Prevalence of hearing impairment in neonatal encephalopathy due to hypoxia-ischemia: a systematic review and meta-analysis.

BACKGROUND: This systematic review was undertaken to estimate the overall prevalence of hearing impairment in survivors of neonatal HIE. METHODS: PubMed, EMBASE, CINAHL, EMCARE and Cochrane databases, mednar (gray literature) were searched till January 2023. Randomized controlled trials and observational studies were included. The main outcome was estimation of overall prevalence of hearing impairment in survivors of HIE. RESULTS: A total of 71studies (5821 infants assessed for hearing impairment) were included of which 56 were from high income countries (HIC) and 15 from low- or middle-income countries (LMIC). Overall prevalence rate of hearing impairment in cooled infants was 5% (95% CI: 3-6%, n = 4868) and 3% (95% CI: 1-6%, n = 953) in non-cooled HIE infants. The prevalence rate in cooled HIE infants in LMICs was 7% (95% CI: 2-15%) and in HICs was 4% (95% CI: 3-5%). The prevalence rate in non-cooled HIE infants in LMICs was 8% (95% CI: 2-17%) and HICs was 2% (95% CI: 0-4%). CONCLUSIONS: These results would be useful for counseling parents, and in acting as benchmark when comparing institutional data, and while monitoring future RCTs testing new interventions in HIE. There is a need for more data from LMICs and standardization of reporting hearing impairment. IMPACT: The overall prevalence rate of hearing impairment in cooled infants with HIE was 5% (95% CI: 3-6%) and 3% (95% CI: 1-6%) in the non-cooled infants. The prevalence rate in cooled HIE infants in LMICs was 7% (95% CI: 2-15%) and in HICs was 4% (95% CI: 3-5%). The prevalence rate in non-cooled HIE infants in LMICs was 8% (95% CI: 2-17%) and HICs was 2% (95% CI: 0-4%). These results would be useful for counseling parents, and in acting as benchmark when comparing institutional data, and while monitoring future RCTs testing new interventions in HIE.

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.

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.

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.

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.

Skin-Microbiome Assembly in Preterm Infants during the First Three Weeks of Life and Impact of Topical Coconut Oil Application.

The structure and function of infant skin is not fully developed until 34 weeks of gestation, and this immaturity is associated with risk of late-onset sepsis (LOS). Topical coconut oil improves preterm-infant skin integrity and may reduce LOS. However, data on early-life skin-microbiome succession and potential effects of emollient skin care in preterm infants are scarce. We therefore collected skin-microbiome samples from the ear, axilla, and groin on days 1, 7, 14, and 21 from preterm infants born <30 weeks of gestation as part of a randomized clinical trial of standard skin care vs. topical coconut oil. We found that within-sample microbiome diversity was highest on day 1 after birth, with a subsequent decline and emergence of Staphylococcus genus dominance from day 7. Moreover, microbiome assembly was less diverse in infants receiving coconut oil vs. standard skin care. Our study provides novel data on preterm-infant skin-microbiome composition and highlights the modifying potential of emollient skin care.

Probiotic supplementation in neonates with congenital gastrointestinal surgical conditions: a pilot randomised controlled trial.

OBJECTIVE: To evaluate whether probiotic supplementation attenuates gut-dysbiosis in neonates with congenital gastrointestinal surgical conditions (CGISC). METHODS: Sixty-one neonates (≥35 weeks gestation) with CGISC were randomised to receive daily supplementation with a triple-strain bifidobacterial probiotic (n = 30) or placebo (n = 31) until discharge. Stool microbiota was analysed using 16S ribosomal RNA gene sequencing on samples collected before (T1), 1 week (T2), and 2 weeks (T3) after supplementation and before discharge (T4). The primary outcome was the sum of the relative abundance of potentially pathogenic families of Clostridiaceae, Enterobacteriaceae, Enterococcaceae, Pseudomonaceae, Staphylococcaeae, Streptococcaceae, and Yersiniaceae at T3. RESULTS: The median gestational age [38 weeks (IQR: 37.1-38.9)] was similar in both groups. The probiotic group had lower rates of caesarean deliveries (40% versus 70%, p = 0.02). The relative abundance of potentially pathogenic families was lower in the probiotic group compared to placebo at T3 [(median: 50.4 (IQR: 26.6-67.6) versus 67.1 (IQR: 50.9-96.2); p = 0.04). Relative abundance of Bifidobacteriaceae was higher in the probiotic group at T3 [(median: 39.8 (IQR: 24.9-52.1) versus 0.03 (IQR 0.02-2.1); p < 0.001). Stratified analysis continued to show a higher abundance of Bifidobacteriaceae in the probiotic group, irrespective of the mode of delivery. CONCLUSIONS: Probiotic supplementation attenuated gut dysbiosis in neonates with CGISC. TRIAL REGISTRATION: http://www.anzctr.org.au (ACTRN12617001401347). IMPACT: Probiotic supplementation attenuates gut dysbiosis and improves stool short-chain fatty acid levels in neonates with congenital gastrointestinal surgical conditions. This is the second pilot RCT of probiotic supplementation in neonates with congenital gastrointestinal conditions. These findings will pave the way for conducting multicentre RCTs in this area.

Use of parenteral nutrition in term and late preterm infants: an Australian and New Zealand survey.

There is limited information regarding the use of parenteral nutrition (PN) in term and late preterm infants. We conducted a survey to study the current clinical practices within Australia and New Zealand (ANZ). A fifteen-question online survey was distributed to 232 neonatologists and fifty-five paediatric intensivists across ANZ between September and November 2019. At least one neonatologist from twenty-seven out of thirty tertiary neonatal intensive care units responded (90 %). Responses were received from sixty-nine neonatologists (30 %) and seven paediatric intensivists (13 %). The overall response rate was 26 % (76/287). Thirty-three percent (25/76) commenced PN within 24 h of admission, 27 % (20/75) between 24 and 48 h, 24 % (18/75) between 48 and 72 h, 9 % (7/75) between 72 and 96 h and 4 % (3/75) between 96 h and 7 days. None of the respondents commenced PN after 7 d of admission. Sixty-one percent (46/75) aimed for 1·5-3 g/kg per d of parenteral amino acids, whereas 27 % (20/75) aimed for 2-3 g/kg per d. Renal failure (59 %; 38/64) and high plasma urea (44 %; 28/64) were the major indications for withholding/decreasing the amino acid intake. Eighty-three percent (63/76) aimed for a dose of 2·5g-3·5 g/kg per d of parenteral lipids; about 9 % (7/76) targeted a dose of 1-2·5 g/kg per d and 4 % (3/76) for > 3·5 g/kg per d. Thirty-two percent (24/74) reported that they would withhold/decrease the dose of parenteral lipids in infants with sepsis. The variations in clinicians' practices with respect to the use of PN in term and late preterm infants highlight the need for high-quality research in this population.

Does abnormal Doppler on cranial ultrasound predict disability in infants with hypoxic-ischaemic encephalopathy? A systematic review.

AIM: To evaluate whether abnormal resistive index or cerebral blood flow velocity (CBFV) on cranial ultrasound predicts disability (≥1 year) in infants with hypoxic-ischaemic encephalopathy (HIE). METHOD: This was a systematic review and meta-analysis of studies comparing developmental outcomes of infants with HIE with normal versus abnormal resistive index or CBFV. RESULTS: Twenty-six studies were included (pre-therapeutic hypothermia era, 20; therapeutic hypothermia era, six). Data from 15 studies (pre-therapeutic hypothermia, 10; therapeutic hypothermia, five) were available for meta-analysis. Pooled sensitivity and specificity, summary area under the receiver operating characteristic curve, and diagnostic odds ratio of resistive index or CBFV for predicting 'death or severe disability' were as follows. Pre-therapeutic hypothermia era: 0.83 (95% confidence interval [CI] 0.45-0.97) and 0.92 (95% CI 0.74-0.98), 0.94 (95% CI 0.92-0.96), 54 (95% CI 7-391). Therapeutic hypothermia era (measurements before therapeutic hypothermia): 0.62 (95% CI 0.41-0.80) and 0.96 (95% CI 0.88-0.99), 0.93 (95% CI 0.89-0.94), 23 (95% CI 6-91). Therapeutic hypothermia era (measurements during/after therapeutic hypothermia): 0.51 (95% CI 0.24-0.78) and 0.83 (95% CI 0.73-0.90), 0.81 (95% CI 0.78-0.85), 5 (95% CI 2-13). Overall Grading of Recommendations Assessment, Development and Evaluation (GRADE) rating of evidence was 'low' or 'very low'. INTERPRETATION: Low-level evidence suggests that abnormal resistive index or CBFV can predict death or disability with high sensitivity and specificity in infants with HIE who are not cooled. The specificity of these tests was high when performed before starting cooling in infants who received therapeutic hypothermia. WHAT THIS PAPER ADDS: Cerebral doppler ultrasound may be useful in predicting death or disability in infants with hypoxic-ischaemic encephalopathy who are not cooled. Cerebral doppler ultrasound may also be useful in infants who are cooled, if done before starting cooling. Cerebral doppler ultrasound may not be useful when performed during or after completing cooling.

OBJETIVO: Avaliar se o índice de resistência anormal ou a velocidade do fluxo sanguíneo cerebral (VFSC) na ultrassonografia craniana prediz incapacidade (≥1 ano) em bebês com encefalopatia hipóxico-isquêmica (EHI). MÉTODO: Esta foi uma revisão sistemática e meta-análise de estudos comparando os resultados do desenvolvimento de bebês com EHI com índice de resistência normal versus anormal ou VFSC. RESULTADOS: Vinte e seis estudos foram incluídos (hipotermia pré-terapêutica, 20; hipotermia terapêutica, 6). Dados de 15 estudos (hipotermia pré-terapêutica, 10; hipotermia terapêutica, 5) estavam disponíveis para meta-análise. Sensibilidade e especificidade agrupadas, área de resumo sob a curva característica de operação do receptor e razão de chances de diagnóstico do índice resistivo ou VFSC para prever "morte ou incapacidade grave" foram os seguintes. (1) Hipotermia pré-terapêutica: 0,83 (intervalo de confiança de 95% [IC] 0,45-0,97) e 0,92 (IC 95% 0,74-0,98), 0,94 (IC 95% 0,92-0,96),54 (IC 95% 7-391). (2) Hipotermia terapêutica (medições antes da hipotermia terapêutica): 0,62 (IC 95% 0,41-0,80) e 0,96 (IC 95% 0,88-0,99), 0,93 (IC 95% 0,89-0,94), 23 (IC 95% 6-91). (3) Hipotermia terapêutica (medidas durante/após a hipotermia terapêutica): 0,51 (IC 95% 0,24-0,78) e 0,83 (IC 95% 0,73-0,90), 0,81 (IC 95% 0,78-0,85),5 (IC 95% 2 -13). A classificação geral das evidências de Avaliação, Desenvolvimento e Avaliação de Recomendações (GRADE) foi 'baixa' ou 'muito baixa'. INTERPRETAÇÃO: Evidências de baixo nível sugerem que anormalidades índice resistivo ou VFSC pode prever morte ou incapacidade com alta sensibilidade e especificidade em bebês com EHI que não são resfriados. A especificidade desses testes foi alta quando realizados antes do início do resfriamento em bebês que receberam hipotermia terapêutica.

Early erythropoietin for preventing necrotizing enterocolitis in preterm neonates - an updated meta-analysis.

Previous systematic reviews suggest reduction in necrotizing enterocolitis (NEC) among preterm infants supplemented with erythropoietin (EPO). We aimed to update our 2018 systematic review in this field considering the evidence accumulated over the last 3 years. Randomized controlled trials (RCTs) reporting the effect of early EPO supplementation vs placebo/no EPO supplementation on any stage NEC in preterm infants were included. Fixed effect model was used for meta-analysis. Trial sequential analysis (TSA) was conducted to verify the effects of EPO on NEC after accounting for repeated significance testing. A total of 22 RCTs (n = 5359) were included, of which six were new (n = 2541 additional preterm infants) in comparison to our previous systematic review. EPO significantly decreased the risk of any stage NEC (232/2669 (8.7%) vs 313/2690 (11.6%); RR: 0·76; TSA adjusted 95% CI (0·64, 0·90); p = 0·0008, number needed to treat (NNT) = 34). The risk of definite NEC (≥ Stage II) was also significantly reduced by EPO administration (105/2219 (4.7%) vs 141/2246 (6.3%); RR: 0.77; 95% CI (0.61, 0.98); p = 0.03, NNT: 62). However, the results for definite NEC were no longer significant on sensitivity analyses that included (a) only double-blind RCTs and (b) only prospectively registered trials. The quality of evidence was deemed moderate-to-low for the reported outcomes. CONCLUSION: There is moderate to low-quality evidence that early prophylactic EPO reduces any stage and ≥ Stage II NEC in preterm neonates. Prospectively registered, adequately powered, double-blind RCTs are required to confirm these findings. WHAT IS KNOWN: • Experimental studies have shown that erythropoietin (EPO) has gastrointestinal trophic effects. • Systematic reviews have shown that early treatment with EPO may decrease the risk of gut injury in preterm or low birth weight infants. WHAT IS NEW: • Early EPO supplementation significantly reduced the incidence of any stage NEC and definite NEC in preterm infants < 34 weeks of gestation. • EPO had no significant effect on definite NEC in the analyses that included only double-blinded and prospectively registered RCTs. How might it impact clinical practice in the foreseeable future? • Early prophylactic EPO can be recommended for NEC prevention if its benefits are consistently demonstrated in adequately powered randomized trials with a low risk of bias.

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.

Probiotic sepsis in preterm neonates-a systematic review.

Sepsis due to the administered probiotic strain/s is a barrier against adoption of prophylactic probiotic supplementation in preterm infants to reduce the risk of necrotising enterocolitis (NEC ≥ Stage II), all-cause mortality, late-onset sepsis, and feeding intolerance. We aimed to conduct a systematic review for reports of probiotic sepsis in preterm infants (gestation < 37 weeks). Databases including PubMed, Embase, Emcare, Cochrane Central library, and Google Scholar were searched in August 2021 and updated in Jan 2022. Probiotic sepsis was defined as positive blood/CSF culture isolating administered probiotic strain with symptoms suggestive of infection. Data collection included birth weight, gestation, comorbidities (e.g. gut surgery, NEC), presence of central venous catheters, treatment, and outcome. Literature search revealed 1569 studies. A total of 16 reports [randomised control trial (RCT): none; non-RCT: 1; case series: 8; case report: 7] involving 32 preterm infants with probiotic sepsis were included after exclusions for various reasons. Majority of the cases were born < 32 weeks' gestation. Bifidobacterium (N = 19) was the most commonly isolated organism followed by Lactobacillus (N = 10), and Saccharomyces (N = 3). A total of 25/32 cases were confirmed to be due to the administered probiotic strain on full genomic analysis. Two studies reported one neonatal death each. Twelve neonates had comorbidities. Majority were treated with antibiotics (29/32) whereas others (3/32) required antifungal treatment. CONCLUSION: Probiotics sepsis is relatively an uncommon event in preterm infants. Majority of the cases recovered after antibiotic or antifungal treatment. The importance of optimal surveillance and treatment of probiotic sepsis and research towards alternatives to probiotics (e.g. postbiotics) is emphasised. WHAT IS KNOWN: • Probiotics have been shown to reduce necrotising enterocolitis, late-onset sepsis, all-cause mortality, and time to reach full enteral feeds in preterm infants. • Despite the evidence, use of probiotics is not universal due to concerns regarding probiotic-associated sepsis in preterm infants. WHAT IS NEW: • This comprehensive systematic review showed that probiotic sepsis is a relatively rare phenomenon in preterm infants. • All except one case where the diagnosis was uncertain recovered after antimicrobial therapy.

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).

Stability of the Initial Diagnosis of Autism Spectrum Disorder by DSM-5 in Children: A Short-Term Follow-Up Study.

BACKGROUND: Assessing the stability of the diagnosis of autism spectrum disorder (ASD) in children is important. Only few such studies have been reported from India. We aimed to assess the stability after 18-30 months, of an initial diagnosis of ASD based on DSM-5, in children ≤ 5 years of age using Autism Diagnostic Observation Schedule, 2nd Edition (ADOS-2). METHODS: A total of 125 children with ASD diagnosed by DSM-5 at ≤ 5 years of age were followed up at 18-30 months using ADOS-2, which is considered as the 'gold-standard' observational assessment for diagnosing ASD and hence suitable for confirming the stability of the diagnosis. RESULTS: Similar to previous studies from developed countries, the stability of ASD diagnosis was 80%. There was no significant correlation between gender, socioeconomic status and the stability of the final diagnosis. All the children continued to have some developmental difficulties mainly in the domain of language, attention or social communication. CONCLUSION: Our results suggest that DSM-5 can be used for the initial diagnosis ASD to initiate early intervention for children with this condition in resource-limited set-ups. Adequately powered prospective studies with long-term follow-up are needed to confirm our findings.

Gut microbiota in neonates with congenital gastrointestinal surgical conditions: a prospective study.

BACKGROUND: There is limited information on gut microbiota of neonates with congenital gastrointestinal surgical conditions (CGISCs) available. METHODS: This study compared stool microbiota and short-chain fatty acids (SCFAs) of 37 term infants with CGISCs with 36 term healthy infants (HIs). Two stool samples were collected from each infant: as soon as possible after birth (week 1) and 10-14 days of life (week 2). RESULTS: Bacterial richness and alpha diversity were comparable between CGISCs and HIs at week 1 and week 2 (all p > 0.05). Beta diversity analysis revealed that at week 1, CGISCs had similar community structures to HIs (p = 0.415). However, by week 2, community structures of CGISCs were significantly different from HIs (p = 0.003). At week 1, there were no significant differences in the relative abundances of genera Bifidobacterium and Bacteroides between CGISCs and HIs. At week 2, the relative abundance of Bifidobacterium was significantly lower in CGISCs (mean percentage 7.21 ± 13.49 vs. 28.96 ± 19.6; p = 0.002). Bacteroides were also less abundant in the CGISC group (mean percentage 0.12 ± 0.49 vs. 6.59 ± 8.62; p = 0.039). Relative abundance of genera Pseudomonas and Escherichia-Shigella were higher in CGISCs. At week 2, stool concentrations of all SCFAs were lower in CGISCs (all p < 0.001). CONCLUSIONS: During hospitalization, neonates with CGISCs develop gut dysbiosis and deficiency of SCFAs. IMPACT: During hospitalisation, neonates with congenital gastrointestinal surgical conditions develop gut dysbiosis with deficiency of Bifidobacteria and Bacteroides and increased abundance of Escherichia-Shigella and Pseudomonas. They also have low levels of short chain fatty acids in their stools compared to healthy infants. This is the first study evaluating the gut microbiota using 16S ribosomal RNA sequencing methods and stool short chain fatty acids in neonates with congenital gastrointestinal surgical conditions and comparing them to healthy infants. The findings of this study will pave the way for randomised trials of bifidobacterial supplementation in neonates with congenital gastrointestinal surgical conditions.

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.

Effects of maturation and size on population pharmacokinetics of pentoxifylline and its metabolites in very preterm infants with suspected late-onset sepsis or necrotizing enterocolitis: a pilot study incorporating clinical outcomes.

AIMS: Infection-induced inflammation is associated with adverse long-term outcomes in preterm infants. Pentoxifylline (PTX) is a candidate for adjunct immunomodulatory therapy in preterm infants with late-onset sepsis (LOS) and necrotizing enterocolitis (NEC), but pharmacokinetic data in this population are extremely limited. This study aims to characterize the pharmacokinetic properties of intravenous PTX and its metabolites in preterm infants. METHOD: An open label pilot clinical study of intravenous PTX as an adjunct therapy in preterm infants (gestation <32 weeks) with suspected LOS or NEC was undertaken. PTX was infused for 12 h for two days (60 mg kg-1 per 12 h), and in infants with confirmed diagnosis of LOS or NEC, for 6 h for another 4 days (30 mg kg-1 per 6 h). Plasma concentrations of PTX and its principal metabolites from collected blood samples were measured using a validated LCMS assay. NONMEM was used to analyse the data using population pharmacokinetic modelling. RESULTS: The preterm infants (n = 26) had a median (range) gestation of 24.8 weeks (23.3-30.4) and birthweight of 689 g (370-1285). PTX was well tolerated and without treatment-limiting adverse effects. Changes in size (weight) and maturation were successfully modelled for PTX and metabolites. After allometric scaling, clearance increased with postmenstrual age, increasing by approximately 30% per week for PTX and M1 (lisofylline) and simulations of current dosing demonstrated a six-fold difference in exposure between 24 and 35 weeks postmenstrual age. CONCLUSIONS: The developed model can be used to explore dosing strategies based on size and maturation for preterm infants.

Probiotics for cow's milk protein allergy: a systematic review of randomized controlled trials.

Cow's milk protein allergy (CMPA) is the commonest food allergy in infancy and is associated with significant health burden. Given their immune modulatory properties, probiotics have been proposed as a strategy for management of CMPA. We aimed to systematically review efficacy and safety of probiotics in the management of CMPA. Databases PubMed, EMBASE, CINAHL, Cochrane Central Library, and Google scholar were searched in August 2018 for randomized controlled trials (RCT) of probiotic supplementation as an adjunct in the management of infants with suspected/proven CMPA. Primary outcomes were resolution of hematochezia and acquisition of tolerance to CMP at 6, 12, 24, and 36 months. Secondary outcomes included effect on allergic symptoms (SCORAD index), growth, gut microbiota, and adverse effects. A total of 10 RCTs (n = 845; probiotics, 422; control, 423) with low to unclear risk of bias were included. Meta-analysis showed probiotic supplementation was not associated with earlier resolution of hematochezia (n = 87; RR: 1.45 (95% CI: 0.96-2.18), p = 0.08; level of evidence (LOE), very low), in presumed CMPA. In confirmed CMPA, probiotics were associated with higher rate of acquisition of tolerance to CMP at the end of 3 years compared with placebo (N = 493; RR, 1.47; 95% CI, (1.17-1.84); p = 0.0009; LOE, low]. Meta-analysis was not possible for other outcomes. There were no probiotic related adverse effects. Conclusion: Limited low-quality evidence indicates that probiotic supplementation may be associated with earlier acquisition of tolerance to CMP in children with CMPA. Large well-designed trials are essential to confirm these findings. What is Known: • Cow's milk protein allergy (CMPA) is one of the commonest food allergies in children. CMPA is associated with significant socioeconomic burden. • Elimination diet and extensively hydrolyzed formula is the mainstay of the management of CMPA. What is New: • This first systematic review of randomized controlled trials shows that probiotics as an adjuvant can lead to earlier acquisition of tolerance to CMP in children at 36 months of age. However, the evidence is low quality and influenced by data from one large study. • Probiotic supplementation was not associated with earlier resolution of hematochezia.

Topical application of coconut oil to the skin of preterm infants: a systematic review.

Preterm infants are at risk of increased trans-epidermal water loss and infections due to epidermal immaturity. The emollient and anti-infective properties of coconut oil make it a potentially beneficial topical agent for this population. We aimed to systematically review randomised trials assessing the effects of topical coconut oil in preterm infants. Medline, EMBASE, Cochrane Central Register of Controlled Trials and CINAHL were searched. Seven trials (n = 727 infants) were included. The majority of trials included relatively mature infants (gestation > 32 weeks, birth weight > 1200 g). The duration of intervention (5-31 days) and outcomes of interest varied among included studies. Meta-analysis using random effects model found significantly lower incidence of hospital-acquired blood stream infections (HABSI) in the coconut oil group (11/164 vs 32/166; relative risk 0.35, 95% confidence interval 0.18, 0.67, p = 0.001; I2 = 0%, two RCTs). Overall, infants in the coconut oil group had decreased water loss, decreased infection rates, better growth and skin condition. There were no significant adverse effects associated with coconut oil application. The overall quality of evidence was considered moderate for the outcome of HABSI and low for the outcome of physical growth based on GRADE guidelines.Conclusion: Topical coconut oil application to the skin may be beneficial in preterm infants, but the quality of evidence is low to moderate. Adequately powered randomised controlled trials, especially in very preterm (< 32 weeks) and extremely preterm (< 28 weeks) infants, are needed. What is Known: • Coconut oil has been used traditionally for topical application in terms of infants in Asian countries What is New: • This systematic review found that topical application of coconut oil may reduce the risk of infection and improve weight gain and skin condition in preterm infants. However, the quality of evidence was considered to be moderate to low based on GRADE guidelines.

Effects of probiotics on experimental necrotizing enterocolitis: a systematic review and meta-analysis.

BackgroundMeta-analyses of randomized controlled trials (RCTs) suggest that probiotics decrease the risk of necrotizing enterocolitis (NEC) in preterm infants. Many animal RCTs have evaluated probiotics for preventing NEC. We systematically reviewed the literature on this topic.MethodsThe protocol for systematic review of animal intervention studies (SYRCLE) was followed. Medline, Embase, ISI Web of Science, e-abstracts from the Pediatric Academic Society meetings, and other neonatal conferences were searched in December 2015 and August 2016. RCTs comparing probiotics vs. placebo/no probiotic were included.ResultsA total of 29 RCTs were included (Rats: 16, Mice: 7, Piglets: 3, Quail: 2, Rabbit: 1; N~2,310), with 21 reporting on histopathologically confirmed NEC; remaining 8 assessed only pathways of probiotic benefits. Twenty of the 21 RCTs showed that probiotics significantly reduced NEC. Pooling of data was possible for 16/21 RCTs. Meta-analysis using random-effects model showed that probiotics significantly decreased the risk of NEC (203/641 (31.7%) vs. 344/571 (60.2%); relative risk: 0.51; 95% confidence interval (CI): 0.42-0.62; P<0.00001; I2=44%; number needed to treat: 4; 95% CI: 2.9, 4.3).ConclusionProbiotics significantly reduced NEC via beneficial effects on immunity, inflammation, tissue injury, gut barrier, and intestinal dysbiosis.