Current evidence supports the use of probiotics in preterm neonates for prevention of necrotizing enterocolitis, mortality and late onset sepsis. Despite the strong evidence, the uptake of this intervention has not been universal due to concerns including probiotic sepsis, pro-inflammatory response and transmission of antibiotic resistance. Critically ill extremely preterm neonates with potentially compromised gut integrity are at higher risk of probiotic sepsis due to translocation. In most countries, probiotics are sold as food supplements with poor quality control. The traditional definition of probiotics as “live microorganisms” has been challenged as many experts have questioned the importance of viability in the context of the beneficial effects of probiotics. Paraprobiotics (ghost probiotics), are defined as non-viable microbial cells (intact or broken) or crude cell extracts (i.e., with complex chemical composition), which, when administered (orally or topically) in adequate amounts, confer a benefit on the human or animal consumer. Current evidence indicates that paraprobiotics could be safe alternatives to probiotics in preterm neonates. High-quality pre-clinical and clinical studies including adequately powered randomised controlled trials (RCTs) are warranted in preterm neonates to explore this new frontier.

Objective Although there is an overall reduction in underfive mortality rate, the progress in reducing neonatal mortality rate has been very slow. Over the last 20 years, preterm births have steadily increased in low-income and medium-income countries (LMICs) particularly in sub-Saharan Africa and South Asia. Preterm birth is associated with increased mortality and morbidity, particularly in LMICs. Based on systematic reviews of randomised controlled trials (RCTs), many neonatal units in high-income countries have adopted probiotics as standard of care for preterm neonates. We aimed to systematically review the safety and efficacy of probiotics in reducing mortality and morbidity in preterm neonates in LMICs. Design Systematic review and meta-analysis of RCTs. Data sources Medline, Embase, Cochrane Central Register of Controlled Trials, Cumulative Index of Nursing and Allied Health Literature and E-abstracts from Pediatric Academic Society meetings and other paediatric and neonatal conference proceedings were searched in January 2017. Eligibility criteria RCTs comparing probiotics versus placebo/no probiotic in preterm neonates (gestation<37 weeks) conducted in LMICs. Results Total 23 (n=4783) RCTs from 4 continents and 10 LMICs were eligible for inclusion in the meta-analysis using fixed effect model. The risk of necrotising enterocolitis (NEC greater than or equal to stage II) (risk ratio (RR) 0.46 (95% CI 0.34 to 0.61), P<0.00001, numbers needed to treat (NNT) 25 (95% CI 20 to 50)), late-onset sepsis (LOS) (RR 0.80 (95% CI 0.71 to 0.91), P=0.0009, NNT 25 (95% CI 17 to 100)) and all-cause mortality (RR 0.73 (95% CI 0.59 to 0.90), P=0.003, NNT 50 (95% CI 25 to 100)) were significantly lower in probiotic supplemented neonates. The results were significant on random effects model analysis and after excluding studies with high risk of bias. No significant adverse effects were reported. Conclusion Probiotics have significant potential to reduce mortality and morbidity (eg, NEC, LOS) in preterm neonates in LMICs.

Gut dysbiosis is associated with sepsis and necrotizing enterocolitis in preterm infants, which can adversely affect long-term growth and neurodevelopment. We aimed to synthesise evidence for the effect of probiotic supplementation on growth and neurodevelopmental outcomes in preterm infants. MEDLINE, EMBASE, EMCARE, Cochrane CENTRAL, and grey literature were searched in February 2022. Only randomized controlled trials (RCTs) were included. Meta-analysis was performed using random effects model. Effect sizes were expressed as standardized mean difference (SMD), mean difference (MD) or risk ratio (RR) and their corresponding 95% confidence intervals (CI). Risk of Bias (ROB) was assessed using the ROB-2 tool. Certainty of Evidence (CoE) was summarized using GRADE guidelines. Thirty RCTs (n = 4817) were included. Meta-analysis showed that probiotic supplementation was associated with better short-term weight gain [SMD 0.24 (95%CI 0.04, 0.44); 22 RCTs (n = 3721);p = 0.02;I² = 88%; CoE: low]. However, length [SMD 0.12 (95%CI −0.13, 0.36); 7 RCTs, (n = 899);p = 0.35;I² = 69%; CoE: low] and head circumference [SMD 0.09 (95%CI −0.15, 0.34); 8 RCTs (n = 1132);p = 0.46;I² = 76%; CoE: low] were similar between the probiotic and placebo groups. Probiotic supplementation had no effect on neurodevelopmental impairment [RR 0.91 (95%CI 0.76, 1.08); 5 RCTs (n = 1556);p = 0.27;I² = 0%; CoE: low]. Probiotic supplementation was associated with better short-term weight gain, but did not affect length, head circumference, long-term growth, and neurodevelopmental outcomes of preterm infants. Adequately powered RCTs are needed in this area. Prospero Registration: CRD42020064992.

Objective Evidence indicates that multistrain probiotics benefit preterm infants more than single-strain (SS) probiotics. We assessed the effects of SS versus triple-strain (TS) probiotic supplementation (PS) in extremely preterm (EP) infants. Design EP infants (gestational age (GA) <28 weeks) were randomly allocated to TS or SS probiotic, assuring blinding. Reference (REF) group was EP infants in the placebo arm of our previous probiotic trial. PS was commenced with feeds and continued until 37 weeks’ corrected GA. Primary outcome was time to full feed (TFF: 150 mL/kg/day). Secondary outcomes included short-chain fatty acids and faecal microbiota collected at T1 (first week) and T2 (after 3 weeks of PS) using 16S ribosomal RNA gene sequencing. Results 173 EP (SS: 86, TS: 87) neonates with similar GA and birth weight (BW) were randomised. Median TFF was comparable (11 (IQR 8–16) vs 10 (IQR 8–16) days, p=0.92). Faecal propionate (SS, p0.05) between groups, whereas beta-diversity analysis revealed significant differences between PS and REF groups (both p=0.001). Actinobacteria were higher (both p<0.01), and Proteobacteria, Firmicutes and Bacteroidetes were lower in PS versus REF. Gammaproteobacteria, Clostridia and Negativicutes were lower in both PS versus REF. Conclusion TFF in EP infants was similar between SS and TS probiotics. Both probiotics were effective in reducing dysbiosis (higher bifidobacteria and lower Gammaproteobacteria). Long-term significance of increased propionate and butyrate needs further studies. Trial registration number ACTRN 12615000940572.

Objectives: The purpose of this study was to characterise neonatal Staphylococcus aureus (SA) sepsis in Western Australia (WA) between 2001 and 2020 at the sole tertiary neonatal intensive care unit (NICU), examine risk factors for sepsis in the cohort, and compare short- and long-term outcomes to control infants without any sepsis. Methods: Retrospective cohort study at the Neonatal Directorate at King Edward Memorial Hospital (KEMH) and Perth Children’s Hospital, using electronic databases and patient medical records. Results: The overall incidence of SA sepsis was 0.10 per 1000 live births (62/614207). From 2001 to 2010 the incidence was 0.13/1000 live births, reducing to 0.07/1000 live births from 2011 to 2020. SA was most frequently isolated from endotracheal aspirates, and infants with SA sepsis had longer median duration of ventilatory support than those without any sepsis (31 days vs 18 days respectively, p < 0.001). In our cohort, SA sepsis was associated with worse neurodevelopmental outcomes compared to infants without any sepsis. Conclusions: The incidence of neonatal SA sepsis has reduced over the last 20 years, suggesting potential effectiveness of the preventative interventions implemented. Endotracheal tube (ETT) colonisation and prolonged ventilation may be under-recognised as potential sources of SA infection. Our study suggests SA sepsis may negatively impact neurodevelopmental outcomes.