Evidence-based guidelines for use of probiotics in preterm neonates.

BACKGROUND: Current evidence indicates that probiotic supplementation significantly reduces all-cause mortality and definite necrotising enterocolitis without significant adverse effects in preterm neonates. As the debate about the pros and cons of routine probiotic supplementation continues, many institutions are satisfied with the current evidence and wish to use probiotics routinely. Because of the lack of detail on many practical aspects of probiotic supplementation, clinician-friendly guidelines are urgently needed to optimise use of probiotics in preterm neonates. AIM: To develop evidence-based guidelines for probiotic supplementation in preterm neonates. METHODS: To develop core guidelines on use of probiotics, including strain selection, dose and duration of supplementation, we primarily used the data from our recent updated systematic review of randomised controlled trials. For equally important issues including strain identification, monitoring for adverse effects, product format, storage and transport, and regulatory hurdles, a comprehensive literature search, covering the period 1966-2010 without restriction on the study design, was conducted, using the databases PubMed and EMBASE, and the proceedings of scientific conferences; these data were used in our updated systematic review. RESULTS: In this review, we present guidelines, including level of evidence, for the practical aspects (for example, strain selection, dose, duration, clinical and laboratory surveillance) of probiotic supplementation, and for dealing with non-clinical but important issues (for example, regulatory requirements, product format). Evidence was inadequate in some areas, and these should be a target for further research. CONCLUSION: We hope that these evidence-based guidelines will help to optimise the use of probiotics in preterm neonates. Continued research is essential to provide answers to the current gaps in knowledge about probiotics.

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.

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.

Neurodevelopmental outcomes of very low-birth-weight infants with necrotizing enterocolitis: a systematic review of observational studies.

OBJECTIVE: To systematically review observational studies reporting long-term neurodevelopmental outcomes in very low-birth-weight neonates surviving after necrotizing enterocolitis (NEC). DATA SOURCES: The Cochrane Central Register of Controlled Trials, MEDLINE, EMBASE, CINAHL (Cumulative Index to Nursing and Allied Health), and proceedings of the Pediatric Academic Societies (published in Pediatric Research since 1970) were searched in June and September 2006. The reference lists of identified studies and personal files were searched. STUDY SELECTION: All studies with a control group were eligible for inclusion. MAIN OUTCOME EXPOSURE: Necrotizing enterocolitis (stage II or higher) vs no NEC. MAIN OUTCOME MEASURE: Neurodevelopmental impairment at 1 year or older of corrected age. RESULTS: Eleven nonrandomized studies, including 5 with "matched controls," were included in the analyses. The risk of long-term neurodevelopmental impairment was significantly higher in the presence of at least stage II NEC vs no NEC (odds ratio, 1.82; 95% confidence interval, 1.46-2.27). Significant heterogeneity (I2 = 47.9%; P = .06) between the studies indicated variations in patient, illness, and intervention characteristics and in follow-up methods. Patients with NEC requiring surgery were at higher risk for neurodevelopmental impairment vs those managed medically (odds ratio, 1.99; 95% confidence interval, 1.26-3.14). Results of analyses based on study design, follow-up rate, and year of birth were not statistically significantly different from those of the overall analysis. Risk of cerebral palsy and cognitive and severe visual impairment was significantly higher in neonates with NEC. CONCLUSION: Survivors of stage II or higher NEC are at risk for long-term neurodevelopmental impairment, especially if they require surgery for the illness.

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.