Human Milk Fortifier Research Articles

Source of human milk (mother or donor) is more important than fortifier type (human or bovine) in shaping the preterm infant microbiome

SummaryMilk fortifiers help meet the nutritional needs of preterm infants receiving their mother’s own milk (MOM) or donor human milk. We conducted a randomized clinical trial (NCT03214822) in 30 very low birth weight premature neonates comparing bovine-derived human milk fortifier (BHMF) versus human-derived fortifier (H2MF). We found that fortifier type does not affect the overall microbiome, although H2MF infants were less often colonized by an unclassified member of Clostridiales Family XI. Secondary analyses show that MOM intake is strongly associated with weight gain and microbiota composition, including Bifidobacterium, Veillonella, and Propionibacterium enrichment. Finally, we show that while oxidative stress (urinary F2-isoprostanes) is not affected by fortifier type or MOM intake, fecal calprotectin is higher in H2MF infants and lower in those consuming more MOM. Overall, the source of human milk (mother versus donor) appears more important than the type of milk fortifier (human versus bovine) in shaping preterm infant gut microbiota.

Early calcium and phosphorus supplementation in VLBW infants to reduce metabolic bone disease of prematurity: a quality improvement initiative

ObjectiveTo reduce the incidence of metabolic bone disease (MBD) among very low birthweight (VLBW) infants admitted to neonatal intensive care unit from baseline of 35% by 50% over 2 years...

More evidence: Mothers’ own milk is personalized medicine for very low birthweight infants

“Human milk sources and fortification: Impact on fecal microbiota and calprotectin in premature infants” highlights improved outcomes in predominantly mothers’ own milk-fed versus predominantly pasteurized donor human milk-fed VLBW infants, regardless of fortifier type. Research and practice implications are reviewed.

Postdischarge Nutrition in Preterm Infants.

The field of postdischarge nutrition for preterm infants arose when concerns that using diets suitable for term infants-breastfeeding without fortification or standard formulas-might not meet the postdischarge nutritional needs of infants born preterm, who often exhibited growth restriction and evidence of undernutrition. A decade ago, there were already 27 randomized controlled trials (RCTs) of nutritional supplementation from which an eligible subsample of trials have provided evidence on whether nutritional fortification of human milk or nutrient-enriched formula favorably affects postdischarge growth in these infants. These RCTs also allowed exploration of the quality of growth, bone mineralization, and the ad libitum-fed infant's own regulation of milk volume and nutrient intake. Importantly, such RCTs, augmented by observational data on the links between growth and neurodevelopment, have allowed exploration of the potential impact of postdischarge nutrition on neurocognitive function. However, the interpretation of published data and the implication for practice has proven difficult and contentious. In this review, we examine, and to an extent reanalyze, existing evidence to elucidate its strengths and limitations, with the goal of adding more clarity to the ways in which this sizeable body of clinical scientific research may have a positive impact on the postdischarge nutritional approach to infants born preterm.

Using Human Milk Fortifiers to Improve the Preoperative Nutritional Status of Infants With Non-restricted Ventricular Septal Defect.

ObjectiveTo explore the effects of human milk fortifier (HMF) on improving the preoperative nutritional status of infants with non-restricted ventricular septal defect (VSD).MethodsA prospective randomized controlled study was conducted in a provincial hospital in China. Participants were randomly divided into an intervention group (n = 29) and a control group (n = 29). HMFs were added proportionally to the infants' feeds in the intervention group based on breastfeeding status, and the infants in the control group received exclusive breastfeeding as needed. The nutritional status of the two groups was compared 1 month after the intervention.ResultsCompared with the control group, the weight, head circumference, height, albumin level, and prealbumin level of the human milk fortifier group were significantly higher 1 month after the intervention (p < 0.05). The STRONGkids score of the HMF group was significantly lower than that of the non-HMF group (p < 0.05). There was no significant difference in pneumonia, liver insufficiency, feeding intolerance, or jaundice between the two groups.ConclusionThe addition of HMFs based on the breastfeeding status of infants with non-restricted VSD can improve the preoperative nutritional status and does not increase the incidence of gastrointestinal complications.Clinical Trial Registrationhttp://www.chictr.org.cn/index.aspx, identifier: ChiCTR2000041135.

Randomised controlled trial of human derived breast milk fortifier versus bovine milk fortifier on body composition in very preterm babies

BackgroundPreterm infants receiving a diet of exclusive human milk compared to predominantly preterm formula have lower weight and non-adipose tissue mass by term. Human milk fortification is recommended. However, it is not known if the protein source affects body composition. AimsTo compare the effect of an exclusive human milk based diet (intervention) with a diet containing cow milk products (control) on body composition. ParticipantsInfants born below 30 weeks gestation. Study designRandomised multicentre, open label, controlled trial. Infants preferentially received their own mother's milk. Infants were randomised to either an exclusive human milk diet (human milk formula to make up a shortfall in own mother's milk and human milk derived fortifier) or cow milk-based supplementation (preterm formula to make up a shortfall in own mother's milk and cow milk-based fortifier). Fortification began at an enteral intake of 150 ml/kg/day. Infants underwent whole-body magnetic resonance imaging at term. Primary outcomeBody composition (adipose tissue (ATM) and non-adipose tissue mass (N-ATM)) at term. ResultsWe randomly assigned 38 infants to intervention (n = 19) and control arms (n = 19). Primary outcomes were analysed in 15 infants in the intervention arm and 12 in the control arm. The estimates of the effect of the intervention following adjustment for length and sex, were non-significant (ATM (kg): 0.137, 95 % confidence interval (CI) -0.01, 0.29; N-ATM: −0.137; −0.01, 0.29). ConclusionsWe identified no clinically relevant differences in body composition in preterm babies <30 weeks gestation receiving a macronutrient-equivalent exclusive human milk diet compared with a diet containing cow milk products.

Supplementing human milk with a donkey or bovine milk derived fortifier: Consequences on proteolysis, lipolysis and particle structure under in vitro dynamic digestion

Fortification of human milk (HM) is often necessary to meet the nutritional requirements of preterm infants. This study sought to establish whether HM supplemented with an experimental donkey milk-derived fortifier (DMF) or a commercial bovine milk-derived fortifier (BMF) affected digestion, using an in vitro dynamic system at the preterm stage. Particle size in gastric phase was higher in DMF than in BMF, due to protein aggregates surrounding lipid globules. Before digestion, BMF, with its extensively hydrolysed proteins, had a higher degree of proteolysis (30%) than DMF (11%), which contained intact proteins. After digestion, this difference was reduced concomitantly to a similar net degree of proteolysis (33%). DMF, with a higher proportion of ω3, resulted in a lower ω6/ω3 free PUFA ratio than BMF throughout digestion, although the final degree of lipolysis was similar (54%). In summary, DMF could represent a better source of proteins and lipids for the preterm infant.

A survey among healthcare professionals from seven countries reported diverse nutritional practices of late preterm infants.

To gain insight into nutritional practices and expected growth outcomes of infants born between 34 and 36 gestational weeks defined as late preterm infants (LPT). An anonymous online survey among paediatricians and neonatologists from Bangladesh, Indonesia, Mexico, Nigeria, Malaysia, Singapore and Taiwan was conducted from March until October 2020. The questionnaire consisted of 40 questions on the nutritional management and expected growth outcomes of LPT in and after-hospital care. Healthcare professionals from low to high Human Development (HDI) countries (n=322) and very high HDI countries (n=169) participated in the survey. Human milk was the preferred feeding, resulting in an adequate growth of LPT (weight, length and occipitofrontal circumference), according to a majority of respondents (low to high HDI, 179/265, 68% vs. very high HDI, 73/143, 51%; p=0.002). The expected growth outcome was higher after-hospital discharge. Less than half of healthcare professionals started enteral feeding during the 1st hour of life. Lactation difficulties, limited access to human milk fortifiers and donor human milk, especially among low to high HDI countries, were reported as major hurdles. Human milk is the first feeding choice for LPT. The diverse opinions on nutritional practices and expected growth outcomes among healthcare professionals indicate the necessity to develop general nutritional guidelines for LPT.

Benefits of a Standardized Enteral Feeding Protocol on the Nutrition and Health Outcomes of Very Low Birth Weight Preterm Infants.

Purpose: To compare nutrition and health outcomes before and after implementing a standardized enteral feeding protocol on nutrition and health outcomes in very low birth weight preterm infants.Methods: A retrospective chart review was performed evaluating preterm infants, born less than 34weeks gestation and weighing less than 1500g, before and after the implementation of a standardized enteral feeding protocol. Outcomes included weaning of parenteral nutrition, initiation and advancement of enteral feeds, initiation of human-milk fortifier (HMF), change in weight z-score and neonatal morbidities.Results: Fifty-six infants (30 in pre-group, 26 in post-group) met the inclusion criteria. Infants in the standardized enteral feeding protocol group started enteral feeds earlier (p=0.039) and received full HMF fortification at lower weights (p=0.033) than those in the pre-group. Fewer days on continuous positive airway pressure (p=0.021) and lower rates of bronchopulmonary dysplasia (p=0.018) were also observed in the post-group. Weaning of parenteral nutrition and weight z-score were not significantly different between groups. There were no differences in other morbidities.Conclusion: Study results suggest that adopting a standardized enteral feeding protocol may promote early initiation of enteral feeds and fortification.

Metabolic Bone Disease of Prematurity.

Metabolic Bone Disease of Prematurity.

Effect of Fortified Human Milk on the Growth Parameters of Babies With Very Low Birth Weight.

ObjectiveThe objective of this study is to assess the effect of fortified human milk on growth parameters of very low birth-weight babies.Study place and durationThis randomized controlled trial took place at the neonatal intensive care unit (NICU), Children's Hospital, and Institute of Child Health in Multan from the 1st of January 2020 to the 1st of July 2021.Material and methodsIn group I, 25ml human milk was fortified with a 1g human milk fortifier (HMF) sachet (1g of HMF gives 4kcal added to 25ml of human milk). In group II, newborns were fed preterm formula (493 kcal/100 g where 0.8 g=4 kcal added to 25 ml of human milk) mixed with human milk. Infants were administered human milk + olive oil (0.4 mL = 4Kcal per 25ml human milk) in group III. Everyday weight gain, digestive intolerance (vomiting and/or abdominal distension), sepsis, hospital stay, electrolyte imbalance (derangement of serum sodium, potassium, chloride, and magnesium levels), albumin, and cholesterol/triglyceride levels were assessed. The data was analyzed through descriptive and inferential means using Pearson's chi-square tests and one-way analysis of variance (ANOVA).ResultsResults indicate that preterm formula infants gain higher weight compared to human fortifier infants and olive oil. Similarly, the difference was statistically significant (p=0.001). However, olive oil infants gained a lower head circumference compared to the other two groups, and the difference was statistically significant as well (p=0.000). Moreover, feeding intolerance and electrolyte imbalance were higher in olive oil infants, p=0.020 and p=0.024, respectively.ConclusionIt can be concluded that the use of and preterm formula can prove beneficial in increasing the growth rate in terms of weight gain, length gain, and head circumference.

Impact of Early Fortification in Very Low Birth Weight Infants on the Incidence of Malnutrition During a Trophamine Shortage.

The devastation of pharmaceutical production facilities from Hurricane Maria caused a national shortage of parenteral amino acids in October 2017. Our institution decreased trophamine in very low birth weight (VLBW) infants and initiated human milk fortification at a lower feeding volume to increase enteral protein intake more quickly. The objective of this study was to assess how protein management during the shortage period affected the incidence of malnutrition. This was a retrospective cohort study of infants admitted to 2 neonatal intensive care units from June 1, 2017 to May 31, 2018. Infants between 23 and 32 weeks' gestation were included in this study. The primary outcome was the incidence of malnutrition at 14 days, defined as a z score decline of ≥0.8 SDs, in the pre-shortage period compared with the shortage period. Clinical data regarding adverse effects associated with early fortification and pharmacy costs were recorded. There were 68 infants prior to and 65 during the shortage who met inclusion criteria. There was no difference in malnutrition between the pre-shortage and shortage groups; however, a significant increase in malnutrition was observed in infants who did not receive early fortification during the shortage. No difference in time to full enteral feeds or necrotizing enterocolitis was observed with early fortification. Early fortification in VLBW infants receiving less trophamine during the shortage was not associated with an increase in malnutrition. Restricting trophamine in neonates during the shortage allowed for distribution to other critically ill patients.

Human Milk Fortification in Very Preterm Infants in China: A Multicenter Survey.

AimTo investigate the use of human milk fortifier (HMF) for very preterm infants (VPIs) and complications and nutritional status of VPIs due to various breast milk enhancement strategies among the Chinese population.MethodsVPIs with birth weight < 1,800 g and wholly or predominantly breastfed were assigned to the following fortification groups: no HMF, early HMF (adding HMF at an enteral volume of ≤ 80 ml·kg−1·day−1), middle HMF (adding HMF at an enteral volume of 80–100 ml·kg−1·day−1), and late HMF (adding HMF at an enteral volume of ≥100 ml·kg−1·day−1). The growth status and complications for various groups were evaluated.ResultsWe enrolled 985 VPIs, of which 847 VPIs (86.0%) received HMF, whereas 138 VPIs (14.0%) did not. The number of VPIs in the early, middle, and late fortification groups were 89 (9.0%), 252 (25.6%), and 506 (51.4%), respectively. The complete fortification of the early, middle, and late fortification groups was achieved in 13.2 ± 11.0, 13.8 ± 11.7, and 12.3 ± 13.0 days, respectively, without significant differences (p > 0.05). The groups did not exhibit significant differences in the incidence of feeding intolerance, necrotizing enterocolitis (Bell stage ≥ 2), late-onset sepsis, and metabolic bone diseases (p > 0.05). The middle fortification groups exhibited the fastest growth velocity and the least dramatic decrease in the Z-score of weight and length, and the lowest incidence of EUGR (35.7%), whereas the “no HMF” groups exhibited the slowest growth velocity and the largest decline in the Z-score, and the highest incidence of EUGR (61.6%).ConclusionsThe usage rate of HMF was relatively low among Chinese VPIs, fortification often occurred in the late feeding stage, and the time to reach complete fortification was long. Adding HMF and different breast milk enhancement strategies did not increase the incidence of feeding intolerance and necrotizing enterocolitis. The enteral volume of 80–100 ml·kg−1·day−1 with HMF addition led to increased growth in the weight and length and lower EUGR incidence, indicating that the addition of HMF at the specific feeding volume might be the best practice for promoting growth.

State of the evidence from clinical trials on human milk fortification for preterm infants.

Infants born preterm or low birth weight are at risk for morbidity, mortality and later neuroimpairment. Appropriate early post-natal growth is associated with better outcomes in-hospital and post-discharge. Therefore, nutritional strategies that support growth may improve the long-term health of this population. Mother's milk with donor milk as a supplement are preferred sources of nutrition for these infants but may not always support growth, especially amongst infants born of very low birth weight (<1500g) and or those with a major morbidity. Systematic reviews of randomised controlled trials to date demonstrate that multi-nutrient fortification of human milk improves in-hospital growth of preterm infants although data on long-term neurodevelopment are lacking. Further, individualised approaches to fortification based on milk analysis or the infant's metabolic response may improve growth over standard fortification. The evidence is insufficient to inform the timing of introducing fortifier, routine fortification of feeds post-discharge or routine use of fortifiers made from human instead of bovine milk. Importantly, there is insufficient data to determine if these fortification practices improve relevant clinical or neurodevelopmental outcomes. In sum, there is an urgent need for well-designed clinical trials to assess potential benefits and risks of fortification practices and at what cost.

Incidence of extrauterine growth retardation and its risk factors in very preterm infants during hospitalization: a multicenter prospective study.

To investigate the incidence of extrauterine growth retardation (EUGR) and its risk factors in very preterm infants (VPIs) during hospitalization in China. A prospective multicenter study was performed on the medical data of 2 514 VPIs who were hospitalized in the department of neonatology in 28 hospitals from 7 areas of China between September 2019 and December 2020. According to the presence or absence of EUGR based on the evaluation of body weight at the corrected gestational age of 36 weeks or at discharge, the VPIs were classified to two groups: EUGR group (n=1 189) and non-EUGR (n=1 325). The clinical features were compared between the two groups, and the incidence of EUGR and risk factors for EUGR were examined. The incidence of EUGR was 47.30% (1 189/2 514) evaluated by weight. The multivariate logistic regression analysis showed that higher weight growth velocity after regaining birth weight and higher cumulative calorie intake during the first week of hospitalization were protective factors against EUGR (P<0.05), while small-for-gestational-age birth, prolonged time to the initiation of total enteral feeding, prolonged cumulative fasting time, lower breast milk intake before starting human milk fortifiers, prolonged time to the initiation of full fortified feeding, and moderate-to-severe bronchopulmonary dysplasia were risk factors for EUGR (P<0.05). It is crucial to reduce the incidence of EUGR by achieving total enteral feeding as early as possible, strengthening breastfeeding, increasing calorie intake in the first week after birth, improving the velocity of weight gain, and preventing moderate-severe bronchopulmonary dysplasia in VPIs.

Human Milk Fortifiers for Preterm Infants: Do We Offer the Best Amino Acid Mix?

For preterm and small-for-gestational age infants on enteral nutrition, the best solution is to add human milk fortifier (HMF) to human milk (HM) which is provided by the mother or a milk bank. HMF provides a means to add additional protein, energy, and micronutrients, while maintaining HM as the main source of nutrition. Because of their rapid increase of lean body mass, preterm infants have much higher protein requirements than term infants. Recommendations on protein requirements of preterm infants are available, but protein quality - i.e. the amino acid (AA) profile in HMFs has not been systematically assessed. Present guidelines for enteral nutrition recommend protein intakes around 4 g/kg body weight (BW) for preterm infants <1,500 g, an intake that is not achievable with unfortified HM intakes <200 mL/kg BW/day. It is generally assumed that the AA profile of HM is the best reference for the AA profile of HMF. We calculated advisable intakes of AAs for preterm infants between 400-2,500 g which are based on AA increments of the fetus. Corrections for absorption, inevitable losses, oxidation, and variation of AAs in HM were introduced. Our calculations indicate that extremely low birth weight (ELBW <1,000 g) and very low birth weight (VLBW <1,500 g) infants have substantially higher AA requirements than low birth weight (LBW) infants growing from 1,900 to 2,400 g. In ELBW infants, daily intakes of the different indispensable AAs (IAA) with 4 g of (term) HM protein/kg BW range between 59 and 125% of the respective advisable intakes. Intakes of 7 IAAs and 3 conditionally indispensable AAs (CIAA) are below advisable intakes. On the other hand, with 4 g HM protein per kg BW/day, the IAAs isoleucine and leucine and some dispensable AAs are already supplied in abundance. In VLBW infants, daily intakes of the IAA methionine and 3 CIAAs are still below the advisable intakes. In LBW infants (<2,000 g) receiving 3.5 g HM protein per kg BW daily intakes of 1 IAA and 3 CIAAs would be too low. Preterm infants should receive HMFs which provide adequate amounts of AAs which are needed for their rapid growth and development while avoiding excessive intakes. In particular, very high AA requirements of ELBW infants are a challenge. AA composition of present HMFs for preterm infants should be reconsidered: spiking HMF protein with the AAs which are presently undersupplied or providing targeted AA-based HMF are options to further improve the AA profile in fortifiers.

Comparison between Efficacy of Human Milk Fortification Using Human Milk Fortifier versus Preterm Formula: A Retrospective Single-institutional Experience.

This study sought to evaluate the relative efficacy of expressed breast milk (EBM) fortified using human milk fortifier (HMF) compared to commercial preterm formula (PF) on preterm and very low birth weight (VLBW) infants in a major tertiary healthcare center in Oman. This retrospective cohort study included two cohorts of preterm (< 32 weeks gestation) or VLBW infants (birth weight < 1500 g) treated in the neonatal intensive care unit (NICU). Cohort one included infants who were given PF-fortified EBM between January and December 2016, and cohort two were given newly-introduced HMF-fortified EBM between November 2018 and December 2019. Analysis was performed to compare the cohorts with respect to baseline characteristics, primary outcomes, and secondary outcomes. A total of 103 neonates were included (cohort 1: n = 55, cohort 2: n = 48). There were no significant differences in the growth of the weekly length, the growth of the head circumference, or discharge growth parameters. Compared to PF, HMF was associated with significantly better weight gain velocity (g/kg/day) during the first week (p = 0.009) and second week (p = 0.050) after starting fortification, lower need for other adjunctive forms of fortification (p = 0.035), and lower rates of necrotizing enterocolitis in premature infants or VLBW (p = 0.018). This is likely to be the first study to analyze the relative efficacy of HMF and PF in the Middle East. The results of this study will be helpful in guiding standards of nutritional care in NICUs in Oman.

Human Milk-Based or Bovine Milk-Based Fortifiers Differentially Impact the Development of the Gut Microbiota of Preterm Infants.

Background: Preterm infants are exposed to different dietary inputs during their hospitalization in the neonatal intensive care unit (NICU). These include human milk (HM), with a human milk-based (HMF) or a bovine milk-based (BMF) fortifier, or formula. Milk consumption and the type of fortification will cause changes in the gut microbiota structure of preterm infants. This study aimed to characterize the gut microbiota of PT infant according to the type of feeding and the type of HM fortification and its possible association with infant's growth.Methods: Ninety-seven infants born ≤33 wks of gestation or <1,500 g were followed during the hospitalization period in the NICU after birth until discharge. Clinical and dietary information was collected, including mode of delivery, pregnancy complications, mechanical ventilation, use of antibiotics, weight, and type and amount of milk consumed. To characterize the gut microbiota composition, weekly stool samples were collected from study participants. The V3–V4 region of the 16S rRNA bacterial gene was Sequenced using Illumina MiSeq technology.Results: After birth, black maternal race, corrected gestational age (GA) and exposure to pregnancy complications, had a significant effect on gut microbial diversity and the abundance of Enterococcus, Veillonella, Bifidobacterium, Enterobacter, and Bacteroides. Over the course of hospitalization, corrected GA and exposure to chorioamnionitis remained to have an effect on gut microbial composition. Two different enterotypes were found in the gut microbiota of preterm infants. One enriched in Escherichia-Shigella, and another enriched in uncharacterized Enterobacteriaceae, Klebsiella and Clostridium sensu stricto 1. Overall, HM and fortification with HMF were the most common feeding strategies. When consuming BMF, PT infants had higher growth rates than those consuming HMF. Milk and type of fortification were significantly associated with the abundance of Clostridium sensu stricto 1, Bifidobacterium and Lactobacillus.Conclusions: This observational study shows the significant association between milk consumption and the exposure to HMF or BMF fortification in the fecal microbiota composition of preterm infants. Additionally, these results show the effect of other perinatal factors in the establishment and development of PT infant's gut microbiota.

Evidence summary of human milk fortifier in preterm infants.

BackgroundTo search for and collect evidence on human milk fortifier in preterm infants, and to summarize the latest and best evidence, so as to provide reference for clinical work.MethodsWe searched the databases of UpToDate, American Guide Network, Cochrane Library, Joanna Briggs Institute (JBI), PubMed, ResearchGate, China National Knowledge Infrastructure (CNKI), Wan Fang, Chinese Biology Medicine disc (CBM), and Yi Maitong, and collected relevant guidelines, systematic reviews, evidence summaries, expert consensuses, and randomized controlled trials (RCTs). The retrieval time limit was from the database establishment to July 2021. The quality of the literature was independently evaluated by 2 researchers, who then extracted and summarized the evidence from qualifying articles.ResultsA total of 16 articles were selected, including 3 guidelines, 3 systematic reviews, 5 expert consensuses, 3 RCTs, and 1 best practice guideline, including indications, time for usage, methods, monitoring and management, time of cessation, health education, and post-discharge feeding.ConclusionsThis study summarized the best evidence for human milk fortifier in preterm infants. Medical staff should assess the specific clinical conditions and parental wishes when applying the best evidence to ensure the effectiveness and safety of human milk fortifier, thus improving the quality of clinical nursing.

Early versus delayed introduction of human milk fortification in enterally fed preterm infants: A systematic review and meta-analysis.

To assess effects of early versus delayed introduction of human milk fortification in preterm infants. We searched Cochrane Central Register of Controlled Trials, MEDLINE, Embase, PubMed and CINAHL for randomised controlled trials evaluating start time for human milk fortification in preterm infants (March 2020). Two authors assessed trial eligibility and risk of bias, extracted data and assessed evidence certainty. We identified 1307 publications and included three trials (378 infants). Meta-analysis comparing fortification commencing at an enteral feed volume of ≤40 mL/kg/day versus ≥75 mL/kg/day, showed little to no difference in rates of necrotising enterocolitis (3 trials), sepsis (3 trials), feeding intolerance (2 trials) (low-quality evidence) and infant growth (1 trial, very low-quality evidence). Whether early introduction of fortification, at an enteral feed volume of ≤40 mL versus delayed at ≥75 mL/kg/day improves growth or influences adverse feeding outcomes is very uncertain.