The effect of lactoferrin supplementation on death or major morbidity in very low birthweight infants (LIFT): a multicentre, double-blind, randomised controlled trial.

BACKGROUND: Very low birthweight or preterm infants are at increased risk of adverse outcomes including sepsis, necrotising enterocolitis, and death. We assessed whether supplementing the enteral diet of very low-birthweight infants with lactoferrin, an antimicrobial protein, reduces all-cause mortality or major morbidity. METHODS: We did a multicentre, double-blind, pragmatic, randomised superiority trial in 14 Australian and two New Zealand neonatal intensive care units. Infants born weighing less than 1500 g and aged less than 8 days, were eligible and randomly assigned (1:1) using minimising web-based randomisation to receive once daily 200 mg/kg pasteurised bovine lactoferrin supplements or no lactoferrin supplement added to breast or formula milk until 34 weeks' post-menstrual age (or for 2 weeks, if longer), or until discharge from the study hospital if that occurred first. Designated nurses preparing the daily feeds were not masked to group assignment, but other nurses, doctors, parents, caregivers, and investigators were unaware. The primary outcome was survival to hospital discharge or major morbidity (defined as brain injury, necrotising enterocolitis, late-onset sepsis at 36 weeks' post-menstrual age, or retinopathy treated before discharge) assessed in the intention-to-treat population. Safety analyses were by treatment received. We also did a prespecified, PRISMA-compliant meta-analysis, which included this study and other relevant randomised controlled trials, to estimate more precisely the effects of lactoferrin supplementation on late-onset sepsis, necrotising enterocolitis, and survival. This trial is registered with the Australian and New Zealand Clinical Trials Registry, ACTRN12611000247976. FINDINGS: Between June 27, 2014, and Sept 1, 2017, we recruited 1542 infants; 771 were assigned to the intervention group and 771 to the control group. One infant who had consent withdrawn before beginning lactoferrin treatment was excluded from analysis. In-hospital death or major morbidity occurred in 162 (21%) of 770 infants in the intervention group and in 170 (22%) of 771 infants in the control group (relative risk [RR] 0·95, 95% CI 0·79-1·14; p=0·60). Three suspected unexpected serious adverse reactions occurred; two in the lactoferrin group, namely unexplained late jaundice and inspissated milk syndrome, but were not attributed to the intervention and one in the control group had fatal inspissated milk syndrome. Our meta-analysis identified 13 trials completed before Feb 18, 2020, including this Article, in 5609 preterm infants. Lactoferrin supplements significantly reduced late-onset sepsis (RR 0·79, 95% CI 0·71-0·88; p<0·0001; I2=58%), but not necrotising enterocolitis or all-cause mortality. INTERPRETATION: Lactoferrin supplementation did not improve death or major morbidity in this trial, but might reduce late-onset sepsis, as found in our meta-analysis of over 5000 infants. Future collaborative studies should use products with demonstrated biological activity, be large enough to detect moderate and clinically important effects reliably, and assess greater doses of lactoferrin in infants at increased risk, such as those not exclusively receiving breastmilk or infants of extremely low birthweight. FUNDING: Australian National Health and Medical Research Council.

Standardised neonatal parenteral nutrition formulations - Australasian neonatal parenteral nutrition consensus update 2017.

BACKGROUND: The first consensus standardised neonatal parenteral nutrition formulations were implemented in many neonatal units in Australia in 2012. The current update involving 49 units from Australia, New Zealand, Singapore, Malaysia and India was conducted between September 2015 and December 2017 with the aim to review and update the 2012 formulations and guidelines. METHODS: A systematic review of available evidence for each parenteral nutrient was undertaken and new standardised formulations and guidelines were developed. RESULTS: Five existing preterm Amino acid-Dextrose formulations have been modified and two new concentrated Amino acid-Dextrose formulations added to optimise amino acid and nutrient intake according to gestation. Organic phosphate has replaced inorganic phosphate allowing for an increase in calcium and phosphate content, and acetate reduced. Lipid emulsions are unchanged, with both SMOFlipid (Fresenius Kabi, Australia) and ClinOleic (Baxter Healthcare, Australia) preparations included. The physicochemical compatibility and stability of all formulations have been tested and confirmed. Guidelines to standardise the parenteral nutrition clinical practice across facilities have also been developed. CONCLUSIONS: The 2017 PN formulations and guidelines developed by the 2017 Neonatal Parenteral Nutrition Consensus Group offer concise and practical instructions to clinicians on how to implement current and up-to-date evidence based PN to the NICU population.

Summary of Proceedings and Expert Consensus Statements From the International Summit "Lipids in Parenteral Nutrition".

BACKGROUND: The 2018 Lipids in Parenteral Nutrition summit involved a panel of experts in clinical nutrition, lipid metabolism, and pharmacology, to assess the current state of knowledge and develop expert consensus statements regarding the use of intravenous lipid emulsions in various patient populations and clinical settings. The main purpose of the consensus statements is to assist healthcare professionals by providing practical guidance on common clinical questions related to the provision of lipid emulsions as part of parenteral nutrition (PN). METHODS: The summit was designed to allow interactive discussion and consensus development. The resulting consensus statements represent the collective opinion of the members of the expert panel, which was informed and supported by scientific evidence and clinical experience. RESULTS: The current article summarizes the key discussion topics from the summit and provides a set of consensus statements designed to complement existing evidence-based guidelines. Lipid emulsions are a major component of PN, serving as a condensed source of energy and essential fatty acids. In addition, lipids modulate a variety of biologic functions, including inflammatory and immune responses, coagulation, and cell signaling. A growing body of evidence suggests that lipid emulsions containing ω-3 fatty acids from fish oil confer important clinical benefits via suppression of inflammatory mediators and activation of pathways involved in the resolution of inflammation. CONCLUSIONS: This article provides a set of expert consensus statements to complement formal PN guideline recommendations.

Use of Lipids in Neonates Requiring Parenteral Nutrition.

Neonates have limited antioxidative capacity and are at increased risk of infection and inflammation-a situation that is exacerbated in preterm neonates. Together, oxidative stress and inflammation are implicated in many serious conditions affecting neonates, such as bronchopulmonary dysplasia and periventricular leukomalacia. Neonates requiring parenteral nutrition have certain nutritional requirements. For example, very long-chain ω-3 polyunsaturated fatty acids (PUFAs) such as docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA) are regarded as conditionally essential with critical roles during early retinal and brain development, and may also have other benefits such as anti-inflammatory effects. Because of these factors, the choice of lipid emulsion used as part of parenteral nutrition support may influence clinical outcomes in neonates. There are concerns that lipid emulsions based purely on soybean oil may increase lipid peroxidation, oxidative stress, and inflammation because of their high ω-6 PUFA and low ω-3 PUFA concentrations. Composite fish-oil containing lipid emulsions may provide advantages for neonates owing to their high DHA and EPA content and high antioxidant (α-tocopherol) levels. Here, we discuss clinical trials of lipid emulsions in preterm and term neonatal populations, with a particular emphasis on markers of oxidative stress and DHA and EPA levels. Olive oil/soybean oil lipid emulsions have shown few advantages in neonates over other lipid emulsions. However, compared with either pure soybean or soybean/olive-oil based emulsions, composite fish-oil containing lipid emulsions reduce oxidative stress/lipid peroxidation and also increase DHA and EPA levels. These advantages may translate into clinical benefits for neonates requiring parenteral nutrition.

Probiotic Supplementation and Late-Onset Sepsis in Preterm Infants: A Meta-analysis.

CONTEXT: Late-onset sepsis (LOS) is a major cause of mortality and morbidity in preterm infants. Despite various preventive measures, its incidence continues to remain high, hence the urgent need for additional approaches. One such potential strategy is supplementation with probiotics. The updated Cochrane Review (2014) did not find benefits of probiotics in reducing the risk of LOS in preterm infants (19 studies, N = 5338). Currently there are >30 randomized controlled trials (RCTs) of probiotics in preterm infants that have reported on LOS. OBJECTIVES: To conduct a systematic review including all relevant RCTs. DATA SOURCES: PubMed, Embase, Cochrane Central Register of Controlled Trials, Cumulative Index of Nursing and Allied Health Literature, and E-abstracts from the Pediatric Academic Society meetings and other pediatric and neonatal conference proceedings were searched in June and August 2015. STUDY SELECTION: RCTs comparing probiotics versus placebo/no probiotic were included. DATA EXTRACTION: Relevant data were extracted independently by 3 reviewers. RESULTS: Pooled results from 37 RCTs (N = 9416) using fixed effects model meta analysis showed that probiotics significantly decreased the risk of LOS (675/4852 [13.9%] vs 744/4564 [16.3%]; relative risk, 0.86; 95% confidence interval, 0.78-0.94; P = .0007; I(2) = 35%; number needed to treat, 44). The results were significant even after excluding studies with high risk of bias. CONCLUSIONS: Probiotic supplementation reduces the risk of LOS in preterm infants.

Lactobacillus reuteri DSM 17938 for managing infant colic: protocol for an individual participant data meta-analysis.

INTRODUCTION: Infant colic, or excessive crying of unknown cause in infants less than 3 months old, is common and burdensome. Its aetiology is undetermined, and consensus on its management is still lacking. Recent studies suggest a possible link between infant colic and gut microbiota, indicating probiotics to be a promising treatment. However, only a few strains have been tested, and results from randomised controlled trials are conflicting. It is important to clarify whether probiotics are effective for treating infant colic in general, and to identify whether certain subgroups of infants with colic would benefit from particular strains of probiotics. METHODS AND ANALYSIS: Through an individual participant data meta-analysis (IPDMA), we aim to identify whether the probiotic Lactobacillus reuteri DSM 17938 is effective in the management of infant colic, and to clarify whether its effects differ according to feeding method (breast vs formula vs combined), proton pump inhibitor exposure, and antibiotic exposure. The primary outcomes are infant crying duration and treatment success (at least 50% reduction in crying time from baseline) at 21 days postintervention. Individual participant data from all studies will be modelled simultaneously in multilevel generalised linear mixed-effects regression models to account for the nesting of participants within studies. Subgroup analyses of participant-level and intervention-level characteristics will be undertaken on the primary outcomes to assess if the intervention effect differs between certain groups of infants. ETHICS AND DISSEMINATION: Approved by the Royal Children's Hospital Human Research Ethics Committee (HREC 34081). Results will be reported in a peer-reviewed journal in 2015. TRIAL REGISTRATION NUMBER: PROSPERO CRD42014013210.

Benefits of probiotics on enteral nutrition in preterm neonates: a systematic review.

INTRODUCTION: The optimization of enteral nutrition is a priority in preterm neonates worldwide. Probiotics are known to improve gut maturity and function in preterm neonates. To our knowledge, previous systematic reviews have not adequately assessed the effects of probiotic supplementation on enteral nutrition in preterm neonates. OBJECTIVE: We assessed the evidence on effects of probiotics on enteral nutrition in preterm neonates. DESIGN: A systematic review of randomized controlled trials (RCTs) of probiotic supplementation in preterm (gestation <37 wk) or low-birth-weight (birth weight <2500 g) neonates was conducted. With the use of the Cochrane Neonatal Review Group strategy, we searched the Cochrane Central Register of Controlled Trials, PubMed, EMBASE, and Cumulative Index of Nursing and Allied Health Literature databases and proceedings of Pediatric Academic Society meetings in April 2014. RESULTS: A total of 25 RCTs (n = 5895) were included in the review. A meta-analysis (random-effects model) of data from 19 of 25 trials (n = 4527) estimated that the time to full enteral feeds was shorter in the probiotic group (mean difference: -1.54 d; 95% CI: -2.75, -0.32 d; P < 0.00001, I(2) = 93%). Other benefits included fewer episodes of feed intolerance, better weight gain and growth velocity, decreased transition time from orogastric to breast feeds, and increased postprandial mesenteric flow. There were no adverse effects of probiotic supplementation. CONCLUSIONS: Probiotics reduced the time to full enteral feeds in preterm neonates. Additional research is necessary to assess the optimal dose, duration, and probiotic strain or strains used specifically for facilitating enteral nutrition in this population.

Fish Oil (SMOFlipid) and olive oil lipid (Clinoleic) in very preterm neonates.

OBJECTIVES: Fat emulsions used in Australia for parenteral nutrition in preterm neonates have been based on either soybean oil or olive oil (OO). OO lipid Clinoleic has a high ratio of n-6 to n-3 fatty acids (9:1); this may not be ideal for long-chain polyunsaturated fatty acids supply. Newly available SMOFlipid has an appropriate ratio of n-6 to n-3 fatty acids (2.5:1). SMOFlipid also contains OO (25%), coconut oil (30%), and soybean oil (30%). The aims of the study were to evaluate the safety of the SMOFlipid and to test the hypothesis that SMOFlipid would lead to increased omega-3 long-chain polyunsaturated fatty acid levels and reduced oxidative stress as compared with Clinoleic in preterm neonates (<30 weeks). METHODS: Preterm neonates (23-30 weeks) were randomised to receive Clinoleic or SMOFlipid emulsion for 7 days. Investigators and outcome assessors were masked to allocation. Plasma F2-isoprostanes (lipid peroxidation marker), red blood cell fatty acids, and vitamin E were measured before and after the study. Blood culture positive sepsis and growth were monitored for safety. RESULTS: Thirty of 34 participants completed the study. Both emulsions were well tolerated without any adverse events. F2-isoprostane levels were reduced in the SMOFlipid group as compared with baseline. Eicosapentanoic acid and vitamin E levels were significantly increased in the SMOFlipid group. Oleic acid and linoleic acid levels were increased in both groups. No significant differences were noted in poststudy docosahexaenoic acid levels in both groups despite higher levels of docosahexaenoic acid in SMOFlipid. CONCLUSIONS: SMOFlipid was safe, well tolerated, and showed beneficial effect in terms of reduction of oxidative stress by reducing lipid peroxidation levels in high-risk preterm neonates.

Standardised parenteral nutrition.

Parenteral nutrition (PN) has become an integral part of clinical management of very low birth weight premature neonates. Traditionally different components of PN are prescribed individually considering requirements of an individual neonate (IPN). More recently, standardised PN formulations (SPN) for preterm neonates have been assessed and may have advantages including better provision of nutrients, less prescription and administration errors, decreased risk of infection, and cost savings. The recent introduction of triple-chamber bag that provides total nutrient admixture for neonates may have additional advantage of decreased risk of contamination and ease of administration.

Lipids for parenteral nutrition in neonates.

PURPOSE OF REVIEW: In neonatal intensive care units, the interest and scope for research in the field of intravenous lipids has significantly widened in recent years. This brief review covers the advances in this field in the last 2 years. RECENT FINDINGS: These include a significant amount of research in evaluating safety and efficacy of novel lipid emulsions that include olive oil or fish oil. Short-term studies involving novel lipid emulsions have documented safety and benefits in terms of reduced inflammation and lipid peroxidation. Fish oil-based lipid emulsions have also been used to prevent and treat parenteral nutrition-induced cholestasis. Other areas of progress include stability studies of all-in-one parenteral nutrition mixtures including lipid emulsions for neonates. SUMMARY: Since the first soybean oil-based lipid emulsions were introduced 50 years ago, progress has been made in understanding the composition, dose and clinical effects of parenteral lipids in neonatal patients. However there is a paucity of data in terms of definitive head-to-head trials of different novel lipid emulsions evaluating short-term as well as long-term clinically important outcomes including neurodevelopment. Future research is required to determine long-term benefits of novel lipid emulsions for neurological outcome and effects on the immune system.

Parenteral lipid emulsions based on olive oil compared with soybean oil in preterm (<28 weeks' gestation) neonates: a randomised controlled trial.

BACKGROUND: : New olive oil-based (OL) lipid emulsions (olive:soy oil = 4:1) have lower polyunsaturated fatty acid (PUFA) (20% vs 60%) and higher vitamin E content (an antioxidant) compared with traditional soybean oil (SO) emulsions. OBJECTIVE: : Compare efficacy and safety of OL with SO emulsions in preterm neonates (<28 weeks) at high risk for oxidative stress. PATIENTS AND METHODS: : Preterm neonates (gestation 23-<28 weeks) were randomised to receive OL or SO emulsion for 5 days using a standard protocol in a tertiary perinatal centre (King Edward Memorial Hospital for Women, Perth, Western Australia). Investigators and outcome assessors were masked to allocation. Plasma F2-isoprostanes (lipid peroxidation marker), plasma, and red blood cell fatty acids were measured before and after the study. Safety was monitored by liver function tests. RESULTS: : Forty-four of 50 participants (OL-23, SO-21) completed the study. Both emulsions were well tolerated with no significant adverse events. F2-isoprostane levels were comparable at baseline and study end. Oleic and linoleic acid levels were significantly high on day 6 in OL and SO groups, respectively. Long-chain PUFA levels were similar between groups despite the lower PUFA content of OL. The olive oil-based group had significantly higher levels of C18:4n-3, suggesting Delta6-desaturase enzyme inhibition in the SO group. CONCLUSIONS: : Olive oil-based emulsion was safe and well tolerated by preterm neonates. Similar long-chain PUFA levels were achieved in the OL group despite significantly lower amount of PUFA content; however, there was no difference in lipid peroxidation (F2-isoprostane levels). Large trials are needed to confirm these benefits.