although at 4 weeks of fortification the decrease in weight Z scores was slightly more pronounced in the ALHMF group (Fig.\u0026nbsp;\u003cspan refid=\"Fig5\" class=\"InternalRef\"\u003e2\u003c/span\u003eB).\u003c/p\u003e \u003cp\u003eFeeding intolerance was relatively uncommon and occurred in equal proportion within each week of fortification using either product (week 1 ALHMF\u0026thinsp;=\u0026thinsp;3%, NALHMF\u0026thinsp;=\u0026thinsp;4%; week 2 ALHMF\u0026thinsp;=\u0026thinsp;8%, NALHMF\u0026thinsp;=\u0026thinsp;6%; week 3 ALHMF\u0026thinsp;=\u0026thinsp;5%, NALHMF\u0026thinsp;=\u0026thinsp;5% and week 4 ALHMF\u0026thinsp;=\u0026thinsp;2%, NALHMF\u0026thinsp;=\u0026thinsp;3%). Overall, metabolic acidosis was diagnosed less frequently in the group receiving the NALHMF. The diagnosis of metabolic acidosis decreased in all centers; however, there were marked discrepancies within centers in the proportion of infants with this abnormality (Table\u0026nbsp;\u003cspan refid=\"Tab4\" class=\"InternalRef\"\u003e4\u003c/span\u003e). Most of those infants diagnosed with metabolic acidosis were treated with either discontinuation of fortification or administering sodium citrate with rapid resolution.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab4\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 4\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eMetabolic acidosis (serum bicarb. \u0026lt;18 mEq/L or base deficit below \u0026minus;\u0026thinsp;6)\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"5\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBetty Cameron Children\u0026rsquo;s Hospital\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eALHMF\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eNALHMF\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003ep\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eN\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e88\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e91\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAcidosis Diagnosed (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eNo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e67 (76.1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e77 (84.6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.21\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eYes\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e21 (23.9)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e14 (15.4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003ePalm Beach Children\u0026rsquo;s Hospital\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eN\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e42\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e50\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAcidosis Diagnosed (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eNo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e33 (78.6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e49 (98.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.008\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eYes\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e9 (21.4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1 (2.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eEast Carolina Health\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eN\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e113\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e131\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAcidosis Diagnosed (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eNo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e32 (28.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e53 (40.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.064\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eYes\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e81 (71.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e78 (59.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eTotal\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eNo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e132 (54.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e179 (65.8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eYes\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e111 (45.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e93 (34.2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.010\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003eAlthough all values favored the NALHMF group, there were no significant differences in median [25\u0026ndash;75% IQ] length of stay (ALHMF 68 [48, 91] days, NALHMF 66 [48, 54] days) or corrected gestational age at discharge (ALHMF 38.5 [37.0, 40.6] weeks, NALHMF 38.1 [36.4, 40.5] weeks). Likewise, discharge median [25\u0026ndash;75% IQ] for weight, length and head circumference were similar between groups (2670 [2286, 3173] grams vs. 2635 [2302, 3170] grams; 45.6 [43.5, 47.5] cm vs. 45.1 [43.5, 47.0] cm; 33.0 [31.5, 34.5] cm vs. 33.0 [31.5, 34.5] cm, for the ALHMF and NALHMF groups, respectively). Culture proven sepsis was diagnosed in 9.8% and 8.7% of infants in the ALHMF and NALHMF groups, respectively. Also, confirmed NEC was uncommon in both groups (ALHMF 5.7%, NALHMF 4.7%).\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eFortification of human milk is critical to ensure that VLBW infants receive an appropriate intake of protein and other nutrients needed for optimal growth (3\u0026ndash;5). Currently, there are several commercially available fortifiers of human or bovine milk origin in liquid or powder form, which vary in their nutrient composition (8). At present, the evidence does not support better outcomes with human milk-derived fortifiers over bovine products (9,19). This notwithstanding, it is very important to examine clinical outcomes, particularly growth, among populations of infants receiving these fortifiers. In this study we report growth outcomes in a large population of VLBW infants exposed to a new bovine-derived fortifier and compared them to those observed among infants receiving a previous formulation of this fortifier. For this retrospective evaluation we used entry criteria that were quite similar to previous controlled trials of bovine-derived fortifiers (10,11,13). Also, we examined these outcomes in three NICU\u0026rsquo;s from separate regions, managed by different providers. This real-world approach could enhance the generalizability of our findings. There were significant albeit small differences in many demographic characteristics between infants enrolled at the three participating centers; perhaps the most striking being the median days of age when fortification was initiated where one center added fortification many days before the other two NICUs (Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e). This is probably a reflection of each NICU\u0026rsquo;s feeding guidelines and the lack of a widely accepted approach to nutritional support. However, when infants from all three NICUs were grouped according to which fortifier they received, the groups were comparable. Only gender approximated significance, and therefore, this variable was incorporated into regression models.\u003c/p\u003e \u003cp\u003eAs anticipated and reflecting current practice, the majority of VLBW infants received fortified MOM or DHM for several weeks (2). Whereas we could not consistently retrieve the exact amount of DHM used each day, the proportion of infants receiving DHM was similar between groups when all three NICUs were compared separately, or once grouped according to the fortifier received. Likewise, in the NICU that utilized Prolacta to initiate feedings, the proportion of infants in the ALHMF and NALHMF groups that received Prolacta was similar. Donor milk use in infants in our study is well within what has been reported in other recent studies (7,13,17). Moreover, the proportion of infants that received fortification for 4 weeks is quite similar to what has been reported previously in clinical trials of bovine-derived fortifiers (10,13).\u003c/p\u003e \u003cp\u003eGrowth velocity was higher among infants receiving the new NALHMF during the first several weeks of fortification. This benefit seemed to persist beyond 4 weeks of fortification; however, there was considerable attrition in the number of infants still receiving either fortifier past this time. In addition, when growth velocity was compared only among those infants that received either fortifier for 4 weeks, an outcome reported in several previous fortifier studies (10,11,13), the group receiving NALHMF still had a greater growth velocity in weight. This advantage in weight gain was also suggested by comparing Z scores, since the usual decrease in weight Z scores observed in VLBW infants during their NICU stay was less pronounced in those fed the new fortifier. Better weight gain was seen despite similar intakes of total fluids and calories between both groups, although overall protein intake was higher among infants fed the ALHMF. We focused mainly on weight gain because measurements of length can be variable if not using length boards. This was the case in one of our NICUs. Growth velocity in both groups, but particularly in the NALHMF group approximated that reported in recent controlled trials of bovine-based fortifiers and appears to be higher than growth velocity seen when human milk-derived fortifiers are used (10,11, 13, 17, 18). The reasons why growth velocity was higher among infants receiving the NALHMF are unclear. This could not be attributed to a different intake of volume or energy since these did not differ between groups during fortification. However, there was a higher protein intake in the group receiving the ALHMF whereby excess protein may have led to slower growth and more metabolic acidosis (see below). Also, feeding intolerance was not a factor since it was reported with similar frequency in either group. A potential explanation may also relate to the occurrence of metabolic acidosis. We chose a threshold to diagnose this abnormality that has been used before, although the clinical significance of it remains unclear since other studies have utilized a much lower threshold of bicarbonate or base deficit to diagnose metabolic acidosis, or have not reported it at all (7,11,13,17,20). Nonetheless, the presence of metabolic acidosis has been associated with slower growth and a longer length of stay (13,21,22). In our study, there were marked differences in the diagnosis of metabolic acidosis, with one center reporting it between 3 to 7 times more frequently than the other two NICUs. Infants from this NICU were on average a few days less mature and weighed a fraction less at birth than the other groups. Even though this could be a contributing factor, it is unlikely to have played a major role in the pathogenesis of metabolic acidosis. Perhaps the most meaningful differences identified in this center were a shorter interval of exposure to parenteral nutrition and a much earlier initiation of enteral feeds and fortification.\u003c/p\u003e \u003cp\u003eMetabolic acidosis is common among preterm infants and relates, in part, to protein intake and renal maturation (21,24). Neonatologists often add early in the NICU course acetate salts to parenteral nutrition or umbilical arterial solutions to buffer any decrease in pH and base deficit observed in preterm infants. Therefore, it is possible that attempts to aggressively nourish these infants enterally early on and shortening the days of parenteral nutrition may have translated into more metabolic acidosis or a serum bicarbonate level below 18 mEq/L. Several reports have associated the use of the ALHMF with metabolic acidosis (25\u0026ndash;28), which may also be associated to a higher protein intake as seen in the ALHMF group in our study. This notwithstanding, the frequency of metabolic acidosis was significantly lower with the NALHMF than the ALHMF and decreased in all three centers. This decreased to about 10% of infants in two of the three centers with use of the NALHMF, which is a frequency of metabolic acidosis commonly reported among infants getting human milk fortifiers (13,20,29). A recent experimental study demonstrated that there are minimal drops in the pH of human milk with the addition of the NALHMF, which is unlikely to be a contributing factor to the pathogenesis of metabolic acidosis among infants receiving this fortifier (30).\u003c/p\u003e \u003cp\u003eEven though there was a trend towards a shorter length of stay and earlier corrected gestational age at discharge, these differences were not significant. Several other studies have failed to show advantages in these outcomes with fortification. This is not surprising given that the decision to discharge an infant depends on many factors and not only on their nutritional/growth status. Furthermore, no differences in anthropometrics at discharge between groups were identified. This suggests that any growth advantage observed during fortification may no longer be observed once this stops or is modified (10,11,29). Likewise, no differences were observed in late onset sepsis or NEC. Both these complications occurred with relatively low frequency as one might expect in a stable population of VLBW infants receiving human milk as their main source of nutrition (7,10,11,13,17,20).\u003c/p\u003e \u003cp\u003eIn summary, among VLBW infants, fortification of human milk using the new NALHMF resulted in faster growth velocity during fortification, less metabolic acidosis and similar tolerance and other morbidities compared with feeding human milk fortified with an ALHMF.\u003c/p\u003e"},{"header":"Declarations","content":" \u003ch2\u003eConflict of Interest\u003c/h2\u003e \u003cp\u003eFernando Moya, Jennifer Fowler, Adrian Florens and Kirsten Frank are part of Reckitt Mead Johnson Nutrition Speaker\u0026rsquo;s Bureau.\u003c/p\u003e \u003ch2\u003eFunding\u003c/h2\u003e \u003cp\u003eThis study was funded by an unrestricted research grant from Reckitt Mead Johnson Nutrition. The investigators designed the study, collected, and analyzed all data independently from the funding organization. Reckitt Mead Johnson Nutrition had no input on conducting the study and writing the final manuscript.\u003c/p\u003e\u003cp\u003e\u003cstrong\u003eAuthor Contributions:\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eFM designed the study, analyzed the data and helped to write the manuscript.\u003c/p\u003e\n\u003cp\u003eJF collected the data and helped to write the manuscript.\u003c/p\u003e\n\u003cp\u003eAF collected the data and helped to write the manuscript.\u003c/p\u003e\n\u003cp\u003eKF collected the data and helped to write the manuscript.\u003c/p\u003e\n\u003cp\u003eJD collected the data and helped to write the manuscript.\u003c/p\u003e\n\u003cp\u003eOD collected the data and helped to write the manuscript.\u003c/p\u003e\n\u003cp\u003eTF collected the data and helped to write the manuscript.\u003c/p\u003e\n\u003cp\u003eAG analyzed the data and helped to write the manuscript.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n \u003cli\u003e\u003cspan\u003eSilveira R, Corso A, Procianoy R. The influence of early nutrition on neurodevelopmental outcomes in preterm infants. Nutrients 2023; 15: 4644.\u003c/span\u003e\u003c/li\u003e\n \u003cli\u003e\u003cspan\u003eChiang K, Sharma A, Nelson J, Olson C, Perrine C. Receipt of breast milk by gestational age\u0026mdash;United States 2017. MMWR 2019; 68: 489\u0026ndash;493.\u003c/span\u003e\u003c/li\u003e\n \u003cli\u003e\u003cspan\u003ePerrin M, Belfort M, Hagadorn J, McGrath J, Taylor S, Tosi L et al. The nutritional composition and energy content of donor human milk: a systematic review. Adv Nutr 2020; 11: 960\u0026ndash;970.\u003c/span\u003e\u003c/li\u003e\n \u003cli\u003e\u003cspan\u003eParker MG, Stellwagen LM, Noble L, Kim J, Poindexter B, Puopolo K; AAP Section on Breastfeeding, Committee on Nutrition, Committee on Fetus and Newborn. Promoting human milk and breastfeeding for the very low birth weight infant. Pediatrics 2021; 148: e2021054272.\u003c/span\u003e\u003c/li\u003e\n \u003cli\u003e\u003cspan\u003eArslanoglu S, Boquien C, King C, Lamireaux D, Tonetto P, Barnett D et al. Fortification of Human Milk for Preterm Infants: Update and Recommendations of the European Milk Bank Association (EMBA) Working Group on Human Milk Fortification. Front Pediatr 2019; 22: 76.\u003c/span\u003e\u003c/li\u003e\n \u003cli\u003e\u003cspan\u003eSullivan S, Schanler R, Kim J, Patel A, Traw\u0026ouml;ger R, Kiechl-Kohlendorfer 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\u0026ndash;567.\u003c/span\u003e\u003c/li\u003e\n \u003cli\u003e\u003cspan\u003eO\u0026rsquo;Connor D, Kiss A, Tomlinson C, Bando N, Bayliss A, Campbell D et al. Nutrient enrichment of human milk with human and bovine milk-based fortifiers for infants weighing\u0026thinsp;\u0026lt;\u0026thinsp;1250 g: a randomized clinical trial. Am J Clin Nutr 2018; 108: 108\u0026ndash;116.\u003c/span\u003e\u003c/li\u003e\n \u003cli\u003e\u003cspan\u003eAdamkin D. Use of human milk and fortification in the NICU. J Perinatol 2023; 4: 551\u0026ndash;559.\u003c/span\u003e\u003c/li\u003e\n \u003cli\u003e\u003cspan\u003eFu T and Poindexter B. Human milk fortification strategies in the neonatal intensive care unit. Clin Perinatol 2023; 50: 643\u0026ndash;652.\u003c/span\u003e\u003c/li\u003e\n \u003cli\u003e\u003cspan\u003eMoya F, Sisk P, Walsh K, Berseth C. A new liquid human milk fortifier and linear growth. Pediatrics 2012; 130: e928-935.\u003c/span\u003e\u003c/li\u003e\n \u003cli\u003e\u003cspan\u003eKim J, Chan G, Schanler R, Groh-Wargo S, Bloom B, Dimmit R et al. Growth and tolerance of preterm infants fed a new liquid extensively hydrolyzed human milk fortifier. J Pediatr Gastroenterol Nutr 2015; 61: 661\u0026ndash;675.\u003c/span\u003e\u003c/li\u003e\n \u003cli\u003e\u003cspan\u003eGates A, Marin T, De Leo G, Waller J, Stansfield B. Nutritional composition of preterm mother\u0026rsquo;s milk and factors that influence nutrient content. Am J Clin Nutr 2021; 114: 1719\u0026ndash;1728.\u003c/span\u003e\u003c/li\u003e\n \u003cli\u003e\u003cspan\u003eSchanler R, Groh-Wargo S, Barrett-Reis B, White R, Ahmad K, Oliver J et al. Improved outcomes in preterm infants fed a liquid nonacidified human milk fortifier: a prospective, randomized clinical trial. J Pediatr 2018; 202: 31\u0026ndash;37.\u003c/span\u003e\u003c/li\u003e\n \u003cli\u003e\u003cspan\u003eFenton T, Kim J. A systematic review and meta-analysis to revise the Fenton growth chart for preterm infants. BMC Pediatr 2013; 13: 59.\u003c/span\u003e\u003c/li\u003e\n \u003cli\u003e\u003cspan\u003eBell MJ, Ternberg JL, Feigin RD, Keating J, Marshall R, Barton L et al. Neonatal necrotizing enterocolitis. Therapeutic decisions based upon clinical staging. Ann Surg. 1978; 187: 1\u0026ndash;7.\u003c/span\u003e\u003c/li\u003e\n \u003cli\u003e\u003cspan\u003eFenton T, Anderson D, Groh-Wargo S, Hoyos A, Ehrenkranz R, Senterre T. An attempt to standardize the calculation of growth velocity of preterm infants-Evaluation of practical bedside methods. J Pediatr 2018; 196: 77\u0026ndash;83.\u003c/span\u003e\u003c/li\u003e\n \u003cli\u003e\u003cspan\u003eO\u0026rsquo;Connor D, Gibbins S, Kiss A, Bando N, Brennan-Donnan J, Ng E et al. Effect of Supplemental Donor Human Milk Compared with Preterm Formula on Neurodevelopment of Very Low-Birth-Weight Infants at 18 Months: A Randomized Clinical Trial. JAMA 2016; 316: 1897\u0026ndash;1905.\u003c/span\u003e\u003c/li\u003e\n \u003cli\u003e\u003cspan\u003eHair A, Blanco C, Moreira A, Hawthorne K, Lee M, Retchman D et al. Randomized trial of human milk cream as a supplement to standard fortification of an exclusive human milk-based diet in infants 750\u0026ndash;1250 g birth weight. J Pediatr 2014; 165: 915\u0026thinsp;\u0026minus;\u0026thinsp;20.\u003c/span\u003e\u003c/li\u003e\n \u003cli\u003e\u003cspan\u003eJensen G, Domell\u0026ouml;f M, Ahlsson F, Elfvin A, Navers L, Abrahamsson T. Effect of human milk-based fortification in extremely preterm infants fed exclusively with breast milk: a randomised controlled trial. EClinicalMedicine 2024; 68: 102375.\u003c/span\u003e\u003c/li\u003e\n \u003cli\u003e\u003cspan\u003eShah S, Dereddy S, Jones T, Dhanireddy R, Talati A. Early versus Delayed Human Milk Fortification in Very Low Birth Weight Infants-A Randomized Controlled Trial. J Pediatr 2016; 174: 126\u0026ndash;131.\u003c/span\u003e\u003c/li\u003e\n \u003cli\u003e\u003cspan\u003eRochow N, Jochum F, Redlich A, Korinekova Z, Linnemann K, Weitmann K et al. Fortification of breast milk in VLBW infants: metabolic acidosis is linked to the composition of fortifiers and alters weight gain and bone mineralization. Clin Nutr. 2011; 30: 99-105.\u003c/span\u003e\u003c/li\u003e\n \u003cli\u003e\u003cspan\u003ePaul M, Partridge J, Barrett-Reis B, Ahmad K, Machiraju P, Jayapalan H et al. Metabolic acidosis in preterm infants is associated with a longer length of stay in the neonatal intensive care unit. Pharmacoecon Open. 2020; 4: 541-547.\u003c/span\u003e\u003c/li\u003e\n \u003cli\u003e\u003cspan\u003eSchwartz GJ, Haycock GB, Edelmann Jr. CM, Spitzer A. Late metabolic acidosis: a reassessment of the definition. J Pediatr 1979; 95:102-107.\u003c/span\u003e\u003c/li\u003e\n \u003cli\u003e\u003cspan\u003eSvenningsen NW, Lindquist B. Incidence of metabolic acidosis in term, preterm and small-for-gestational age infants in relation to dietary protein intake. Acta Paediatr. 1973; 62: 1-10.\u003c/span\u003e\u003c/li\u003e\n \u003cli\u003e\u003cspan\u003eLainwala S, Kosyakova N, Spizzoucco AM, Herson V, Brownell EA. Clinical and nutritional outcomes of two liquid human milk fortifiers for premature infants. J Neonatal Perinatal Med. 2017; 10: 393-401.\u003c/span\u003e\u003c/li\u003e\n \u003cli\u003e\u003cspan\u003eCordova EG, Soldateli B, Rosner B, Drouin K, Davitt E, Pepin H et al. Growth and clinical outcomes of very low-birth-weight infants receiving acidified vs nonacidified liquid human milk fortifiers. Nutr Clin Pract. 2021; 36: 1304-1311.\u003c/span\u003e\u003c/li\u003e\n \u003cli\u003e\u003cspan\u003eDarrow CJ, Bai-Tong SS, Kang EM, Thompson CL, Walsh MC. Use of acidified versus non-acidified liquid human milk fortifier in very low birth weight infants: a retrospective comparison of clinical outcomes. J Neonatal Perinatal Med. 2020; 13: 71-79.\u003c/span\u003e\u003c/li\u003e\n \u003cli\u003e\u003cspan\u003eThoene M, Lyden E, Weishaar K, Elliot E, Wu R, White K et al. Comparison of a powdered, acidified liquid, and non-acidified liquid human milk fortifier on clinical outcomes in premature infants. Nutrients. 2016; 8: 451.\u003c/span\u003e\u003c/li\u003e\n \u003cli\u003e\u003cspan\u003eSalas A, Gunagam E, Nguyen K, Reeves A, Argent V, Finck A et al. Early human milk fortification in infants born extremely preterm: A randomized trial. Pediatrics 2023; 152: e2023061603.\u003c/span\u003e\u003c/li\u003e\n \u003cli\u003e\u003cspan\u003ePineda D, Bingham R, Gates A, Thompson AB, Stansfield BK. Acid/base balance in fortified donor human milk: an experimental study. J Parenter Enteral Nutr. 2023; 47: 904-910.\u003c/span\u003e\u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"","lastPublishedDoi":"10.21203/rs.3.rs-4331662/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-4331662/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eObjective\u003c/h2\u003e \u003cp\u003eTo compare nutritional outcomes among infants receiving a new non-acidified liquid human milk fortifier (NALHMF) or an acidified liquid human milk fortifier (ALHMF).\u003c/p\u003e\u003ch2\u003eStudy Design:\u003c/h2\u003e \u003cp\u003eRetrospective, multicenter study including 515 VLBW infants. Primary outcome was growth velocity during fortification. Student\u0026rsquo;s t, ANOVA, Wilcoxon, and Kruskal-Wallis tests were used for numeric variables, or, chi-squared and Fisher\u0026rsquo;s exact test for categorical variables. Growth velocity between groups was compared with repeated measures regression.\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e \u003cp\u003e242 and 273 infants received ALHMF and NALHMF, respectively, with no demographic differences between the groups. Growth velocity during fortification was significantly higher in the group receiving NALHMF, despite similar total fluid or calorie intake. Metabolic acidosis was diagnosed less frequently with the NALHMF, with marked differences between centers.\u003c/p\u003e\u003ch2\u003eConclusion\u003c/h2\u003e \u003cp\u003eFortification of human milk using the new NALHMF resulted in faster growth velocity during fortification and less metabolic acidosis compared with feeding human milk fortified with an ALHMF.\u003c/p\u003e","manuscriptTitle":"Clinical Experience with a New, Non-Acidified Liquid Human Milk Fortifier in Very Low Birth Weight Infants.","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-05-07 19:15:59","doi":"10.21203/rs.3.rs-4331662/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"d24507be-7609-4d00-9d54-0b5b31c0bcb0","owner":[],"postedDate":"May 7th, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[{"id":31324430,"name":"Health sciences/Medical research/Outcomes research"},{"id":31324431,"name":"Health sciences/Health care/Paediatrics"}],"tags":[],"updatedAt":"2024-05-31T10:51:06+00:00","versionOfRecord":[],"versionCreatedAt":"2024-05-07 19:15:59","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-4331662","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-4331662","identity":"rs-4331662","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}