Early versus late parenteral nutrition in term and late preterm infants: a randomised controlled trial.

BACKGROUND: There is limited evidence regarding the optimal time to commence parenteral nutrition (PN) in term and late preterm infants. DESIGN: Single-centre, non-blinded, exploratory randomised controlled trial. SETTING: A level-3 neonatal unit in a stand-alone paediatric hospital. PATIENTS: Infants born ≥34 weeks of gestation and ≤28 days, who needed PN. Eligible infants were randomised on day 1 or day 2 of admission. INTERVENTIONS: Early (day 1 or day 2 of admission, N=30) or late (day 6 of admission, N=30) PN. MAIN OUTCOME MEASURES: Plasma phenylalanine and F2-isoprostane levels on day 4 and day 8 of admission. Secondary outcomes were amino-acid and fatty-acid profiles on day 4 and day 8, and clinical outcomes. RESULTS: The postnatal age at randomisation was similar between the groups (2.3 (SD 0.8) vs 2.3 (0.7) days, p=0.90). On day 4, phenylalanine levels in early-PN infants were higher than in late-PN (mean (SD) 62.9 (26.7) vs 45.5 (15.3) µmol/L; baseline-adjusted percentage difference 25.8% (95% CI 11.6% to 39.9%), p<0.001). There was no significant difference in phenylalanine levels between the two groups on day 8. There was no significant difference between the groups for F2-isoprostane levels on day 4 (early-PN mean (SD) 389 (176) vs late-PN 419 (291) pg/mL; baseline-adjusted percentage difference: -4.4% (95% CI -21.5% to 12.8%) p=0.62) and day 8 (mean (SD) 305 (125) vs 354 (113) pg/mL; adjusted mean percentage difference -16.1 (95% CI -34.1 to 1.9) p=0.09).Postnatal growth restriction for weight was less severe in the early-PN group (change in weight z-score from baseline to discharge: -0.6 (0.6) vs -1.0 (0.6); p=0.02). The incidence of hyperglycaemia was greater in the early-PN group (20/30 (66.7%) vs 11/30 (36.7%), p=0.02). CONCLUSIONS: The timing of the commencement of PN did not seem to affect the degree of oxidative stress in critically ill term and late preterm infants. The effect of transiently high plasma phenylalanine with early PN on clinical outcomes requires further investigation. TRIAL REGISTRATION NUMBER: ACTRN12620000324910.

Topical glyceryl trinitrate to increase radial artery diameter in neonates: study protocol for a randomized controlled trial.

BACKGROUND: Newborn infants admitted to the neonatal intensive care unit require arterial cannulation for hemodynamic monitoring and blood sampling. Arterial access is achieved through catheterization of umbilical or peripheral arteries. Peripheral artery cannulation is performed in critically ill newborns, but artery localization and cannulation is often challenging and unsuccessful. Therefore, increasing the internal diameter and preventing vasospasm are important for successful peripheral artery cannulation in neonates. Topical glyceryl trinitrate has the potential to increase cannulation success by relaxing arterial smooth muscles and thus increasing the internal diameter. We aim to conduct a pilot randomized controlled trial to evaluate the efficacy and safety of topycal glyceryl trinitrate in increasing the diameter of the radial artery in neonates. METHODS/DESIGN: This study will be a single-center, observer-blind, randomized, placebo-controlled trial conducted in the neonatal intensive care unit of Perth Children's Hospital, Western Australia. A total of 60 infants born at >34 weeks of gestation who are admitted for elective surgery or medical reasons and for whom a peripheral arterial line is needed for sampling or blood pressure monitoring will be recruited after informed parental consent is obtained. The primary outcome will be the change in radial arterial diameter from baseline to postintervention. Secondary outcomes will be the absolute and percentage change from baseline in the radial arterial diameter in both limbs and safety (hypotension and methemoglobinemia). DISCUSSION: This will be the first randomized controlled trial evaluating the use of topical glyceryl trinitrate to facilitate peripheral artery cannulation in neonates. If our pilot randomized controlled trial confirms the benefits of glyceryl trinitrate patches, it will pave the way for large multicenter randomized controlled trials in this field.

Plant-Derived Substances for Prevention of Necrotising Enterocolitis: A Systematic Review of Animal Studies.

Inflammation, oxidative injury, and gut dysbiosis play an important role in the pathogenesis of necrotising enterocolitis (NEC). Plant-derived substances have historically been used as therapeutic agents due to their anti-inflammatory, antioxidant, and antimicrobial properties. We aimed to review pre-clinical evidence for plant-derived substances in the prevention and treatment of NEC. A systematic review was conducted using the following databases: PubMed, EMBASE, EMCARE, MEDLINE and Cochrane Library (PROSPERO CRD42022365477). Randomized controlled trials (RCTs) and quasi-RCTs that evaluated a plant-derived substance as an intervention for NEC in an animal model of the illness and compared pre-stated outcomes (e.g., clinical severity, severity of intestinal injury, mortality, laboratory markers of inflammation and oxidative injury) were included. Sixteen studies (n = 610) were included in the systematic review. Ten of the sixteen included RCTs (Preterm rat pups: 15, Mice: 1) reported mortality and all reported NEC-related histology. Meta-analysis showed decreased mortality [12/134 vs. 27/135; RR: 0.48 (95% CI: 0.26 to 0.87); p = 0.02, 10 RCTs] and decreased NEC in the experimental group [24/126 vs. 55/79; RR: 0.34 (95% CI: 0.22 to 0.52); p < 0.001, 6 RCTs]. Markers of inflammation (n = 11) and oxidative stress (n = 13) improved in all the studies that have reported this outcome. There was no significant publication bias for the outcome of mortality. Plant-derived substances have the potential to reduce the incidence and severity of histologically diagnosed NEC and mortality in rodent models. These findings are helpful in guiding further pre-clinical studies towards developing a food supplement for the prevention of NEC in preterm infants.

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.

Effects of bumetanide on neonatal seizures: A systematic review of animal and human studies.

BACKGROUND: Bumetanide, an inhibitor of the sodium-potassium-chloride cotransporter-1, has been suggested as an adjunct to phenobarbital for treating neonatal seizures. METHODS: A systematic review of animal and human studies was conducted to evaluate the efficacy and safety of bumetanide for neonatal seizures. PubMed, Embase, CINAHL and Cochrane databases were searched in March 2023. RESULTS: 26 animal (rat or mice) studies describing 38 experiments (28 in-vivo and ten in-vitro) and two human studies (one RCT and one open-label dose-finding) were included. The study designs, methods to induce seizures, bumetanide dose, and outcome measures were heterogeneous, with only 4/38 experiments being in animal hypoxia/ischaemia models. Among 38 animal experiments, bumetanide was reported to have antiseizure effects in 21, pro-seizure in six and ineffective in 11. The two human studies (n = 57) did not show the benefits of bumetanide as an add-on agent to phenobarbital in their primary analyses, but one study reported benefit on post-hoc analysis. Overall, hearing impairment was detected in 5/37 surviving infants in the bumetanide group vs. 0/13 in controls. Four of the five infants with hearing impairment had received aminoglycosides concurrently. Other adverse effects reported were diuresis, mild-to-moderate dehydration, hypotension, and electrolyte disturbances. The studies did not report on long-term neurodevelopment. The certainty of the evidence was very low. CONCLUSION: Animal data suggest that bumetanide has inconsistent effects as an antiseizure medication in neonates. Data from human studies are scarce and raise some concerns regarding ototoxicity when given with aminoglycosides. Well conducted studies in animal models of hypoxic-ischaemic encephalopathy are urgently needed. Future RCTs, if conducted in human neonates, should have an adequate sample size, assess neurodevelopment, minimize using aminoglycosides, be transparent about the potential ototoxicity in the parent information sheet, conduct early hearing tests and have trial-stopping rules that include hearing impairment as an outcome.

Outcomes of Neonates with Hypoxic-Ischemic Encephalopathy Treated with Magnesium Sulfate: A Systematic Review with Meta-analysis.

OBJECTIVE: To assess magnesium sulfate (MgSO4) as a neuroprotective agent in hypoxic-ischemic encephalopathy. STUDY DESIGN: For this systematic review, PubMed, EMBASE, the Cochrane Library, EMCARE, and MedNar were searched in November 2022 for randomized controlled trials (RCTs). Meta-analysis was conducted using Stata 16.0 and RevMan 5.3. RESULTS: Twenty RCTs with a total sample size of 1485 were included, of which 16 were from settings where therapeutic hypothermia (TH) was not offered. Regarding MgSO4 in settings where TH was not offered, only 1 study evaluated composite outcome of death or disability at ≥18 months and reported such poor outcome in 8 of 14 control infants and 4 of 8 in the MgSO4 group. MgSO4 was not associated with mortality (RR, 0.86; 95% CI, 0.72-1.03; 13 RCTs) or hypotension (RR, 1.02; 95% CI, 0.88-1.18; 5 RCTs). Thirteen studies reported that MgSO4 improved in-hospital outcomes, such as reduced seizure burden and improved neurological status at discharge. MgSO4 reduced the risk of poor suck feeds (RR, 0.52; 95% CI, 0.40-0.68; 6RCTs) and abnormal electroencephalogram (RR, 0.64; 95% CI, 0.45-0.93; 5 RCTs). Certainty of evidence was moderate for mortality and low or very low for other outcomes. For studies with MgSO4 as an adjunct to TH, none reported on death or neurodevelopmental disability at ≥18 months. MgSO4 was not associated with mortality (RR, 0.65; 95% CI, 0.34-1.27; 3 RCTs) or hypotension (RR, 1.0; 95% CI, 0.71-1.40; 3 RCTs). CONCLUSIONS: Evidence around long-term outcomes of MgSO4 when used with or without TH was scant. MgSO4 therapy may improve in-hospital neurological outcomes without affecting mortality in settings where TH is not offered. Well-designed RCTs for neuroprotection are needed, especially in low-resource settings. TRIAL REGISTRATION: "Open Science Forum" (https://doi.org/10.17605/OSF.IO/FRM4D).

Bifidobacterium infantis as a probiotic in preterm infants: a systematic review and meta-analysis.

BACKGROUND: Bifidobacterium infantis has special abilities to utilise human milk oligosaccharides. Hence we hypothesised that probiotic supplements containing B. infantis may confer greater benefits to preterm infants than probiotic supplements without B. infantis. METHODS: A systematic review with meta-analysis was conducted according to standard guidelines. We selected RCTs evaluating probiotics compared to placebo or no treatment in preterm and/or low birth weight infants. Probiotic effects on Necrotizing Enterocolitis (NEC), Late Onset Sepsis (LOS) and Mortality were analysed separately for RCTs in which the supplemented probiotic product contained B. infantis and those that did not contain B. infantis. RESULTS: 67 RCTs were included (n = 14,606), of which 16 used probiotics containing B. infantis (Subgroup A) and 51 RCTs did not (Subgroup B) Meta-analysis of all RCTs indicated that probiotics reduced the risk of NEC, LOS, and mortality. The subgroup meta-analysis demonstrated greater reduction in the incidence of NEC in subgroup A than subgroup B [(relative risk in subgroup A: 0.38; 95% CI, 0.27-0.55) versus (0.67; 95% CI, 0.55-0.81) in subgroup B; p value for subgroup difference: 0.01]. CONCLUSIONS: These results provide indirect evidence that probiotic supplements that include B. infantis may be more beneficial for preterm infants. Well-designed RCTs are necessary to confirm these findings. IMPACT: Evidence is emerging that beneficial effects of probiotics are species and strain specific. This systematic review analyses if B. infantis supplementation provides an advantage to preterm infants. This is the first systematic review evaluating the effects of probiotics containing B. infantis in preterm infants. The results of this systematic review provides indirect evidence that probiotics that include B. infantis may be more beneficial for preterm infants. These results will help in guiding future research and clinical practice for using B. infantis as a probiotic in preterm infants.

Prevalence of symptomatic tracheal morbidities after fetoscopic endoluminal tracheal occlusion: a systematic review and meta-analysis.

BACKGROUND: Fetoscopic endoluminal tracheal occlusion (FETO) has been shown to improve survival of infants with congenital diaphragmatic hernia (CDH). However, there are concerns that FETO may lead to tracheomegaly, tracheomalacia and related complications. METHODS: A systematic review was conducted to estimate the prevalence of symptomatic tracheal complications in infants who underwent FETO for CDH. Presence of one or more of the following was considered as tracheal complication: tracheomalacia, stenosis, laceration or tracheomegaly with symptoms such as stridor, effort-induced barking cough, recurrent chest infections or the need for tracheostomy, tracheal suturing, or stenting. Isolated tracheomegaly on imaging or routine bronchoscopy without clinical symptoms was not considered as tracheal morbidity. Statistical analysis was performed using the metaprop command on Stata V.16.0. RESULTS: A total of 10 studies (449 infants) were included (6 retrospective cohort, 2 prospective cohort and 2 randomised controlled trials). There were 228 infants who survived to discharge. Prevalence rates of tracheal complications in infants born alive were 6% (95% CI 2% to 12%) and 12% (95% CI 4% to 22%) in those who survived to discharge. The spectrum of severity ranged from relatively mild symptoms such as effort-induced barking cough to the need for tracheostomy/tracheal stenting. CONCLUSION: A significant proportion of FETO survivors have symptomatic tracheal morbidities of varying severity. Units that are planning to adopt FETO for managing CDH should consider ongoing surveillance of survivors to enable early identification of upper airway issues. Inventing FETO devices that minimise tracheal injury is needed.

Performance of smartphone application to accurately quantify hyperbilirubinemia in neonates: a systematic review with meta-analysis.

Neonatal jaundice is a common clinical condition that can progress to severe hyperbilirubinemia if identification and intervention are delayed. In this study, we aimed to analyze the current evidence on the accurate performance of smartphone applications to quantify bilirubin levels. PubMed, Embase, Emcare, MEDLINE, the Cochrane Library, and Google Scholar were searched from inception until July 2022. Grey literature was searched on "OpenGrey" and "MedNar" databases. We included prospective and retrospective cohort studies that recruited infants with a gestation of ≥ 35 weeks and reported paired total serum bilirubin (TSB) and smartphone app-based bilirubin (ABB) levels. We conducted the review using the guidelines of the Cochrane Collaboration Diagnostic Test Accuracy Working Group and reported using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses-diagnostic test accuracy (PRISMA-DTA) statement. The data were pooled using the random effects model. The outcome of interest was agreement between ABB and TSB measurements, provided as correlation coefficient, mean difference, and standard deviation. Certainty of evidence (COE) was assessed based on GRADE guidelines. Fourteen studies were included in the meta-analysis. The number of infants in individual studies ranged between 35 and 530. The pooled correlation coefficient (r) between ABB and TSB was 0.77 (95% CI 0.69 to 0.83; p < 0.01). Reported sensitivities for predicting a TSB of 250 µmol/L in individual studies ranged between 75 and 100% and specificities ranged from 61 to 100%. Similarly, a sensitivity of 83 to 100% and a specificity of 19.5 to 76% were reported for predicting a TSB of 205 µmol/L. Overall COE was considered moderate.    Conclusion: Smartphone app-based bilirubin estimation showed a reasonable correlation to TSB levels. Well-designed studies are required to determine its utility as a screening tool for various TSB cut-off levels. What is Known: • Neonatal jaundice is a common clinical condition. Timely screening and intervention are necessary to prevent neurological morbidities • Transcutaneous bilirubinometer is a widely used non-invasive screening device but is mostly available in hospital settings and has cost limitations. Researchers have recently explored the utility of smartphone applications to estimate bilirubin levels in neonates. What is New: • This is the first systematic review and meta-analysis conducted to assess the performance of smartphone applications to detect neonatal hyperbilirubinemia. • Bilirubin estimates of newborn infants obtained through smartphone applications had a reasonable correlation with serum bilirubin levels.

Current parenteral nutrition practice and clinical outcomes of term and late preterm infants: A retrospective study.

BACKGROUND AND AIMS: Limited studies have described parenteral nutrition (PN) practices and clinical outcomes in term and late preterm infants. The aim of this study was to describe the current practice of PN in term and late preterm infants and their short-term clinical outcomes. METHODS: We conducted a retrospective study in a tertiary NICU between October 2018 and September 2019. Infants (gestation ≥34 weeks) admitted on the day of birth or the following day and received PN were included. We collected data on patient characteristics, daily nutrition, clinical and biochemical outcomes until discharge. RESULTS: A total of 124 infants [mean (SD) gestation: 38 (1.92) weeks] were included; 115 (93%) and 77 (77%) commenced on parenteral amino acids and lipids, respectively, by day 2 of admission. The mean parenteral amino acid and lipid intake on day 1 of admission was 1.0 (0.7) g/kg/day and 0.8 (0.6) g/kg/day respectively and increased to 1.5 (1.0) g/kg/day and 2.1 (0.7) g/kg/day by day 5, respectively. Eight (6.5%) infants accounted for 9 episodes of hospital-acquired infections. The mean z-scores for anthropometrics at discharge were significantly lower than at birth (Weight: -0.72 (1.13) vs - 0.04 (1.11); p < 0.001; Head circumference: -0.14 (1.17) vs 0.34 (1.05); p < 0.001; Length: -0.17 (1.69) vs 0.22 (1.34); p < 0.001). A total of 28 (22.6%) and 16 (12.9%) infants had mild and moderate postnatal growth restriction (PNGR), respectively. None had severe PNGR. Thirteen infants (11%) experienced hypoglycaemia, whereas 53 (43%) experienced hyperglycaemia. CONCLUSION: The intakes of parenteral amino acids and lipids in term and late preterm infants were at the lower end of the currently recommended doses, especially in the first five days of admission. One third of the study population had mild to moderate PNGR. Randomised trials investigating the impact of initial PN intakes on clinical, growth and developmental outcomes are recommended.

Outcomes of very preterm infants with hyperglycaemia treated with insulin: A systematic review and meta-analysis.

AIM: To study the outcomes of very preterm infants with hyperglycaemia treated with Insulin. METHODS: This is a systematic review of randomised controlled trials (RCTs) and observational studies. PubMed, Medline, EMBASE, Cochrane Library, EMCARE and MedNar databases were searched in May 2022. Data were pooled separately for adjusted and unadjusted odds ratios (ORs) using random-effects model. MAIN OUTCOME MEASURES: Mortality and morbidities (e.g. Necrotising enterocolitis [NEC], retinopathy of prematurity [ROP]) in very preterm (<32 weeks) or very low birth weight infants (<1500 g) after treatment of hyperglycaemia with insulin. RESULTS: Sixteen studies with data from 5482 infants were included. Meta-analysis of unadjusted ORs from cohort studies showed that insulin treatment was significantly associated with increased mortality [OR 2.98 CI (1.03 to 8.58)], severe ROP [OR 2.23 CI (1.34 to 3.72)] and NEC [OR 2.19 CI (1.11 to 4)]. However, pooling of adjusted ORs did not show significant associations for any outcomes. The only included RCT found better weight gain in the insulin group, but no effect on mortality or morbidities. Certainty of evidence was 'Low' or 'Very low'. CONCLUSION: Very low certainty evidence suggests that Insulin therapy may not improve outcomes of very preterm infants with hyperglycaemia.

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.

Probiotic supplementation in neonates and long-term gut colonisation: A systematic review of randomised controlled trials.

BACKGROUND: Probiotic supplementation in the neonatal period results in improved gut colonisation with probiotic bacteria in the short term. There is limited information on the long-term sustainability of this colonisation. AIMS: To evaluate whether oral probiotic supplementation in the neonatal period results in sustained gut colonisation with probiotic bacteria at or beyond 6 months after its cessation. METHODS: A systematic review of neonatal probiotic randomised controlled trials (RCTs) that reported on the stool microbiota during post-discharge follow-up was carried out using guidelines of the Cochrane neonatal group. RESULTS: Four RCTs (n = 605 infants) were included in the review. The studies were heterogeneous in case selection, choice of probiotics, duration of supplementation, timing and the method of stool microbial analysis. Three RCTs (n = 471) showed the presence of intestinal probiotic bacteria at 6-12 months. The overall certainty of evidence was very low in view of small sample size, heterogeneity and identification only to the genus/species level. CONCLUSION: Low certainty of evidence suggests that probiotic supplementation in the neonatal period may result in sustained gut colonisation 6-12 months post-cessation, but not at 24 months. Adequately powered, well-designed RCTs with strain-specific assays are needed in this area.

Mortality and neurodevelopmental outcomes of infants with spontaneous intestinal perforation: a systematic review and meta-analysis.

BACKGROUND: There is limited information about the mortality and neurodevelopmental outcomes of very preterm infants (<32 weeks) with spontaneous intestinal perforation (SIP). OBJECTIVE: To explore the association between SIP and neurodevelopmental outcomes and mortality in very preterm infants. DATA SOURCES: Medline, EMBASE, Cochrane Library, EMCARE and MedNar. STUDY SELECTION: Databases were searched until September 2021. Studies comparing outcomes of 'SIP' versus 'no SIP or necrotising enterocolitis (NEC)' were included. DATA EXTRACTION: Neurodevelopmental outcomes at ≥1 year corrected age were extracted as the main outcome measure. Data were pooled separately for adjusted and unadjusted ORs using the random-effects model. The evidence level was assessed using the GRADE (Grading of Recommendations, Assessments, Development and Evaluations) framework. RESULTS: Eighteen cohort studies (13 606 infants) were included. Meta-analysis of unadjusted ORs showed that SIP was significantly associated with increased odds of mortality, cerebral palsy, composite outcome of death or disability, visual impairment and hearing impairment. However, pooling of adjusted ORs (aOR) found significant associations only for mortality (aOR (95% CI) 2.27 (2.07 to 2.49); I2: 0%; four studies (n=10 695)), severe disability (aOR (95% CI) 2.06 (1.38 to 3.08); I2: 0%; two studies (n=321)) and composite outcome of 'death or disability' (aOR (95% CI) 2.18 (1.55 to 3.06); I2: 0%; two studies (n=321)). The level of evidence was 'low' or 'very low'. LIMITATIONS: Lack of information on aORs from many studies. CONCLUSIONS: SIP in very preterm infants is associated with higher odds of mortality, severe disability, and death or disability.

Probiotic supplementation for neonates with congenital gastrointestinal surgical conditions: guidelines for future research.

Our pilot RCT found that probiotic supplementation with the three-strain bifidobacterial product (B. breve M-16V, B. longum subsp. infantis M-63 and B. longum subsp. longum BB536) attenuates gut dysbiosis, increases stool short-chain fatty acid (SCFA) levels and improves the growth of head circumference in neonates with congenital gastrointestinal surgical conditions (CGISC). In this article, we have provided guidelines for designing future multicentre RCTs based on the experience gained from our pilot RCT. The recommendations include advice about sample size, potential confounders, outcomes of interest, probiotic strain selection, storage, dose, duration and microbial quality assurance, collection of stool samples, storage and analysis and reporting. Following these guidelines will increase the validity of future RCTs in this area and hence confidence in their results. IMPACT: Probiotic supplementation attenuates gut dysbiosis, increases stool short-chain fatty acid (SCFA) levels and improves the growth of head circumference in neonates with congenital gastrointestinal surgical conditions. The current review provides evidence-based guidelines to conduct adequately powered RCTs in this field.

Early versus late parenteral nutrition in term and late preterm infants: study protocol for a randomised controlled trial.

BACKGROUND: Despite the wide use of parenteral nutrition (PN) in neonatal intensive care units (NICU), there is limited evidence regarding the optimal time to commence PN in term and late preterm infants. The recommendations from the recently published ESPGHAN/ESPEN/ESPR/CPEN and NICE guidelines are substantially different in this area, and surveys have reported variations in clinical practice. The aim of this randomised controlled trial (RCT) is to evaluate the benefits and risks of early versus late PN in term and late preterm infants. METHODS/DESIGN: This study is a single-centre, non-blinded RCT in the NICU of Perth Children's Hospital, Western Australia.A total of 60 infants born ≥34 weeks of gestation who have a high likelihood of intolerance to enteral nutrition (EN) for at least 3-5 days will be randomised to early (day 1 or day 2 of admission) or late commencement (day 6 of admission) of PN after informed parental consent. In both groups, EN will be commenced as early as clinically feasible. Primary outcomes are plasma phenylalanine and plasma F2-isoprostane levels on Day 4 and Day 8 of admission. Secondary outcomes are total and individual plasma amino acid profiles, plasma and red blood cell fatty acid profiles, in-hospital all-cause mortality, hospital-acquired infections, length of hospital/NICU stay, z scores and changes in z scores at discharge for weight, height and head circumference, time to full EN, duration of respiratory (mechanical, non-invasive) support, duration of inotropic support, the incidence of hyper and hypoglycaemia, incidence of metabolic acidosis, liver function, blood urea nitrogen, and C-reactive protein (CRP). DISCUSSION: This RCT will examine the effects of early versus late PN in term and late preterm infants by comparing key biochemical and clinical outcomes and has the potential to identify underlying pathways for beneficial or harmful effects related to the timing of commencement of PN in such infants. TRIAL REGISTRATION: ANZCTR; ACTRN12620000324910 (3rd March 2020).

Utility of the Ages and Stages Questionnaire to Identify Developmental Delay in Children Aged 12 to 60 Months: A Systematic Review and Meta-analysis.

Importance: The Ages and Stages Questionnaire (ASQ) is a commonly used developmental screening tool, but its utility is debated. Objectives: To conduct a a systematic review and meta-analysis to evaluate ASQ's utility as a screening or diagnostic tool to identify developmental delay in children aged 12-60 months. Data Sources: Medline, EMBASE, CINAHL, PsycINFO, and Mednar were searched from inception until December 2021. Study Selection: Studies meeting both criteria were included. ASQ was performed at age 12 to 60 months or where the median age at ASQ was at least 12 months and formal developmental assessments were done within 2 months of ASQ. Data Extraction and Synthesis: True positive, false positive, false negative, and true negatives from individual studies were extracted. Meta-analysis was conducted with Stata version 16.1. Risk of bias was assessed using the QUADAS-2 tool. Certainty of evidence (COE) was assessed using GRADE guidelines. Main Outcomes and Measures: Ability of ASQ scores more than 2 SDs below the mean in more than 1 domain (ASQ-2SD) to identify any developmental delay or severe delay. Based on generally accepted interpretation of likelihood ratio (LR) values, a positive LR (PLR) more than 5 and a negative LR (NLR) of 0.2 or less were considered necessary to rule in or rule out developmental delay, respectively, with at least moderate probability. Results: Initial search yielded 5777 citations of which 43 were included in the review. Of them, 36 were included in the meta-analysis. The pooled sensitivity, specificity, PLR, and NLR are as follows: ASQ-2SD to predict any delay in 1 or more domain (n = 16), 0.77 (95% CI, 0.64-0.86), 0.81 (95% CI, 0.75-0.86), 4.10 (95% CI, 3.17-5.30), and 0.28 (95% CI, 0.18-0.44); ASQ-2SD to predict severe delay in 1 or more domain (n = 15), 0.84 (95% CI, 0.75-0.90), 0.77 (95% CI, 0.71-0.82), 3.72 (95% CI, 2.98-4.64), and 0.20 (95% CI, 0.13-0.32); ASQ-2SD motor domain to predict motor delay (n = 7), 0.41 (95% CI, 0.26-0.57), 0.94 (95% CI, 0.87-0.97), 6.5 (95% CI, 3.8-11.1), and 0.63 (95% CI, 0.50-0.81); and ASQ-2SD cognitive domain to predict cognitive delay (n = 2), 0.44 (95% CI, 0.24-0.65), 0.93 (95% CI, 0.81-0.95), 6.4 (95% CI, 2.4-16.8), and 0.61 (95% CI, 0.43-0.86). The COE was low/very low. Conclusions and Relevance: If a child aged 12 to 60 months passes all ASQ domains, there is a moderate probability that they do not have severe developmental delay (low COE). If a child aged 12-60 months fails the motor or cognitive domain of ASQ, there is a moderate probability that they have some motor or cognitive delay, respectively (very low COE). Trial Registration: PROSPERO (CRD42021268543).