Effect of Probiotic Dose Escalation on Gut Microbiota and Clinical Outcomes in Preterm Infants-A Systematic Review.

Probiotics are known to decrease incidences of necrotising enterocolitis, feeding intolerance, late-onset sepsis, and mortality in preterm infants. Administering an adequate dose is important for optimizing the benefits and safety of probiotics. We conducted a systematic review to assess the effect of probiotic dose escalation on clinical outcomes and gut microbiota in preterm neonates. We searched PubMed, EMBASE, EMCARE, Medline, Cochrane Library, Google Scholar, and MedNar databases in July 2023. Three studies were included. In one of the randomized studies (n = 149, gestation 27 to 33 weeks), no significant differences in faecal Lactobacillus and Bifidobacterium counts and clinical outcomes were seen between the high- and low-dose groups. There was a trend towards increased Lactobacillus and Bifidobacterium counts in the high-dose group. In the other randomized study (n = 120, birth weight 500 to 2000 gm), smaller infants (500 to 1000 gm) required higher doses to display Lactobacillus in their faeces. The cohort study (n = 12, gestation < 33 weeks) showed a trend towards an increase in faecal abundance of bifidobacteria and bacterial diversity in the B. infantis group with increasing dose/time. Limited evidence suggests a higher dose might improve gut colonization in preterm infants. Further studies are urgently needed to address this gap in the knowledge considering the increasing use of probiotics for preterm infants.

Limosilactobacillus reuteri DSM 17938 as a probiotic in preterm infants: An updated systematic review with meta-analysis and trial sequential analysis.

BACKGROUND: Our previous strain-specific systematic review (SR) showed that Lactobacillus reuteri (LR) DSM 17938 reduces necrotizing enterocolitis (NEC), late-onset sepsis (LOS), and time to full feeds (TFF) in preterm infants. Considering progress in the field over the past 6 years, we aimed to update our SR. METHODS: SR of randomized controlled trials (RCTs) and non-RCTs was conducted. MEDLINE, Embase, Emcare, Cochrane CENTRAL, and gray literature were searched in June 2023. Primary outcomes were TFF, NEC stage ≥II, LOS, and all-cause mortality. Meta-analysis was performed using random-effects model. Certainty of evidence (CoE) was summarized using Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) guidelines. Trial sequential analysis (TSA) was applied for outcome of NEC in RCTs. RESULTS: Twelve RCTs (n = 2284) and four non-RCTs (n = 1616) were included. Six RCTs and three non-RCTs were new. Meta-analysis of RCTs showed LR significantly reduced TFF (mean difference, -2.70 [95% CI, -4.90 to -1.31] days; P = 0.0001), NEC stage ≥II (risk ratio [RR], 0.57 [95% CI, 0.37-0.87]; P = 0.009; eight RCTs), and LOS (RR, 0.72 [95% CI, 0.54-0.97]; P = 0.03); but not mortality (RR, 0.76 [95% CI, 0.54-1.06]; P = 0.10). TSA showed diversity-adjusted required information size (DARIS) as 3624 for NEC. Overall CoE was "very low." Meta-analysis of non-RCTs showed LR reduced NEC (odds ratio, 0.34 [95% CI, 0.15-0.77]; P = 0.01) but not LOS. LR had no adverse effects. CONCLUSIONS: Very low CoE suggests that LR DSM 17938 may reduce NEC and LOS and shorten TFF in preterm infants. Additional RCTs are required to confirm our findings.

Growth and neuro-developmental outcomes of probiotic supplemented preterm infants-a systematic review and meta-analysis.

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.

Neonatal Staphylococcus Aureus Sepsis: a 20-year Western Australian experience.

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.

Effect of single versus multistrain probiotic in extremely preterm infants: a randomised trial.

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, p<0.001, and TS, p=0.0009) and butyrate levels (TS, p=0.029) were significantly raised in T2 versus T1 samples. Secondary clinical outcomes were comparable. At T2, alpha diversity was comparable (p>0.05) 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.

Outcomes in extremely low birth weight (≤500 g) preterm infants: A Western Australian experience.

BACKGROUND AND AIM: Extremely preterm (EP) infant survival has significantly improved with advanced neonatal care; however outcomes of infants born with birth weight (BW) ≤500 g remain poor. We aimed to review outcomes of this cohort in our institution. METHODS: Retrospective study of all inborn preterm infants born at ≥22 weeks gestational age (GA) and weighing ≤500 g between January 2001-December 2017. Outcomes included short-term morbidity, mortality, neurodevelopmental impairment and growth up to five years of age. RESULTS: Of a total 438 eligible infants, 92 livebirths were admitted to intensive care [median (range) GA: 24 (22-30) weeks; median (IQR) BW: 427.5 (380-499) grams]. Majority [78/92 (84.7%)] were small for gestational age (SGA). In 50% of non-survivors, median (IQR) age of death was 3.5 (1-17.5) days with no late deaths. Medical morbidities were common. Follow-up, including standardised cognitive assessments, was available for 41/46 (89%) infants. At a median age of 5.06 years, 17/41 (41.5%) had moderate-severe disability; non-statistically higher in SGA compared to appropriate for gestational age/AGA (48.6% vs. 33.3%) group. Cerebral palsy (4/41; 10%), deafness needing amplification (1/41; 2.4%) were noted. Weight (32/41, 78%) and height (27/41, 66%) of most children remained at >2 SD below normal. CONCLUSIONS: In a cohort of preterm infants weighing ≤500 g at birth, 50% survived after admission to intensive care. Medical morbidities were common and 54% were free from moderate to severe disability at five years. SGA infants had higher rates (48.6%) of moderate to severe disability. Ongoing suboptimal growth in childhood is common.

Association of gastric residual volumes with necrotising enterocolitis in extremely preterm infants-a case-control study.

Necrotising enterocolitis (NEC) is a potentially serious illness with significant mortality and morbidity in preterm infants. Previous studies have reported association of volume and colour (bile and blood stained) of gastric residuals (GR) with NEC. We aimed to study this association in our cohort of extremely preterm (EP) infants. In a case-control study using retrospective data (January 2006-December 2011), EP (gestation < 28 weeks) infants with confirmed NEC ≥ stage II (cases) were compared with infants without NEC (controls) matched for birth weight (BW) and gestational age (GA). Forty cases of NEC ≥ stage II diagnosed at a median (IQR) age of 16.5 days (10.3-23) were compared with 40 controls matched for gestation (± 3 days) and birth weight (± 680 g). Median maximum GR volume (GRV) from birth to the day of occurrence of NEC was significantly higher in cases vs. controls (5.9 vs.3.7 ml; p < 0.001). Increased maximum GRV was associated with NEC ≥ Stage II in adjusted analysis (aOR 1.36, 95%CI 1.06-1.75, p = 0.017). There was no significant difference in GRV between cases and controls throughout the clinical course, including 72, 48 and 24 h before the onset of NEC. However, green (65.0% vs. 27.5%, p = 0.001) and haemorrhagic GRs (45.0% vs. 27.5%, p = 0.092) were higher 24 h before the diagnosis of NEC.Conclusion: GRV was not associated with NEC ≥ stage II. However, green and haemorrhagic GRs were significantly higher 24 h before the diagnosis of the illness. Adequately powered prospective studies are needed to confirm the significance of our findings. What is Known: •It is unclear whether large volume, dark-coloured and blood-stained GRs are associated with NEC. •The value of routine monitoring of gastric residuals in preterm infants is currently being questioned. What is New: •Volume of gastric residuals was not associated with significant NEC. •Green and haemorrhagic GRs were significantly higher 24 hours before diagnosis of NEC.

Survey of clinical staff knowledge on the long-term outcomes of very preterm infants delivered in a tertiary referral hospital.

AIM: To assess knowledge of our neonatal intensive care unit clinical staff regarding preterm neurodevelopmental outcomes using the 33-item Preterm Birth Knowledge Scale (PB-KS). METHODS: An anonymous convenience sampling survey of clinical staff in the Neonatal Directorate was conducted between July and December 2019. PB-KS, demographic information and prior staff education on long-term outcomes in very preterm infants were collected. RESULTS: There were 56 responses (five neonatologists, eight paediatric trainees, 41 neonatal nurses and two allied health staff). Responses were scored as correct or incorrect. The mean score on the PB-KS was 19.5 (range: 4-29 out of 40) with 50% correct answers. Accuracy was highest (96%) for rates of cerebral palsy and lowest (11%) for estimation of quality of life among preterm survivors. Staff reported training in long-term outcomes of preterm infants through attending a conference/seminar (20%) or a combination of formal training and seminars (41.1%). Over half of our clinical staff reported a lack of formal training. Formally trained clinical staff scored significantly better in this survey. Didactic seminars were indicated as preferred choice for staff education. CONCLUSIONS: Results of our survey will assist in developing a customised educational programme to address identified gaps in the knowledge of clinical staff as our survey also showed significantly better scores among staff who were formally trained about long-term outcomes in very preterm infants. Staff responses indicated that knowledge on long-term outcomes was variable but more accurate with regard to more severe disabilities and shorter-term developmental outcomes.

Congenital knee dislocation: a rare and unexpected finding.

Congenital knee dislocation is a rare condition of unknown aetiology. It could be associated with syndromes or may occur as an isolated entity. The severity of the deformity determines the method of treatment. Treatment options range from conservative casting to surgical correction. The case presented is of a newborn with an isolated grade II dislocation treated with serial casting. On follow-up at 2 years, the patient had a good outcome, with full range of motion and independent mobility.

Composition of Coloured Gastric Residuals in Extremely Preterm Infants-A Nested Prospective Observational Study.

Green gastric residuals (GR) are often considered as a sign of feed intolerance and discarded in preterm infants. Probiotics are known to enhance feed tolerance in preterm infants. To assess the composition (primary outcome) and volume of discarded green GRs, and feeding outcomes in extremely preterm (EP) infants in a probiotic trial, composition of pale and dark green GRs in the first two weeks of life from EP infants (<28 weeks) in a randomized controlled trial (RCT: SiMPro) of single vs. three-strain probiotics was assessed. Feeding outcomes included time to full feeds (TFF: 150 mL/kg/day) and duration of parenteral nutrition (PN). EP infants given placebo in our previous probiotic RCT served as the reference group. Analysis involved linear regression modelling with clustered standard errors for repeated measurements. GRs of 74/103 from 39 SiMPro infants (18: single-strain, 21: three-strain) were analyzed. Bile acid content was higher but statistically insignificant (825.79 vs. 338.1 µmol/L; p = 0.12) in dark vs. pale green GRs. Mean (95% confidence interval) fat, nitrogen, and carbohydrate loss in GRs over the study period was 0.02 g (0.01-0.03), 0.011 g (0.009-0.013), and 0.05 g (0.04-0.06), respectively. Overall, SiMPro infants had shorter median TFF (10 vs. 14 days, p = 0.02) and duration of PN (10 vs. 16 days, p = 0.022) compared with control group infants. Z scores for growth parameters at discharge were comparable. Discarding dark green GRs meant higher loss of bile acids during early enteral nutrition in EP infants. Probiotic supplementation was associated with reduced TFF and duration of PN.

Early versus late parenteral nutrition for critically ill term and late preterm infants.

BACKGROUND: Recently conducted randomised controlled trials (RCTs) suggest that late commencement of parenteral nutrition (PN) may have clinical benefits in critically ill adults and children. However, there is currently limited evidence regarding the optimal timing of commencement of PN in critically ill term and late preterm infants. OBJECTIVES: To evaluate the benefits and safety of early versus late PN in critically ill term and late preterm infants. SEARCH METHODS: We used the standard search strategy of Cochrane Neonatal to search the Cochrane Central Register of Controlled Trials (5 April 2019), MEDLINE Ovid (1966 to 5 April 2019), Embase Ovid (1980 to 5 April 2019), EMCare (1995 to 5 April 2019) and MEDLINE via PubMed (1966 to 5 April 2019). We searched for ongoing or recently completed clinical trials, and also searched the grey literature and reference lists of relevant publications. SELECTION CRITERIA: We included RCTs comparing early versus late initiation of PN in term and late preterm infants. We defined early PN as commencing within 72 hours of admission, and late PN as commencing after 72 hours of admission. Infants born at 37 weeks' gestation or more were defined as term, and infants born between 34 and 36+6 weeks' gestation were defined as late preterm. DATA COLLECTION AND ANALYSIS: Two review authors independently selected the trials, extracted the data and assessed the risk of bias. Treatment effects were expressed using risk ratio (RR) and risk difference (RD) for dichotomous outcomes and mean difference (MD) for continuous data. The quality of the evidence was assessed using the GRADE approach. MAIN RESULTS: Two RCTs were eligible for inclusion. Data were only available from a subgroup (including 209 term infants) from one RCT in children (aged from birth to 17 years) conducted in Belgium, the Netherlands and Canada. In that RCT, children with medium to high risk of malnutrition were included if a stay of 24 hours or more in the paediatric intensive care unit (PICU) was expected. Early PN and late PN were defined as initiation of PN within 24 hours and after day 7 of admission to PICU, respectively. The risk of bias for the study was considered to be low for five domains and high for two domains. The subgroup of term infants that received late PN had significantly lower risk of in-hospital all-cause mortality (RR 0.35, 95% confidence interval (CI) 0.14 to 0.87; RD -0.10, 95% CI -0.18 to -0.02; number needed to treat for an additional beneficial outcome (NNTB) = 10; 1 trial, 209 participants) and neonatal mortality (death from any cause in the first 28 days since birth) (RR 0.29, 95% CI 0.10 to 0.88; RD -0.09, 95% CI -0.16 to -0.01; NNTB = 11; 1 trial, 209 participants). There were no significant differences in rates of healthcare-associated blood stream infections, growth parameters and duration of hospital stay between the two groups. Neurodevelopmental outcomes were not reported. The quality of evidence was considered to be low for all outcomes, due to imprecision (owing to the small sample size and wide confidence intervals) and high risk of bias in the included studies. AUTHORS' CONCLUSIONS: Whilst late commencement of PN in term and late preterm infants may have some benefits, the quality of the evidence was low and hence our confidence in the results is limited. Adequately powered RCTs, which evaluate short-term as well as long-term neurodevelopmental outcomes, are needed.

Spinal needle size and traumatic neonatal lumbar puncture: an observational study (neo-LP).

The incidence of 'traumatic' lumbar puncture (LP; CSF red cells > 500/mm) has been reported to be 35-46% in the neonatal period. A traumatic LP incurs challenges in diagnosis and management of the underlying condition and increases the risk of complications. We aimed to assess the benefits of a smaller outer diameter, larger gauge 25G needle in reducing the incidence of traumatic LPs compared with the standard 22G LP needle. This prospective observational study compared data from two consecutive epochs. Epoch 1 (Control, April 2016-October 2016), 22G needle for LP as standard practice. Epoch 2 (Intervention, November 2016-October 2017) 25G needle used for LP. Primary outcome was the incidence of traumatic LP. Multiple logistic regression analyses were conducted adjusting for corrected gestational age (CGA) at LP, proceduralist experience and need for ventilation as an indicator of illness. There were 240 LPs during the study period involving 361 attempts (22G, n = 228; 25G, n = 133). Median gestation at birth (P = 0.617) and CGA at LP (P = 0.163) were comparable. Multivariate analysis revealed lower incidence of traumatic LP using 25G needle (P < 0.001). Incidence of obtaining a successful CSF sample was similar between groups (P = 0.944). Proceduralist experience (P = 0.189) and neonatal illness (P = 0.801) were not significant factors.Conclusion: Our results showed that traumatic LPs were ~ 50% less common with 25G vs 22G needles while retaining a comparable success rate. Dry taps were more likely among the 25G group.What is Known:• The incidence of neonatal 'traumatic' lumbar puncture (CSF red cells > 500/mm) has been reported to be 35-46%.• A traumatic lumbar puncture incurs challenges in diagnosis and management of the underlying condition and increases the risk of complications.What is New:• Multivariate analysis revealed lower incidence of traumatic lumbar puncture using 25G needle (vs 22G).• Incidence of obtaining a successful CSF sample was similar between groups.

Outcomes in preterm small versus appropriate for gestation infants after Bifidobacterium breve M-16 V supplementation.

Introduction: Fecal bifidobacteria response after Bifidobacterium breve M-16 V supplementation was comparable in preterm small (SGA) versus appropriate for gestational age (AGA) infants.Objectives: To compare clinical outcomes between preterm SGA versus AGA infants after routine probiotic supplementation (RPS) with Bifidobacterium breve M-16V (3 × 109 CFU/day).Design: Retrospective cohort study (June 2012-August 2015) comparing outcomes between preterm (<34 weeks, subgroup: <29 weeks) SGA versus AGA infants after RPS with B. breve M-16 V using multivariable regression analysis. Primary outcome: necrotizing enterocolitis (NEC)≥Stage II/all-cause mortality. Secondary outcomes: NEC ≥ Stage II, all-cause mortality, late onset sepsis (LOS), postnatal age at full feeds (PAFF).Results: Outcomes in inborn 1380/1481 (162 SGA versus 1218 AGA) admissions were analyzed. Primary outcome "NEC ≥ Stage II /all-cause mortality" was higher in SGA versus AGA infants <29 weeks (21 versus 12%; p = .040), and showed trend toward reduction (8 versus 6%; p = .057) in AGA <34 weeks. NEC ≥ Stage II, LOS, and all-cause mortality was comparable in SGA versus AGA infants <34 weeks (3 versus 2, 9 versus 8, 9% versus 6%) and <29 weeks (5 versus 4, 16 versus 9, 18% versus 19%), respectively. Median (IQR) PAFF was significantly higher in SGA versus AGA infants <34 weeks (8 (6-12) versus 7 (5-10) days), and <29 weeks (14 (12-17) versus 11 (8-16) days).Conclusions: NEC, LOS and all-cause mortality rates were similar in preterm SGA versus AGA infants after RPS with Bifidobacterium breve M-16 V, but PAFF was higher in SGA infants.

Tarsal-carpal coalition syndrome: importance of early diagnosis.

Tarsal-carpal coalition syndrome is a progressive condition involving synostosis of the wrist, ankle and digits. We describe a mother and her newborn that have this rare inherited condition where the diagnosis was made only after the baby's birth. The baby's condition was suspected on antenatal scanning, and he was born with reduced range of motion of his digits, elbows and ankles. The mother's condition has progressed to involve a fixed flexion deformity of her bilateral elbows, synostoses of her second to fifth digits and extensive coalition of her tarsal and carpal bones. She has required regular osteotomies to improve limb functioning and quality of life.

Oropharyngeal Colostrum for Preterm Infants: A Systematic Review and Meta-Analysis.

Administration of oropharyngeal colostrum (OPC) is safe, feasible, and potentially beneficial in preterm infants. We aimed to assess the effects of OPC in preterm infants. A systematic review of randomized controlled trials (RCTs) and non-RCTs of OPC administration in preterm infants was conducted. We searched MEDLINE via PubMed and Ovid, EMBASE, the Cochrane Central Register of Controlled Trials, Emcare databases, abstracts of Pediatric Academic Societies meetings, and gray literature in April 2018. Six RCTs (n = 269) and 4 non-RCTs (n = 737) were included. One RCT (n = 40) focused on enteral bovine colostrum and hence was excluded from our review. Five of the 6 RCTs had unclear risk of bias in many domains of assessment. Meta-analysis (random effects model) of RCT data showed no significant difference in ≥stage 2 necrotizing enterocolitis (RR: 0.83; 95% CI: 0.39, 1.75; P = 0.62), late-onset sepsis (RR: 0.78; 95% CI: 0.50, 1.22; P = 0.28), all-cause mortality (RR: 0.74; 95% CI: 0.27, 2.06; P = 0.56); duration of hospital stay (mean difference [MD]: -1.65 d; 95% CI: -10.09, 6.80; P = 0.70), and time to full feeds (MD: -2.86 d; 95% CI: -6.49, 0.77; P = 0.12). Meta-analysis of data from non-RCTs also showed no benefit for any of these outcomes. OPC increased secretory IgA and lactoferrin concentrations (4 RCTs), and had only a transient effect on the oral microbiome (1 RCT). There were no adverse effects (e.g., aspiration) of OPC. The overall quality of evidence (Grades of Recommendation, Assessment, Development, and Evaluation analysis) was very low. Adequately powered RCTs are needed to confirm the nutritional and immunomodulatory benefits of OPC in preterm infants.

Probiotics for preterm infants - time to end all controversies.

Mortality, necrotising enterocolitis (NEC), late onset sepsis (LOS) and feeding intolerance are significant issues for very preterm (< 32 weeks) and extremely preterm (< 28 weeks) infants. The complications of ≥ Stage II NEC [e.g. Resection of the gangrenous gut, survival with intestinal failure, recurrent infections, prolonged hospital stay, and long-term neurodevelopmental impairment (NDI)] impose a significant health burden. LOS also carries significant burden including long-term NDI due to adverse effects of inflammation on the preterm brain during the critical phase of development. Frequent stopping of feeds due to feeding intolerance is a significant iatrogenic contributor to postnatal growth failure in extremely preterm infants. Over 25 systematic reviews and meta-analyses of RCTs (~12 000 participants) have reported that probiotics significantly reduce the risk of all-cause mortality, NEC ≥ Stage II, LOS and feeding intolerance in preterm infants. Systematic reviews and meta-analysis of non-RCTs have also shown that the benefits after adopting probiotics as a standard prophylaxis for preterm infants are similar to those reported in RCTs. No intervention comes close to probiotics when it comes to significant reduction in death, NEC, LOS and feeding intolerance at a cost of less than a dollar a day irrespective of the setting and baseline incidence of NEC. The common controversies that are preventing the rapid uptake of probiotics for preterm infants are addressed in this paper.

Para-probiotics for Preterm Neonates-The Next Frontier.

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.