Milk-Based Bionutrient Trials to Improve Outcomes in Preterm Infants: Challenges and Opportunities.

OBJECTIVE: Bionutrients (or immunonutrients) are dietary components present in milk, or supplements that could be added to milk diets, that impact health and disease. With few exceptions, most of these are present in human breastmilk and the majority are also present in amniotic fluid. STUDY DESIGN: Bionutrients can be proteins and peptides including enzymes, hormones, immunoglobulins, and growth factors and can also be molecules such as human milk oligosaccharides, amino acids, or lipids such as docosahexaenoic acid. Many of these have ancient origins, are found in other species, and existed before mammalian lactation evolved. Bionutrients may act in diverse ways when administered enterally: they may impact gut bacterial communities or epithelial cell metabolism, or they may pass into the lamina propria where they interact with the gut and systemic immune systems. Clinical trials have often used bovine analogs such as lactoferrin or may use artificially synthesized or recombinant compounds including insulin, bile salt stimulated lipase, or oligosaccharides. RESULTS: Challenges arise because the bioactivity of proteins, such as lactoferrin, may be affected by processing and pasteurization meaning that the impacts of commercial products may differ. The challenge of determining the optimal bioactivity of any single preparation may be even greater in complex compounds such as milk fat globule membrane. It is also possible that bioactivity is affected by the milk matrix, that is, may differ between formula and human milk. CONCLUSION: Finally, it is important to appreciate that nutrients do not function in isolation, and most will not act like drugs, that is, they may take several days or longer to exert an affect. KEY POINTS: · Breastmilk contains high concentrations of bionutrients and provides more than macro- and micronutrients.. · Bionutrients can be proteins (e.g. enzymes, hormones, or immunoglobulins) or molecules (e.g. human milk oligosaccharides or amino acids).. · Bionutrients can be added to milk feeds but high quality trials are needed..

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.

Fifteen-minute consultation: ABCDE approach to nutritional assessment in preterm infants.

The last 20 years has seen dramatic improvements in the survival of preterm infants due to improved antenatal and neonatal care. Closer attention to nutrition means early parenteral nutrition and mother's own milk are considered as standard of care. Many uncertainties remain however, such as optimal macronutrient intakes for longer term cognitive and metabolic outcomes, and the optimal probiotic regime to reduce the risk of necrotising enterocolitis. Nutrition involves macronutrients and micronutrients, immunonutrients, microbiomic aspects and nutrient delivery. It is also clear that there are behavioural and psychological aspects, and strongly held beliefs for parents and professionals that affect practice. While many healthcare professionals (HCPs) are aware of several key nutritional concepts on the neonatal intensive care unit (NICU), many HCPs lack a concise, systematic approach. This article provides a brief approach to nutritional assessment for use on the NICU summarised as ABCDE: A-anthropometry, B-biochemistry, C-clinical, D-dietary intakes, E-environment and evaluation.

Protein intakes to optimize outcomes for preterm infants.

Proteins are key structural components of all human cells and are also involved in key physiologic processes through their roles as enzymes, hormones and transport proteins. Protein requirements are substantially higher in preterm infants than those born at term, yet inadequate protein intakes are a common problem on many neonatal units. Very preterm infants (VPT, <32 weeks) commonly receive parenteral amino acid solutions which are typically commenced on admission, and increased over the next few days. Several recent studies have explored differing parenteral amino acid intakes in the first few days, and recommendations have recently been updated. Parenteral nutrition intakes are decreased as enteral feeds are tolerated, but human milk alone will not meet protein needs in most VPT and supplementation or fortification will be required. This review paper considers basic protein and amino acid physiology in the newborn period, and the evidence base for current recommendations.

Nutrient-enriched formula versus standard formula for preterm infants.

BACKGROUND: Preterm infants may accumulate nutrient deficits leading to extrauterine growth restriction. Feeding preterm infants with nutrient-enriched rather than standard formula might increase nutrient accretion and growth rates and might improve neurodevelopmental outcomes. OBJECTIVES: To compare the effects of feeding with nutrient-enriched formula versus standard formula on growth and development of preterm infants. SEARCH METHODS: We used the Cochrane Neonatal standard search strategy. This included electronic searches of the Cochrane Central Register of Controlled Trials (CENTRAL; 2018, Issue 11), MEDLINE, Embase, and the Cumulative Index to Nursing and Allied Health Literature (until November 2018), as well as conference proceedings, previous reviews, and clinical trials databases. SELECTION CRITERIA: Randomised and quasi-randomised controlled trials that compared feeding preterm infants with nutrient-enriched formula (protein and energy plus minerals, vitamins, or other nutrients) versus standard formula. DATA COLLECTION AND ANALYSIS: We extracted data using the Cochrane Neonatal standard methods. Two review authors separately evaluated trial quality and extracted and synthesised data using risk ratios (RRs), risk differences, and mean differences (MDs). We assessed certainty of evidence at the outcome level using Grading of Recommendations Assessment, Development and Evaluation (GRADE) methods. MAIN RESULTS: We identified seven trials in which a total of 590 preterm infants participated. Most participants were clinically stable preterm infants of birth weight less than 1850 g. Few participants were extremely preterm, extremely low birth weight, or growth restricted at birth. Trials were conducted more than 30 years ago, were formula industry funded, and were small with methodological weaknesses (including lack of masking) that might bias effect estimates. Meta-analyses of in-hospital growth parameters were limited by statistical heterogeneity. There is no evidence of an effect on time to regain birth weight (MD -1.48 days, 95% confidence interval (CI) -4.73 to 1.77) and low-certainty evidence suggests that feeding with nutrient-enriched formula increases in-hospital rates of weight gain (MD 2.43 g/kg/d, 95% CI 1.60 to 3.26) and head circumference growth (MD 1.04 mm/week, 95% CI 0.18 to 1.89). Meta-analysis did not show an effect on the average rate of length gain (MD 0.22 mm/week, 95% CI -0.70 to 1.13). Fewer data are available for growth and developmental outcomes assessed beyond infancy, and these do not show consistent effects of nutrient-enriched formula feeding. Data from two trials did not show an effect on Bayley Mental Development Index scores at 18 months post term (MD 2.87, 95% CI -1.38 to 7.12; moderate-certainty evidence). Infants who received nutrient-enriched formula had higher Bayley Psychomotor Development Index scores at 18 months post term (MD 6.56. 95% CI 2.87 to 10.26; low-certainty evidence), but no evidence suggested an effect on cerebral palsy (typical RR 0.79, 95% CI 0.30 to 2.07; 2 studies, 377 infants). Available data did not indicate any other benefits or harms and provided low-certainty evidence about the effect of nutrient-enriched formula feeding on the risk of necrotising enterocolitis in preterm infants (typical RR 0.72, 95% CI 0.41 to 1.25; 3 studies, 489 infants). AUTHORS' CONCLUSIONS: Available trial data show that feeding preterm infants nutrient-enriched (compared with standard) formulas has only modest effects on growth rates during their initial hospital admission. No evidence suggests effects on long-term growth or development. The GRADE assessment indicates that the certainty of this evidence is low, and that these findings should be interpreted and applied with caution. Further randomised trials would be needed to resolve this uncertainty.

Current Therapeutic Management of Perinatal Stroke with a Focus on the Upper Limb: A Cross-Sectional Survey of UK Physiotherapists and Occupational Therapists.

AIM: To determine current UK pediatric physiotherapist (PT) and occupational therapist (OT) management of perinatal stroke. DESIGN: Web-based cross-sectional survey. METHODS: Participants were members of the Association of Paediatric Chartered Physiotherapists and Occupational Therapists specialist section: children young people and families working with infants. Items covered prioritization of referrals, assessments, therapy approaches aimed at the upper limb, and parental support. RESULTS: 179 therapists responded. 87.2% of PTs and 63.0% of OTs managed infants with perinatal stroke. Infants with clinical signs of motor dysfunction at referral were prioritized for early initial assessment. The most frequently used assessments were the Alberta Infant Motor Scale (AIMS) and Bayley Scales of Infant Development (BSID). Of PTs and OTs, 41.9 and 40.0% used no standardized assessments. Frequently used therapy interventions were Bobath/Neurodevelopmental Therapy (NDT), positioning aids and passive movements. 88.1% of therapists would choose a bilateral rather than unilateral (affected side) therapy approach for infants with perinatal stroke aged up to 6 months. Of PTs and OTs, 56.9 and 57.1% provided psychological support to families. CONCLUSIONS: Assessment and provision of therapy services following perinatal stroke is variable. Increased use of standardized assessments and centralized data collection regarding service provision for high-risk infants is recommended.

Nutrition in the preterm infant: what's new?

PURPOSE OF REVIEW: The increasing recognition of the role of nutritional care for preterm infants continues to result in a proliferation of review articles, systematic reviews, observational studies and trials. In this article, we review a selection of important studies published in the last 12­18 months. RECENT FINDINGS: The selected studies demonstrate the potential importance of light protecting parenteral nutrition solutions, the benefits of standardized concentrated parenteral nutrition solutions and the importance of insulin-like growth factor I in early life. Trials of immunonutrients (such as bile salt-stimulated lipase) and other bioactive peptides such as lactoferrin are in progress, and emerging data highlight the importance of vitamin D for immune regulation, and therefore its role in sepsis and gut function. Early oro-pharyngeal administration of colostrum appears to safely improve early immune development, and supports the increasingly common practice of immediate commencement of mothers' own breast milk. Despite this, studies continue to show that breastfeeding continuation rates could be improved. Data also highlight the potential role of macronutrient supply on other functional outcomes, such as retinopathy of prematurity. Finally, the importance of the unique nutritional needs of late and moderately preterm infants is starting to be recognized ­ a much larger group than the extremely preterm infants in whom many studies are focused. SUMMARY: Earlier, more aggressive nutrient supply and feeding regimes, including optimal support of breastfeeding mothers to ensure adequate provision of own mother's milk, appear to improve growth and neurodevelopmental outcomes. The addition of bioactive proteins shows promise. Special focus needs to be reestablished for late and moderately preterm infants, who have particular nutritional and feeding support requirements. This review has highlighted the need for further research particularly in the areas of early parenteral nutrition, the optimal regime to improve early growth and neuronal effects, the optimal rate of growth and/or catch-up, and the role of immune nutrients.

Multi-nutrient fortification of human milk for preterm infants.

BACKGROUND: Exclusively breast milk-fed preterm infants may accumulate nutrient deficits leading to extrauterine growth restriction. Feeding preterm infants with multi-nutrient fortified human breast milk rather than unfortified breast milk may increase nutrient accretion and growth rates and may improve neurodevelopmental outcomes. OBJECTIVES: To determine whether multi-nutrient fortified human breast milk improves important outcomes (including growth and development) over unfortified breast milk for preterm infants without increasing the risk of adverse effects (such as feed intolerance and necrotising enterocolitis). SEARCH METHODS: We used the standard search strategy of the Cochrane Neonatal Review Group. This included electronic searches of the Cochrane Central Register of Controlled Trials (CENTRAL; 2016, Issue 2), MEDLINE, EMBASE and the Cumulative Index to Nursing and Allied Health Literature (CINAHL) (until February 2016), as well as conference proceedings and previous reviews. SELECTION CRITERIA: Randomised and quasi-randomised controlled trials that compared feeding preterm infants with multi-nutrient (protein and energy plus minerals, vitamins or other nutrients) fortified human breast milk versus unfortified (no added protein or energy) breast milk. DATA COLLECTION AND ANALYSIS: We extracted data using the standard methods of the Cochrane Neonatal Review Group. We separately evaluated trial quality, data extracted by two review authors and data synthesised using risk ratios (RRs), risk differences and mean differences (MDs). We assessed the quality of evidence at the outcome level using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach. MAIN RESULTS: We identified 14 trials in which a total of 1071 infants participated. The trials were generally small and weak methodologically. Meta-analyses provided low-quality evidence that multi-nutrient fortification of breast milk increases in-hospital rates of growth (MD 1.81 g/kg/d, 95% confidence interval (CI) 1.23 to 2.40); length (MD 0.12 cm/wk, 95% CI 0.07 to 0.17); and head circumference (MD 0.08 cm/wk, 95% CI 0.04 to 0.12). Only very limited data are available for growth and developmental outcomes assessed beyond infancy, and these show no effects of fortification. The data did not indicate other potential benefits or harms and provided low-quality evidence that fortification does not increase the risk of necrotising enterocolitis in preterm infants (typical RR 1.57, 95% CI 0.76 to 3.23; 11 studies, 882 infants). AUTHORS' CONCLUSIONS: Limited available data do not provide strong evidence that feeding preterm infants with multi-nutrient fortified breast milk compared with unfortified breast milk affects important outcomes, except that it leads to slightly increased in-hospital growth rates.

Routine Use of Probiotics in Preterm Infants: Longitudinal Impact on the Microbiome and Metabolome.

BACKGROUND: Probiotics are live microbial supplements that colonize the gut and potentially exert health benefit to the host. OBJECTIVES: We aimed to determine the impact of a probiotic (Infloran®: Lactobacillus acidophilus-NCIMB701748 and Bifidobacterium bifidum-ATCC15696) on the bacterial and metabolic function of the preterm gut while in the neonatal intensive care unit (NICU) and following discharge. METHODS: Stool samples (n = 88) were collected before, during, and after probiotic intake from 7 patients, along with time-matched controls from 3 patients. Samples were also collected following discharge home from the NICU. Samples underwent bacterial profiling analysis by 16S rRNA gene sequencing and quantitative PCR (qPCR), as well as metabolomic profiling using liquid chromatography mass spectrometry. RESULTS: Bacterial profiling showed greater Bifidobacterium (15.1%) and Lactobacillus (4.2%) during supplementation compared to the control group (4.0% and 0%, respectively). While Lactobacillus became reduced after the probiotic had been stopped, Bifidobacterium remained high following discharge, suggestive of successful colonisation. qPCR analysis showed a significant increase (p ≤ 0.01) in B. bifidum in infants who received probiotic treatment compared to controls, but no significant increase was observed for L. acidophilus (p = 0.153). Metabolite profiling showed clustering based on receiving probiotic or matched controls, with distinct metabolites associated with probiotic administration. CONCLUSIONS: Probiotic species successfully colonise the preterm gut, reducing the relative abundance of potentially pathogenic bacteria, and effecting gut functioning. Bifidobacterium (but not Lactobacillus) colonised the gut in the long term, suggesting the possibility that therapeutically administered probiotics may continue to exert important functional effects on gut microbial communities in early infancy.

How to use... alkaline phosphatase in neonatology.

Alkaline phosphatase (ALP) is regularly measured in clinical practice. Changes in serum levels are observed in a number of clinical conditions. In neonatology, it has been proposed as a useful marker for both a diagnosis and an indication of the severity of metabolic bone disease (MBD) in infants born preterm. Nutritional practices, aimed at reducing the occurrence or severity of MBD, have led to ALP being proposed as a stand-alone means of monitoring treatment. The current evidence does not support this use: ALP only achieves usefulness in a diagnostic and monitoring capacity when combined with other serum and imaging techniques.

Oral-motor dysfunction at 10 months corrected gestational age in infants born less than 37 weeks preterm.

Feeding difficulties are common in preterm infants. These may be associated with inadequate dietary intake, poor growth, and parental anxiety. Oral-motor dysfunction has been observed in preterm infants during sucking and the early stages of weaning but has not been rigorously studied in later infancy when eating a range of food consistencies. We aimed to establish if oral-motor dysfunction during feeding occurs in preterm infants in later infancy and to explore the relationships with specific neonatal risk factors: gestational age at birth, prolonged supplementary oxygen requirement, and delay in establishing full oral feeding. Infants born less than 37 weeks gestational age were evaluated once at 10 months corrected gestational age using a validated feeding assessment (Schedule for Oral Motor Assessment). Fifteen infants were enrolled (9 males, 6 females; median gestational age at birth = 33 weeks, range = 25-36 weeks; median birth weight = 1890 g, range = 710-2950 g). Oral-motor dysfunction was observed in three infants all born after 31 weeks gestation. No relationship was found with the neonatal risk factors. This study indicates that oral-motor dysfunction may occur in later infancy and is not easily predicted from specific neonatal risk factors. Further study is required to evaluate the true prevalence and the health implications of oral-motor dysfunction in this population in later infancy.

Probiotics and other preventative strategies for necrotising enterocolitis.

Necrotising enterocolitis (NEC) remains one of the commonest causes of death and significant morbidity in preterm infants after the first few postnatal days. NEC affects approximately 5-10% of infants born at