Mineral supplementation for very preterm infants fed fortified human milk.

OBJECTIVES: The safety and feasibility of human milk fortification with bovine colostrum (BC) were investigated in very preterm infants (FortiColos trial, NCT03537365). The BC product contained lower calcium, phosphate, and iron levels compared to the conventional fortifier (CF). We tested whether fortification with BC plus extra phosphate was sufficient to support the infants' mineral status assessed by blood biochemistry. METHODS: In a randomised controlled trial (FortiColos, NCT03537365), mineral status was compared after fortification with BC versus CF. Blood calcium, phosphate, and haemoglobin were determined before and up to 3 weeks after the start of fortification (at the mean age of 8-9 days). The maximum supplemental doses of calcium, phosphate, and iron given were retrieved from patient medical records. Results were adjusted for gestational age, birth weight, and enteral nutrition with the mother's own milk and/or donor human milk. RESULTS: Blood values of calcium, phosphate, and haemoglobin were similar between groups. Infants in both groups required supplementation with calcium and phosphate, but infants fed BC required higher maximum doses of phosphate and calcium (p < 0.05) to maintain acceptable blood values. Regardless of fortification groups, the most immature (<29 weeks of gestation) and small for gestational age infants showed a higher risk for requiring additional phosphate (odds ratio [OR]: 3.9, p < 0.001; OR: 2.14, p = 0.07, respectively). CONCLUSIONS: The use of BC as a fortifier for human milk requires additional phosphate and calcium relative to a CF. Regardless of the fortification product, the most immature and small infants require additional mineral supplementation.

Bovine colostrum to supplement the first feeding of very preterm infants: The PreColos randomized controlled trial.

BACKGROUND & AIMS: Gut immaturity leads to feeding difficulties in very preterm infants (<32 weeks gestation at birth). Maternal milk (MM) is the optimal diet but often absent or insufficient. We hypothesized that bovine colostrum (BC), rich in protein and bioactive components, improves enteral feeding progression, relative to preterm formula (PF), when supplemented to MM. Aim of the study is to determine whether BC supplementation to MM during the first 14 days of life shortens the time to full enteral feeding (120 mL/kg/d, TFF120). METHODS: This was a multicenter, randomized, controlled trial at seven hospitals in South China without access to human donor milk and with slow feeding progression. Infants were randomly assigned to receive BC or PF when MM was insufficient. Volume of BC was restricted by recommended protein intake (4-4.5 g/kg/d). Primary outcome was TFF120. Feeding intolerance, growth, morbidities and blood parameters were recorded to assess safety. RESULTS: A total of 350 infants were recruited. BC supplementation had no effect on TFF120 in intention-to-treat analysis [n (BC) = 171, n (PF) = 179; adjusted hazard ratio, aHR: 0.82 (95% CI: 0.64, 1.06); P = 0.13]. Body growth and morbidities did not differ, but more cases of periventricular leukomalacia were detected in the infants fed BC (5/155 vs. 0/181, P = 0.06). Blood chemistry and hematology data were similar between the intervention groups. CONCLUSIONS: BC supplementation during the first two weeks of life did not reduce TFF120 and had only marginal effects on clinical variables. Clinical effects of BC supplementation on very preterm infants in the first weeks of life may depend on feeding regimen and remaining milk diet. TRIAL REGISTRATION: http://www. CLINICALTRIALS: gov: NCT03085277.

Bovine colostrum as a fortifier to human milk in very preterm infants - A randomized controlled trial (FortiColos).

BACKGROUND: Human milk for very preterm infants need fortification for optimal growth and development but the optimal fortification product remains to be identified. AIMS: To investigate feasibility, safety and preliminary efficacy on growth and blood biochemistry when using intact bovine colostrum (BC) as a fortifier to human milk in very preterm infants. METHODS: In an open-label, multicenter, randomized controlled pilot trial (infants 26-31 weeks' gestation), mother's own milk or donor human milk was fortified with powdered BC (n = 115) or a conventional fortifier (CF, bovine-milk-based, n = 117) until 35 weeks' postmenstrual age. Fortifiers and additional micronutrients were added to human milk according to local guidelines to achieve optimal growth (additional protein up to +1.4 g protein/100 mL human milk). Anthropometry was recorded weekly. Clinical morbidities including necrotizing enterocolitis (NEC) and late-onset sepsis (LOS) were recorded. Clinical biochemistry included plasma amino acid (AA) levels to assess protein metabolic responses to the new fortifier. RESULTS: A total of 232 infants, gestational age (GA) 28.5 ± 1.4 (weeks + days), fulfilled inclusion criteria. Birthweight, GA and delta Z scores from birth to end of intervention on weight, length or head circumference did not differ between groups, nor between the subgroups of small for gestational age infants. Likewise, incidence of NEC (BC: 3/115 vs. CF: 5/117, p = 0.72, unadjusted values), LOS (BC: 23/113 vs. CF: 14/116, p = 0.08) and other morbidities did not differ. BC infants received more protein than CF infants (+10%, p < 0.05) and showed several elevated AA levels (+10-40%, p < 0.05). CONCLUSION: Infants fortified with BC showed similar growth but received more protein and showed a moderate increase in plasma AA-levels, compared with CF. Adjustments in protein composition and micronutrients in BC-based fortifiers may be required to fully suit the needs for very preterm infants.

Enteral Nutrition in Preterm Infants (2022): A Position Paper From the ESPGHAN Committee on Nutrition and Invited Experts.

OBJECTIVES: To review the current literature and develop consensus conclusions and recommendations on nutrient intakes and nutritional practice in preterm infants with birthweight <1800 g. METHODS: The European Society of Pediatric Gastroenterology, Hepatology and Nutrition (ESPGHAN) Committee of Nutrition (CoN) led a process that included CoN members and invited experts. Invited experts with specific expertise were chosen to represent as broad a geographical spread as possible. A list of topics was developed, and individual leads were assigned to topics along with other members, who reviewed the current literature. A single face-to-face meeting was held in February 2020. Provisional conclusions and recommendations were developed between 2020 and 2021, and these were voted on electronically by all members of the working group between 2021 and 2022. Where >90% consensus was not achieved, online discussion meetings were held, along with further voting until agreement was reached. RESULTS: In general, there is a lack of strong evidence for most nutrients and topics. The summary paper is supported by additional supplementary digital content that provide a fuller explanation of the literature and relevant physiology: introduction and overview; human milk reference data; intakes of water, protein, energy, lipid, carbohydrate, electrolytes, minerals, trace elements, water soluble vitamins, and fat soluble vitamins; feeding mode including mineral enteral feeding, feed advancement, management of gastric residuals, gastric tube placement and bolus or continuous feeding; growth; breastmilk buccal colostrum, donor human milk, and risks of cytomegalovirus infection; hydrolyzed protein and osmolality; supplemental bionutrients; and use of breastmilk fortifier. CONCLUSIONS: We provide updated ESPGHAN CoN consensus-based conclusions and recommendations on nutrient intakes and nutritional management for preterm infants.

A Randomized, Controlled Study to Investigate How Bovine Colostrum Fortification of Human Milk Affects Bowel Habits in Preterm Infants (FortiColos Study).

Background: Human milk does not meet the nutritional needs to support optimal growth of very preterm infants during the first weeks of life. Nutrient fortifiers are therefore added to human milk, though these products are suspected to increase gut dysmotility. The objective was to evaluate whether fortification with bovine colostrum (BC) improves bowel habits compared to a conventional fortifier (CF) in very preterm infants. Methods: In an unblinded, randomized study, 242 preterm infants (26−31 weeks of gestation) were randomized to receive BC (BC, Biofiber Damino, Gesten, Denmark) or CF (FM85 PreNAN, Nestlé, Vevey, Switzerland) as a fortifier. Stools (Amsterdam Stool Scale), bowel gas restlessness, stomach appearance score, volume, and frequency of gastric residuals were recorded before each meal until 35 weeks post-menstrual age. Results: As intake of fortifiers increased, stools became harder in both groups (p < 0.01) though less in BC infants (p < 0.05). The incidence of bowel gas restlessness increased with laxative treatments and days of fortification in both groups (p < 0.01), but laxatives were prescribed later in BC infants (p < 0.01). With advancing age, stomach appearance scores improved, but more so in BC infants (p < 0.01). Conclusions: Although there are limitations, a minimally processed, bioactive milk product such as BC induced similar or slightly improved bowel habits in preterm infants.

Sex-Specific Effects of Nutritional Supplements for Infants Born Early or Small: An Individual Participant Data Meta-Analysis (ESSENCE IPD-MA) I-Cognitive Function and Metabolic Risk.

Neonatal nutritional supplements are widely used to improve growth and development but may increase risk of later metabolic disease, and effects may differ by sex. We assessed effects of supplements on later development and metabolism. We searched databases and clinical trials registers up to April 2019. Participant-level data from randomised trials were included if the intention was to increase macronutrient intake to improve growth or development of infants born preterm or small-for-gestational-age. Co-primary outcomes were cognitive impairment and metabolic risk. Supplementation did not alter cognitive impairment in toddlers (13 trials, n = 1410; adjusted relative risk (aRR) 0.88 [95% CI 0.68, 1.13]; p = 0.31) or older ages, nor alter metabolic risk beyond 3 years (5 trials, n = 438; aRR 0.94 [0.76, 1.17]; p = 0.59). However, supplementation reduced motor impairment in toddlers (13 trials, n = 1406; aRR 0.76 [0.60, 0.97]; p = 0.03), and improved motor scores overall (13 trials, n = 1406; adjusted mean difference 1.57 [0.14, 2.99]; p = 0.03) and in girls not boys (p = 0.03 for interaction). Supplementation lowered triglyceride concentrations but did not affect other metabolic outcomes (high-density and low-density lipoproteins, cholesterol, fasting glucose, blood pressure, body mass index). Macronutrient supplementation for infants born small may not alter later cognitive function or metabolic risk, but may improve early motor function, especially for girls.

Sex-Specific Effects of Nutritional Supplements for Infants Born Early or Small: An Individual Participant Data Meta-Analysis (ESSENCE IPD-MA) II: Growth.

Neonatal nutritional supplements may improve early growth for infants born small, but effects on long-term growth are unclear and may differ by sex. We assessed the effects of early macronutrient supplements on later growth. We searched databases and clinical trials registers from inception to April 2019. Participant-level data from randomised trials were included if the intention was to increase macronutrient intake to improve growth or development of infants born preterm or small-for-gestational-age. Co-primary outcomes were cognitive impairment and metabolic risk. Supplementation did not alter BMI in childhood (kg/m2: adjusted mean difference (aMD) -0.11[95% CI -0.47, 0.25], p = 0.54; 3 trials, n = 333). Supplementation increased length (cm: aMD 0.37[0.01, 0.72], p = 0.04; 18 trials, n = 2008) and bone mineral content (g: aMD 10.22[0.52, 19.92], p = 0.04; 6 trials, n = 313) in infancy, but not at older ages. There were no differences between supplemented and unsupplemented groups for other outcomes. In subgroup analysis, supplementation increased the height z-score in male toddlers (aMD 0.20[0.02, 0.37], p = 0.03; 10 trials, n = 595) but not in females, and no significant sex interaction was observed (p = 0.21). Macronutrient supplementation for infants born small may not alter BMI in childhood. Supplementation increased growth in infancy, but these effects did not persist in later life. The effects did not differ between boys and girls.

Nutrient Restriction has Limited Short-Term Effects on Gut, Immunity, and Brain Development in Preterm Pigs.

BACKGROUND: Extrauterine growth restriction (EUGR) in preterm infants is associated with higher morbidity and impaired neurodevelopment. Early nutrition support may prevent EUGR in preterm infants, but it is not known if this improves organ development and brain function in the short and long term. OBJECTIVE: Using pigs as models for infants, we hypothesized that diet-induced EUGR impairs gut, immunity, and brain development in preterm neonates during the first weeks after birth. METHODS: Forty-four preterm caesarean-delivered pigs (Danish Landrace × Large White × Duroc, birth weight 975 ± 235 g, male:female ratio 23:21) from 2 sows were fed increasing volumes [32-180 mL/(kg·d)] of dilute bovine milk (EUGR group) or the same diet fortified with powdered bovine colostrum for 19 d (CONT group, 50-100% higher protein and energy intake than the EUGR group). RESULTS: The EUGR pigs showed reduced body growth (-39%, P < 0.01), lower plasma albumin, phosphate, and creatine kinase concentrations (-35 to 14%, P < 0.05), increased cortisol and free iron concentrations (+130 to 700%, P < 0.05), and reduced relative weights of the intestine, liver, and spleen (-38 to 19%, all P < 0.05). The effects of EUGR on gut structure, function, microbiota, and systemic immunity were marginal, although EUGR temporarily increased type 1 helper T cell (Th1) activity (e.g. more blood T cells and higher Th1-related cytokine concentrations on day 8) and reduced colon nutrient fermentation (lower SCFA concentration; -45%, P < 0.01). Further, EUGR pigs showed increased relative brain weights (+19%, P < 0.01), however, memory and learning, as tested in a spatial T-maze, were not affected. CONCLUSION: Most of the measured organ growth, and digestive, immune, and brain functions showed limited effects of diet-induced EUGR in preterm pigs during the first weeks after birth. Likewise, preterm infants may show remarkable physiological adaptation to deficient nutrient supply during the first weeks of life although early life malnutrition may exert negative consequences later.

FortiColos - a multicentre study using bovine colostrum as a fortifier to human milk in very preterm infants: study protocol for a randomised controlled pilot trial.

BACKGROUND: Very preterm infants (< 32 weeks gestation) have a relatively high nutrient requirement for growth and development. The composition of human milk is often inadequate to ensure optimal growth so it is common to fortify human milk for very preterm infants with nutrient fortifiers based on bovine milk. However, there are concerns that bovine milk-based fortifiers may increase the risk of feeding intolerance, necrotizing enterocolitis and late-onset sepsis. We hypothesize that a bovine colostrum-based product is a suitable alternative to bovine milk-based products when used as a fortifier to human milk in very preterm infants. METHODS/DESIGN: In an open-label multicentre randomised controlled pilot trial, 200 very preterm infants (26 + 0 to 30 + 6 weeks gestation at birth) will be randomly allocated to a bovine colostrum-based or a bovine milk-based fortifier added to mother's own milk and/or human donor milk. Outcomes are growth rate, incidence of necrotizing enterocolitis and late-onset sepsis, a series of paraclinical endpoints, and practical feasibility of using the novel fortifier for very preterm infants. DISCUSSION: The optimal enteral diet and feeding regimen for very preterm infants remain debated; this clinical trial will document the feasibility, safety and preliminary efficacy of using bovine colostrum, rich in nutrients and bioactive factors, as a novel fortifier for human milk to very preterm infants. Data on infant growth, metabolism, gut function and immunity will be assessed from clinical data as well as blood and stool samples. TRIAL REGISTRATION: Registered retrospectively 25 May 2018 at ClinicalTrials.gov: NCT03537365 .

Free Amino Acids in Human Milk and Associations With Maternal Anthropometry and Infant Growth.

OBJECTIVES: Free glutamic acid has an appetite-regulating effect and studies with infant formula have suggested that free amino acids (FAA), especially glutamic acid, can downregulate intake. The content of glutamic acid and glutamine is high in breast milk but varies considerably between mothers. The aim was to investigate whether maternal anthropometry was associated with the content of the FAA glutamic acid or glutamine in breast milk and whether there was a negative association between these FAA and current size or early infant growth in fully breastfed infants. METHODS: From a subgroup of 78 mothers, of which 50 were fully breast feeding, from the Odense Child Cohort breast milk samples were collected 4 months after birth and analyzed for FAA. Information regarding breastfeeding status and infant weight and length was also recorded. RESULTS: There was a large variation in the concentration of the FAAs between mothers. Glutamic acid was positively correlated with mother's prepregnancy weight and height (P ≤ 0.028), but not body mass index. There was no negative correlation between the 2 FAA and infant weight or body mass index. Infant length at 4 months was, however, positively associated with glutamine, (P = 0.013) but the correlation was attenuated when controlling for birth length (P = 0.089). CONCLUSIONS: The hypothesis that a high content of glutamic acid and glutamine in breast milk could downregulate milk intake to a degree affecting early growth could not be confirmed. Maternal factors associated with the level of these FAA in milk and the potential effect on the infant should be investigated further.

Intravenous iron administration together with parenteral nutrition to very preterm Jehovah's Witness twins.

Preterm twin sisters (monozygotic) were born at gestational age 27 weeks and 5 days with birth weights of 935 and 735 g. They were admitted to our neonatal intensive care unit for a period of 1 month. Their parents were Jehovah's Witnesses and refused blood transfusion for their preterm daughters. Subcutaneous erythropoietin and intravenous iron were given as a prophylactic to avoid anaemia.