Publications by authors named "Shripada Rao"

100 Publications

Time to regain birth weight - a marker to predict the severity of retinopathy of prematurity?

BMC Pediatr 2021 Dec 2;21(1):540. Epub 2021 Dec 2.

Department of Ophthalmology, Perth Children's Hospital, Perth, Australia.

Background: Poor weight gain in the first few weeks of life has been studied as a predictor of retinopathy of prematurity (ROP). Our aim was to assess whether time taken to regain birthweight (BW) be used as an additional marker to identify infants with type 1 ROP.

Methods: In this retrospective study, preterm infants (< 27 weeks gestational age at birth) born during the period from 1/1/2010-31/12/2015 at a tertiary neonatal intensive care unit in Australia were included. Twenty-seven preterm infants with Type 1 ROP were identified. Controls (No ROP or ROP other than type 1) were matched with cases on gestational age at birth and BW (1:4 ratio). Data were collected from the database and medical records.

Results: The median (IQR) gestational age for Type 1 ROP and control groups were 24 (24-26) and 25 (24-26) weeks respectively and median (IQR) BW for Type 1 ROP and control groups were 675 (635-810) and 773 (666-884) grams respectively. Preterm infants with Type 1 ROP were more likely to be small for gestational age (SGA) (18.5% vs 3.7%, p = 0.015) and had increased weeks on oxygen therapy (median 11.9 vs 9.1, p = 0.028). Time to regain BW was longer in preterm infants with type 1 ROP than controls but did not reach statistical significance (median 9 vs 7 days, OR 1.08, 95% CI 1.00-1.17, p = 0.059) adjusted for SGA and duration of oxygen therapy. The area under the curve from the time to regain BW model with adjustment for SGA and duration of oxygen therapy was 0.73 (95% CI 0.62-0.83).

Conclusion: We hypothesize that time to regain BW has potential to aid prediction of Type 1 ROP and this warrants further investigation in a larger prospective study.
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http://dx.doi.org/10.1186/s12887-021-03027-xDOI Listing
December 2021

The Use of Postnatal Weight Gain Algorithms to Predict Severe or Type 1 Retinopathy of Prematurity: A Systematic Review and Meta-analysis.

JAMA Netw Open 2021 Nov 1;4(11):e2135879. Epub 2021 Nov 1.

Department of Ophthalmology, Perth Children's Hospital, Perth, Australia.

Importance: The currently recommended method for screening for retinopathy of prematurity (ROP) is binocular indirect ophthalmoscopy, which requires frequent eye examinations entailing a heavy clinical workload. Weight gain-based algorithms have the potential to minimize the need for binocular indirect ophthalmoscopy and have been evaluated in different setups with variable results to predict type 1 or severe ROP.

Objective: To synthesize evidence regarding the ability of postnatal weight gain-based algorithms to predict type 1 or severe ROP.

Data Sources: PubMed, MEDLINE, Embase, and the Cochrane Library databases were searched to identify studies published between January 2000 and August 2021.

Study Selection: Prospective and retrospective studies evaluating the ability of these algorithms to predict type 1 or severe ROP were included.

Data Extraction And Synthesis: Two reviewers independently extracted data. This meta-analysis was performed according to the Cochrane guidelines and reported according to the Preferred Reporting Items for Systematic Reviews and Meta-analysis of Diagnostic Test Accuracy Studies (PRISMA-DTA) guidelines.

Main Outcomes And Measures: Ability of algorithms to predict type 1 or sever ROP was measured using statistical indices (pooled sensitivity, specificity, and summary area under the receiver operating characteristic curves, as well as pooled negative likelihood ratios and positive likelihood ratios and diagnostic odds ratios).

Results: A total of 61 studies (>37 000 infants) were included in the meta-analysis. The pooled estimates for sensitivity and specificity, respectively, were 0.89 (95% CI, 0.85-0.92) and 0.57 (95% CI, 0.51-0.63) for WINROP (Weight, IGF-1 [insulinlike growth factor 1], Neonatal, ROP), 1.00 (95% CI, 0.88-1.00) and 0.60 (95% CI, 0.15-0.93) for G-ROP (Postnatal Growth and ROP), 0.95 (95% CI, 0.71-0.99) and 0.52 (95% CI, 0.36-0.68) for CHOP ROP (Children's Hospital of Philadelphia ROP), 0.99 (95% CI, 0.73-1.00) and 0.49 (95% CI, 0.03-0.74) for ROPScore, 0.98 (95% CI, 0.94-0.99) and 0.35 (95% CI, 0.22-0.51) for CO-ROP (Colorado ROP). The original PINT (Premature Infants in Need of Transfusion) ROP study reported a sensitivity of 0.98 (95% CI, 0.91-0.99) and a specificity of 0.36 (95% CI, 0.30-0.42). The pooled negative likelihood ratios were 0.19 (95% CI, 0.13-0.27) for WINROP, 0.0 (95% CI, 0.00-0.32) for G-ROP, 0.10 (95% CI, 0.02-0.53) for CHOP ROP, 0.03 (95% CI, 0.00-0.77) for ROPScore, and 0.07 (95% CI, 0.03-0.16) for CO-ROP. The pooled positive likelihood ratios were 2.1 (95% CI, 1.8-2.4) for WINROP, 2.5 (95% CI, 0.7-9.1) for G-ROP, 2.0 (95% CI, 1.5-2.6) for CHOP ROP, 1.9 (95% CI, 1.1-3.3) for ROPScore, and 1.5 (95% CI, 1.2-1.9) for CO-ROP.

Conclusions And Relevance: This study suggests that weight gain-based algorithms have adequate sensitivity and negative likelihood ratios to provide reasonable certainty in ruling out type 1 ROP or severe ROP. Given the implications of missing even a single case of severe ROP, algorithms with very high sensitivity (close to 100%) and low negative likelihood ratios (close to zero) need to be chosen to safely reduce the number of unnecessary examinations in infants at lower risk of severe ROP.
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http://dx.doi.org/10.1001/jamanetworkopen.2021.35879DOI Listing
November 2021

Postnatal weight gain in very preterm infants: are we aiming too high?

Lancet Child Adolesc Health 2021 10 25;5(10):683-685. Epub 2021 Aug 25.

Neonatal Directorate, King Edward Memorial and Perth Children's Hospitals, Perth, WA 6009, Australia; School of Medicine, University of Western Australia, Perth, WA, Australia. Electronic address:

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http://dx.doi.org/10.1016/S2352-4642(21)00247-9DOI Listing
October 2021

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

Br J Nutr 2021 Aug 11:1-8. Epub 2021 Aug 11.

The University of Western Australia, Medical School, Perth, WA, Australia.

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.
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http://dx.doi.org/10.1017/S0007114521003020DOI Listing
August 2021

Management of umbilical granuloma in infants: A systematic review of randomised controlled trials.

Aust J Gen Pract 2021 08;50(8):589-594

MBBS, MD, DM, FRACP, Consultant Neonatologist, Perth Children's Hospital, WA; Associate Professor, University of Western Australia, WA.

Background And Objectives: Umbilical granuloma is a common condition in infants. The aim of this study was to systematically review randomised controlled trials (RCTs) of topical treatment options for umbilical granuloma.

Method: PubMed, Embase, Cochrane Library, Google Scholar and grey literature were searched in September 2020.

Results: Eleven RCTs (n = 890) that studied the use of silver nitrate, topical steroids, ethanol wipes, electrocautery, cryocautery, copper sulphate and common salt were included. Common salt achieved resolution in >90% of cases in five studies and 54-80% in two studies. Topical steroids, silver nitrate, copper sulphate and cryocautery achieved resolution in >90% and ethanol wipes in 50-65% of cases. Local side effects reported with topical steroids, silver nitrate, cryocautery and electrocautery varied in each study. Salt application did not cause side effects. The risk of bias was high in many RCTs.

Discussion: While the majority of the interventions were effective in treating umbilical granuloma, salt application appears to be simple and effective, with minimal complications.
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http://dx.doi.org/10.31128/AJGP-04-20-5371DOI Listing
August 2021

Outcomes of very preterm infants with neonatal hyperglycaemia: a systematic review and meta-analysis.

Arch Dis Child Fetal Neonatal Ed 2021 Jul 30. Epub 2021 Jul 30.

Neonatology, King Edward Memorial Hospital for Women, Subiaco, Western Australia, Australia.

Objective: To explore the association between hyperglycaemia and adverse outcomes in very preterm infants.

Design: Systematic review and meta-analysis. Data were pooled separately for adjusted and unadjusted odds ratios (ORs) using random-effects model. Subgroup analysis was conducted based on study design (cohort and case control).

Main Outcome Measures: Association between hyperglycaemia in preterm neonates (<32 weeks or <1500 g) and mortality and morbidities.

Findings: Forty-six studies (30 cohort and 16 case control) with data from 34 527 infants were included. Meta-analysis of unadjusted ORs from cohort studies found hyperglycaemia to be significantly associated with mortality, any-grade intraventricular haemorrhage (IVH), severe IVH, any-stage retinopathy of prematurity (ROP), severe ROP, sepsis, chronic lung disease and disability. However, pooling of adjusted ORs found significant associations only for mortality (adjusted OR (CI): 2.37 (1.40 to 4.01); I: 36%; 6 studies), 'Any grade IVH' (adjusted OR (CI): 2.60 (1.09 to 6.20); I: 0%; 2 studies) and 'Any stage ROP' (adjusted OR (CI): 3.70 (1.55 to 8.84); I: 0%; 2 studies). Meta-regression analysis found glucose levels >10 mmol/L to be associated with increased odds of mortality compared with <10 mmol/L. Pooled analysis from case-control studies were similar to cohort studies for most outcomes but limited by small sample size. Longer duration of hyperglycaemia was associated with adverse outcomes. GRADE of evidence was 'Low' or 'Very low'.

Conclusion: Hyperglycaemia in very preterm infants is associated with higher odds of mortality, any-grade IVH and any-stage ROP. A limitation was lack of availability of adjusted ORs from many of the included studies.

Prospero Registration Number: CRD42020193016.
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http://dx.doi.org/10.1136/archdischild-2020-321449DOI Listing
July 2021

Trans-anastomotic tube feeding in the management of congenital duodenal obstruction: a systematic review and meta-analysis.

Pediatr Surg Int 2021 Nov 1;37(11):1489-1498. Epub 2021 Jul 1.

Perth Children's Hospital, Perth, WA, Australia.

Background: Feed intolerance is a common problem in neonates with congenital duodenal obstruction (CDO). Some surgeons insert trans-anastomotic tubes (TAT) to facilitate feed tolerance. We conducted a systematic review to evaluate the efficacy and safety of TATs in CDO.

Methods: Medline, EmBase, CINAHL, and Cochrane Library were searched till July 2020. Risk of bias was assessed using ROBINS-I tool. Meta-analysis was conducted using Random Effects Model.

Results: No randomized controlled trials addressing the question were identified. In the 6 included observational studies, 96 infants underwent intraoperative TAT placement and 117 did not. Four studies reported benefits of TAT such as early attainment of full feeds and decreased need for parenteral nutrition. Two studies reported better outcomes in the no-TAT group. Accidental removal of TAT without clinical harm was reported in three studies [5/37 (14%), 4/17 (23%), and 2/4 (50%)]. Overall meta-analysis found no differences between the groups on any outcome. However, sensitivity analysis after excluding two studies with high risk of bias found that TAT tubes are associated with shorter duration of PN and shorter time to full enteral feeds. GRADE of evidence was very low for all outcomes.

Conclusions: Evidence is limited regarding the efficacy and safety of intraoperative TAT placement in neonates with CDO. Well-designed RCTs are needed to address the issue definitively.
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http://dx.doi.org/10.1007/s00383-021-04954-7DOI Listing
November 2021

Comparison of the efficacy and safety of cuffed versus uncuffed endotracheal tubes for infants in the intensive care setting: a pilot, unblinded RCT.

Arch Dis Child Fetal Neonatal Ed 2021 Nov 20;106(6):614-620. Epub 2021 Apr 20.

Department of Neonatology, Perth Children's Hospital, Nedlands, Western Australia, Australia.

Objective: To study effectiveness and safety of cuffed versus uncuffed endotracheal tubes (ETTs) in small infants in the intensive care unit (ICU).

Design: Pilot RCT.

Setting: Neonatal and paediatric ICUs of children's hospital in Western Australia.

Participants: Seventy-six infants ≥35 weeks gestation and infants <3 months of age, ≥3 kg.

Interventions: Patients randomly assigned to Microcuff cuffed or Portex uncuffed ETT.

Main Outcomes Measures: Primary outcome was achievement of optimal ETT leak in target range (10%-20%). Secondary outcomes included: reintubations, ventilatory parameters, ventilatory complications, postextubation complications and long-term follow-up.

Results: Success rate (achievement of mean leak in the range 10%-20%) was 13/42 (30.9%) in the cuffed ETT group and 6/34 (17.6%) in uncuffed ETT group (OR=2.09; 95% CI (0.71 to 6.08); p=0.28). Mean percentage time within target leak range in cuffed ETT group 28% (IQR: 9-42) versus 15% (IQR: 0-28) in uncuffed ETT group (p=0.01). There were less reintubations to optimise size in cuffed ETT group 0/40 versus 10/36 (p<0.001). No differences were found in gaseous exchange, ventilator parameters or postextubation complications. There were fewer episodes of atelectasis in cuffed ETT group 0/42 versus 4/34 (p=0.03). No patient had been diagnosed with subglottic stenosis at long-term follow-up.

Conclusions: There was no difference in the primary outcome, though percentage time spent in optimal leak range was significantly higher in cuffed ETT group. Cuffed ETTs reduced reintubations to optimise ETT size and episodes of atelectasis. Cuffed ETTs may be a feasible alternative to uncuffed ETTs in this group of patients.

Trial Registration Number: ACTRN12615000081516.
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http://dx.doi.org/10.1136/archdischild-2020-320764DOI Listing
November 2021

Umbilical cord milking versus delayed cord clamping in term and late-preterm infants: a systematic review and meta-analysis.

J Matern Fetal Neonatal Med 2021 Feb 10:1-11. Epub 2021 Feb 10.

Surya Hospitals, Mumbai, India.

Objective: To conduct a systematic review and meta-analysis to compare the efficacy and safety of umbilical cord milking (UCM) versus delayed cord clamping (DCC) in term and late-preterm infants.

Methods: MEDLINE, EMBASE, CINAHL, Cochrane Central Register of Controlled Trials, Clinical trial registries, and Gray literature were searched for randomized controlled trials (RCTs) comparing UCM with DCC in term and late-preterm infants for both short-term and long-term outcomes. Intact and cut UCM were compared separately with DCC using subgroup analysis. We used fixed effect model to pool the data. Random effects model was used when there was significant heterogeneity.

Results: Nine studies (1632 infants) were included in the systematic review. Milking was performed on intact cord (i-UCM) in five studies ( = 829) and on cut cord (c-UCM) in four studies ( = 803). Cord milking significantly improved hemoglobin level at 48-72 h of life when compared to DCC (six studies,  = 924, mean difference 0.36 g/dL; 95% CI: 0.19-0.53). In addition, hemoglobin level at six to eight weeks of age was also significantly higher in the studies comparing i-UCM with DCC (two studies,  = 550: mean difference 0.16 g/dL; 95% CI: 0.06-0.27). There was no difference between the UCM group and DCC group for any other outcome. Only one study provided information on growth and hematological parameters at one year of age. Neurodevelopmental outcomes were not reported. None of the studies included non-vigorous infants. The grade of evidence was low to very low for all the outcomes studied.

Conclusion: UCM is comparable to DCC in improving short-term hematological outcomes in term and late-preterm vigorous infants. Trials assessing the effect of UCM on important clinical and long-term outcomes among non-vigorous mature preterm infants are urgently required.
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http://dx.doi.org/10.1080/14767058.2021.1884676DOI Listing
February 2021

Early or delayed parenteral nutrition for infants: what evidence is available?

Curr Opin Clin Nutr Metab Care 2021 05;24(3):281-286

Medical School, The University of Western Australia, Perth.

Purpose Of Review: To review the current evidence evaluating early versus delayed commencement of parenteral nutrition in infants.

Recent Findings: Recent studies in very premature infants (<32 weeks gestation) have shown that early commencement of parenteral nutrition immediately after birth improves physical growth. However, there are concerns that early use of very high dose of amino-acids (>3.5 g/kg/day immediately after birth) may cause metabolic acidosis, elevated blood urea, slower head growth and refeeding-hypophosphatemia syndrome. A recent multicentre randomized controlled trial found that commencement of parenteral nutrition within 24-h of admission increases the risk of infections and prolongs the duration of ventilation and ICU stay in full-term neonates, older infants and children. The study also found that delaying to day 8 of admission increased the risk of hypoglycaemia.

Summary: Benefits of commencing parenteral nutrition on the first day of life appear to outweigh risks in very premature infants; however, it is prudent to avoid early very high doses of amino acids (>3.5 g/kg/day) in the first few days of life. In moderate to late preterm infants, if enteral feeds are not tolerated by 72 h, it is reasonable to commence parenteral nutrition. In full-term and older infants, it is preferable to avoid parenteral nutrition within 24 h of admission and consider delaying by further few days. Diligent monitoring of blood glucose, serum phosphate and other parameters is essential while on parenteral nutrition.
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http://dx.doi.org/10.1097/MCO.0000000000000720DOI Listing
May 2021

Why do neonates receive antiseizure medications?

J Matern Fetal Neonatal Med 2020 Sep 14:1-5. Epub 2020 Sep 14.

Department of Neurology, Children's Neuroscience Service, Perth Children's Hospital, Perth, Australia.

Background: Continuous conventional video-electroencephalography (cVEEG), the gold standard, is not routinely available for monitoring neonatal seizures in Australia. Therefore, seizures are monitored with clinical observation and amplitude-integrated electroencephalography (aEEG), which may result in under- or over-treatment with antiseizure medications (ASMs). We aimed to investigate ASM usage and its relation to the "cVEEG-confirmed seizures" (cVEEG seizures) in the at-risk infants admitted to a tertiary referral neonatal intensive care unit (NICU).

Methods: The study was a part of a diagnostic study comparing cVEEG with aEEG for the detection of neonatal seizures. Thirty-six infants ≥35 weeks gestational age and at risk of seizures and admitted to NICU were recruited after informed parental consent. The infants were monitored and treated with ASMs based on clinical observation and aEEG findings. A simultaneous cVEEG, not available for clinical decision making, was recorded for 24-h and interpreted at a later date. Data regarding ASM usage and seizure burden on cVEEG were collected. Spearman's Rho coefficient was used to assess the correlation between the number of doses of ASMs administered and seizure burden on cVEEG.

Results: cVEEG recordings of 35 infants were available for analysis. The gestational age of the infants ranged from 36 to 42 weeks, and the most common diagnosis was hypoxic-ischemic encephalopathy. Twelve infants received ASMs during the 24-h study period, of which five (42%) did not have cVEEG seizures. Maximum cVEEG seizure burden was 8.3 h, and maximum number of ASMs used was three. The correlation between the number of doses of ASMs administered in an infant and the seizure burden on cVEEG was low (Spearman's Rho: 0.44;  = .148).

Conclusion: Treatment of neonatal seizures based on clinical observation and aEEG, without cVEEG, results in unnecessary or inadequate exposure to ASMs for many infants.
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http://dx.doi.org/10.1080/14767058.2020.1819976DOI Listing
September 2020

A survey on criteria for intubation in moderate to late preterm infants with respiratory distress.

Pediatr Pulmonol 2020 11 17;55(11):2970-2982. Epub 2020 Sep 17.

Neonatal Directorate, King Edward Memorial Hospital and Perth Children's Hospital, Subiaco, Western Australia, Australia.

Background: Majority of preterm infants do well with continuous positive airway pressure (CPAP) as the sole respiratory management; but some require endotracheal intubation and surfactant administration. While intubation is needed predominantly in extremely preterm infants (<28 weeks); some of the more mature preterm infants also require it. Currently, there are no clear guidelines regarding indications for endotracheal intubation in such infants.

Aims: To understand the current practice regarding "criteria for intubation" in moderate to late preterm infants with respiratory distress.

Methods: A survey of neonatologists in Australia New Zealand Neonatal Network (ANZNN) was conducted between April and June 2019.

Results: At least one neonatologist each from 29 of the 30 tertiary ANZNN Neonatal Intensive Care Units (NICUs) responded to the survey. In total, 118/200 (59%) neonatologists responded. The most common criteria for intubation were CPAP = 8 cmH O (61%), pH < 7.2 (55%), pCO  > 70 mmHg (48%), FiO  > 40% (40%), chest retractions (48%), more than two episodes of apnea requiring intervention (54%), and chest X-ray (CXR) showing moderate-severe hyaline membrane disease (HMD, 49%).

Conclusion: While there were variations in practice, nearly 50% of the neonatologists shared a common threshold with regards to the CPAP level, FiO , blood gas parameters, and clinical and radiological findings. The results of this survey will help in designing future randomized controlled trials (RCTs) on this subject.
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http://dx.doi.org/10.1002/ppul.25054DOI Listing
November 2020

Early neurodevelopmental outcomes of congenital gastrointestinal surgical conditions: a single-centre retrospective study.

BMJ Paediatr Open 2020 11;4(1):e000736. Epub 2020 Aug 11.

Neonatal Directorate, Perth Children's Hospital and King Edward Memorial Hospital for Women, Perth, Western Australia, Australia.

Background: Evidence is emerging that surgery in the neonatal period is associated with increased risk of suboptimal neurodevelopmental outcomes (SNDO). The aim of this study was to describe neurodevelopmental outcomes (at 1 year) of neonatal surgery for congenital gastrointestinal surgical conditions (CGSC) and to explore risk factors.

Methods: Retrospective study (2005-2014) of infants born ≥34 weeks gestation with CGSC and admitted to the surgical neonatal intensive care unit of Perth Children's Hospital, Western Australia. Clinical details and 1-year developmental outcomes based on Griffiths Mental Developmental Assessment Scales were collated from the database and by reviewing the medical records of study infants. SNDO was defined as one or more of the following: a general quotient less than 88 (ie, >1 SD below mean), cerebral palsy, blindness or sensorineural deafness. Univariable and multivariable logistic regression analyses were carried out to explore risk factors for SNDO. A total of 413 infants were included, of which 13 died. Median gestation was 37.6 weeks (IQR: 36.4-39.1). Information on developmental outcomes was available from 262 out of 400 survivors. A total of 43/262 (16.4%) had SNDO. On univariable analysis, lower z scores for birth weight, prolonged duration of antibiotics, increased episodes of general anaesthesia and prolonged duration of hospital stay were associated with SNDO. On multivariable analysis, lower z scores for birth weight and prolonged hospital stay were associated with increased risk of SNDO.

Conclusions: Late preterm and term infants undergoing neonatal surgery for CGSC may be at risk for SNDO. Studies with longer duration of follow-up are needed to further evaluate the role of potentially modifiable risk factors on their neurodevelopmental outcomes.
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http://dx.doi.org/10.1136/bmjpo-2020-000736DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7422631PMC
August 2020

Comparison of wide field imaging by nurses with indirect ophthalmoscopy by ophthalmologists for retinopathy of prematurity: a diagnostic accuracy study.

BMJ Open 2020 08 5;10(8):e036483. Epub 2020 Aug 5.

Department of Neonatology, King Edward Memorial Hospital for Women, Perth, Western Australia, Australia.

Objectives: Retinopathy of prematurity (ROP) is a vasoproliferative disease of the preterm retina with the potential to cause irreversible blindness. Timely screening and treatment of ROP are critical. Neonatal nurses trained in wide field digital retinal photography (WFDRP) for screening may provide a safe and effective strategy to reduce the burden of ophthalmologists in performing binocular indirect ophthalmoscopy (BIO). The objective of the study was to determine the diagnostic accuracy of WFDRP in the diagnosis of referral warranting ROP (RWROP).

Design: Prospective diagnostic accuracy study.

Setting: A tertiary neonatal intensive care unit in Perth, Western Australia.

Participants: Preterm infants who fulfilled the Australian ROP screening criteria (gestational age (GA) <31 weeks, birth weight (BW) <1250 g).

Intervention: Sets of 5-6 images per eye (index test) were obtained within 24-48 hours prior to or after the BIO (reference standard), and uploaded onto a secured server. A wide field digital camera (RetCam, Natus, Pleasanton, California, USA) was used for imaging. A paediatric ophthalmologist performed the BIO. The ophthalmologists performing BIO versus reporting the images were masked to each other's findings.

Primary Outcome: The area under the receiver operating characteristic (ROC) curve was used as a measure of accuracy of WFDRP to diagnose RWROP.

Results: A total of 85 infants (mean BW; 973.43 g, mean GA; 29 weeks) underwent a median of two sessions of WFDRP. There were 188 episodes of screening with an average of five images per eye. WFDRP identified RWROP in 7.4% (14/188 sessions) of examinations. In one infant, BIO showed bilateral plus disease and WFDRP did not pick up the plus disease. WFDRP image interpretation had a sensitivity of 80%, specificity of 94.5% for the detection of RWROP. The 'area under the ROC curve' was 88% when adjusted for covariates.

Conclusions: WFDRP by neonatal nurses was feasible and effective for diagnosing RWROP in our set up.

Trial Registration Number: ACTRN12616001386426.
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http://dx.doi.org/10.1136/bmjopen-2019-036483DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7409991PMC
August 2020

Diffuse excessive high signal intensity on term equivalent MRI does not predict disability: a systematic review and meta-analysis.

Arch Dis Child Fetal Neonatal Ed 2021 Jan 25;106(1):9-16. Epub 2020 May 25.

Neonatal Intensive Care Unit, King Edward Memorial Hospital for Women Perth, Subiaco, Western Australia, Australia.

Objective: To evaluate whether diffuse excessive high signal intensity (DEHSI) on term equivalent age MRI (TEA-MRI) predicts disability in preterm infants.

Design: This is a systematic review and meta-analysis. Medline, EMBASE, Cochrane Library, EMCARE, Google Scholar and MedNar databases were searched in July 2019. Studies comparing developmental outcomes of isolated DEHSI on TEA-MRI versus normal TEA-MRI were included. Two reviewers independently extracted data and assessed the risk of bias. Meta-analysis was undertaken where data were available in a format suitable for pooling.

Main Outcome Measures: Neurodevelopmental outcomes ≥1 year of corrected age based on validated tools.

Results: A total of 15 studies (n=1832) were included, of which data from 9 studies were available for meta-analysis. The pooled estimate (n=7) for sensitivity of DEHSI in predicting cognitive/mental disability was 0.58 (95% CI 0.34 to 0.79) and for specificity was 0.46 (95% CI 0.20 to 0.74). The summary area under the receiver operating characteristics (ROC) curve was low at 0.54 (CI 0.50 to 0.58). A pooled diagnostic OR (DOR) of 1 indicated that DEHSI does not discriminate preterm infants with and without mental disability. The pooled estimate (n=8) for sensitivity of DEHSI in predicting cerebral palsy (CP) was 0.57 (95% CI 0.37 to 0.75) and for specificity was 0.41 (95% CI 0.24 to 0.62). The summary area under the ROC curve was low at 0.51 (CI 0.46 to 0.55). A pooled DOR of 1 indicated that DEHSI does not discriminate between preterm infants with and without CP.

Conclusions: DEHSI on TEA-MRI did not predict future development of cognitive/mental disabilities or CP.

Prospero Registration Number: CRD42019130576.
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http://dx.doi.org/10.1136/archdischild-2019-318207DOI Listing
January 2021

Human Milk-Derived Fortifiers Compared with Bovine Milk-Derived Fortifiers in Preterm Infants: A Systematic Review and Meta-Analysis.

Adv Nutr 2020 09;11(5):1325-1333

School of Medicine, University of Western Australia, Perth, Western Australia, Australia.

This systematic review assessed outcomes after using human milk-derived fortifier (HMF) compared with bovine milk-derived fortifier (BMF) in preterm infants. Six randomized controlled trials (RCTs) were included. Meta-analysis using a random-effects model showed the following results: 1) lower risk of necrotizing enterocolitis (NEC; ≥Stage II) (RR: 0.38; 95% CI: 0.15, 0.95; P = 0.04, I2 = 9%; n = 334, 4 RCTs) and surgical NEC (RR: 0.13; 95% CI: 0.02, 0.67; P = 0.02, I2 = 0%; n = 209, 3 RCTs) in the HMF group; 2) no significant difference in mortality (RR: 0.40; 95% CI: 0.14, 1.15; P = 0.09, I2 = 0%; n = 334, 4 RCTs); 3) lower weight gain in the HMF group [mean difference (MD) = -1.08 g · kg-1 · d-1; 95% CI: -1.96, -0.21 g · kg-1 · d-1; P = 0.02, I2 = 0%; n = 241, 4 RCTs]; 4) no differences for length (MD = -0.11 cm/wk; 95% CI: -0.26, 0.04 cm/wk; P = 0.14, I2 = 68%) and head circumference (MD = -0.02 cm/wk; 95% CI: -0.08, 0.05 cm/wk; P = 0.59, I2 = 23%); and 5) no significant difference in late-onset sepsis (RR: 0.96; 95% CI: 0.56, 1.67; P = 0.90, I2 = 63%; n = 334, 4 RCTs). The beneficial effects of HMF for NEC were no longer significant in sensitivity analyses after excluding studies with high risk of bias. Quality of evidence as per Grading of Recommendations, Assessment, Development and Evaluation (GRADE) analysis was low to very low, and hence the confidence in these results is low. In summary, fortification of milk in preterm infants with HMF compared with BMF decreased the risk of NEC but was associated with lower weight gain. Given the low quality of evidence, adequately powered and well-designed RCTs without the influence of industry are required in this field.
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http://dx.doi.org/10.1093/advances/nmaa039DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7490161PMC
September 2020

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

Cochrane Database Syst Rev 2020 04 8;4:CD013141. Epub 2020 Apr 8.

The University of Western Australia, Centre for Neonatal Research and Education, Medical School, Perth, Australia.

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 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.
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http://dx.doi.org/10.1002/14651858.CD013141.pub2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7138920PMC
April 2020

Probiotics for Preterm Infants in India - Systematic Review and Meta-Analysis of Randomized Controlled Trials.

Indian J Pediatr 2020 Oct 17;87(10):817-825. Epub 2020 Mar 17.

School of Medicine, University of Western Australia, Perth, Western Australia, Australia.

The objective of the present study is to review current evidence from randomized controlled trials (RCTs) of probiotics for preterm infants in India. A systematic review of RCTs of probiotics for preterm infants in India was conducted using Cochrane methodology and PRISMA guidelines. Fixed effects model was used for meta-analysis. Nine RCTs (n = 1514) were included. Meta-analysis showed reduced risk of necrotizing enterocolitis (NEC) ≥ Stage II {Risk ratio (RR): 036 [95% confidence interval (CI): 0.20, 0.66], p = 0.0009, (9 RCTs)}, late onset sepsis [RR: 0.56 (95% CI: 0.45, 0.71), p < 0.00001, (7 RCTs)] and mortality [RR: 0.62 (95% CI: 0.41, 0.95, p = 0.03 (8 RCTs)] in the probiotic group. Probiotics also reduced the time to full feeds [Mean difference (MD): -4.09 d (95% CI: -4.52, -3.65), p < 0.00001, 5 RCTs] and duration of hospital stay [Fixed effects model (FEM): MD: -2.00 d (95% CI: -2.46, -1.53), p < 0.00001, 6 RCTs]. Current evidence from RCTs supports probiotic supplementation for optimizing outcomes of preterm infants in India.
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http://dx.doi.org/10.1007/s12098-020-03223-0DOI Listing
October 2020

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

Pediatr Res 2020 12 16;88(6):878-886. Epub 2020 Mar 16.

Centre for Marine Science and Innovation at the University of New South Wales (UNSW), Sydney, NSW, Australia.

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.
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http://dx.doi.org/10.1038/s41390-020-0824-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7223116PMC
December 2020

Umbilical cord milking in preterm infants: a systematic review and meta-analysis.

Arch Dis Child Fetal Neonatal Ed 2020 Nov 9;105(6):572-580. Epub 2020 Mar 9.

Department of Neonatology, Surya Hospitals, Mumbai, Maharashtra, India.

Objective: To conduct a systematic review and meta-analysis of the efficacy and safety of umbilical cord milking in preterm infants.

Design: Randomised controlled trials comparing umbilical cord milking with delayed cord clamping/immediate cord clamping in preterm infants were identified by searching databases, clinical trial registries and reference list of relevant studies in November 2019. Fixed effects model was used to pool the data on various clinically relevant outcomes.

Main Outcome Measures: Mortality and morbidities in preterm neonates.

Results: Nineteen studies (2014 preterm infants) were included. Five studies (n=922) compared cord milking with delayed cord clamping, whereas 14 studies (n=1092) compared milking with immediate cord clamping. Cord milking, as opposed to delayed cord clamping, significantly increased the risk of intraventricular haemorrhage (grade III or more) (risk ratio (RR): 1.95 (95% CI 1.01 to 3.76), p=0.05). When compared with immediate cord clamping, cord milking reduced the need for packed RBC transfusions (RR:0.56 (95% CI 0.43 to 0.73), p<0.001). There was limited information on long-term neurodevelopmental outcomes. The grade of evidence was moderate or low for the various outcomes analysed.

Conclusion: Umbilical cord milking, when compared with delayed cord clamping, significantly increased the risk of severe intraventricular haemorrhage in preterm infants, especially at lower gestational ages. Cord milking, when compared with immediate cord clamping, reduced the need for packed RBC transfusions but did not improve clinical outcomes. Hence, cord milking cannot be considered as placental transfusion strategy in preterm infants based on the currently available evidence.
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http://dx.doi.org/10.1136/archdischild-2019-318627DOI Listing
November 2020

Inter-rater reliability of amplitude-integrated EEG for the detection of neonatal seizures.

Early Hum Dev 2020 04 4;143:105011. Epub 2020 Mar 4.

Neonatal Clinical Care Unit, King Edward Memorial Hospital and Perth Children's Hospital, Perth, Australia; Centre for Neonatal Research and Education, Medical School, University of Western Australia, Australia.

Background: Amplitude-integrated electroencephalogram (aEEG) is being used increasingly for seizure detection in neonates. However, data regarding inter-rater reliability among neonatologists for the use of aEEG for the detection of neonatal seizures is lacking.

Methods: Term and late-preterm infants at risk of seizures were monitored simultaneously with 24-h video-electroencephalography (vEEG) and aEEG. vEEG was interpreted by an experienced neurologist. Five neonatologists with experience in aEEG interpretation from four different neonatal units interpreted aEEG recordings independently. The Brennan and Prediger kappa coefficient and Intra-class Correlation Coefficients (ICC) were used to assess inter-rater reliability between the neonatologists.

Results: Thirty-five infants at risk of seizure with gestational age at birth 35-42 weeks were recruited for the study after informed parental consent. vEEG detected seizures in seven infants with a total of 169 individual seizure episodes. Neonatologists detected seizures in 10 to 15 infants on aEEG. The sensitivities for the detection of individual seizures by neonatologists ranged from 18% to 38%. The inter-rater reliability for detection of: individual seizure was "fair" (kappa = 0.37; 95% CI: 0.32-0.42), infant with seizure was "moderate" (kappa = 0.60; 95% CI: 0.44-0.75), duration of individual seizure (ICC: 0.22; 95% CI: 0.18-0.28) and total duration of seizures in an infant (ICC: 0.46; 95% CI: 0.30-0.63) was "poor". The neonatologists missed 77-90% of the duration of seizures.

Conclusion: The inter-rater reliability of aEEG for the detection of neonatal seizures was suboptimal. Even when interpreted by experienced and trained clinicians, seizure detection with aEEG has limitations and can miss large number and duration of seizures.
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http://dx.doi.org/10.1016/j.earlhumdev.2020.105011DOI Listing
April 2020

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

Eur J Pediatr 2019 Sep 2;178(9):1317-1324. Epub 2019 Jul 2.

Neonatal Directorate, King Edward Memorial Hospital for Women and Perth Children's Hospital, Perth, WA, Australia.

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; I = 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.
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http://dx.doi.org/10.1007/s00431-019-03407-7DOI Listing
September 2019

Current Practice of Therapeutic Hypothermia for Mild Hypoxic Ischemic Encephalopathy.

J Child Neurol 2019 06 22;34(7):402-409. Epub 2019 Mar 22.

1 Department of Neonatology, Princess Margaret and King Edward Hospitals, Perth, Australia.

Context: Therapeutic hypothermia is the recommended treatment for neonates with moderate or severe hypoxic ischemic encephalopathy (HIE). There is an increasing trend to use therapeutic hypothermia even in infants with mild hypoxic ischemic encephalopathy, even though there is little evidence to support/refute this.

Objective: To estimate the incidences of mild hypoxic ischemic encephalopathy among infants who received therapeutic hypothermia, and its short- and long-term outcomes.

Data Sources And Study Selection: PubMed, Embase, CINAHL, and Cochrane library were searched to identify observational studies reporting on therapeutic hypothermia in term and near-term infants with mild hypoxic ischemic encephalopathy. The JBI (Joanna Briggs Institute) tools were used to assess the risk of bias in the included studies. Random effects meta-analysis was conducted to find out the percentage of cooled infants who had only mild hypoxic ischemic encephalopathy.

Results: A total of 3590 citations were screened, of which 13 were included. Of the 2783 infants who received therapeutic hypothermia, 573 had mild hypoxic ischemic encephalopathy. Meta-analysis found that 22% of the infants who underwent therapeutic hypothermia had only mild hypoxic ischemic encephalopathy (95% confidence interval: 16%-27%; I statistic = 90.5%). Five studies provided information on adverse effects of therapeutic hypothermia in mild hypoxic ischemic encephalopathy. The reported adverse effects were extreme hypothermia, bradycardia, hypoglycemia, sepsis, skin necrosis, pulmonary hypertension, and systemic hypotension. Limitation: The limitations included relatively small sample size and the lack of data for short- and long-term neurodevelopmental outcome.

Conclusions: A significant proportion of infants who received therapeutic hypothermia had mild hypoxic ischemic encephalopathy. Randomized trials are urgently needed to evaluate the efficacy and safety of therapeutic hypothermia in infants with mild hypoxic ischemic encephalopathy.
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http://dx.doi.org/10.1177/0883073819828625DOI Listing
June 2019

Endotoxin-induced cerebral pathophysiology: differences between fetus and newborn.

Physiol Rep 2019 02;7(4):e13973

The Ritchie Centre, Hudson Institute of Medical Research, Clayton, Victoria, Australia.

As the comparative pathophysiology of perinatal infection in the fetus and newborn is uncertain, this study contrasted the cerebral effects of endotoxemia in conscious fetal sheep and newborn lambs. Responses to intravenous bacterial endotoxin (lipopolysaccharide, LPS) or normal saline were studied on three consecutive days in fetal sheep (LPS 1 μg/kg, n = 5; normal saline n = 5) and newborn lambs (LPS 2 μg/kg, n = 10; normal saline n = 5). Cerebro-vascular function was assessed by monitoring cerebral blood flow (CBF) and cerebral vascular resistance (CVR) over 12 h each day, and inflammatory responses were assessed by plasma TNF alpha (TNF-α), nitrate and nitrite concentrations. Brain injury was quantified by counting both resting and active macrophages in the caudate nucleus and periventricular white matter (PVWM). An acute cerebral vasoconstriction (within 1 h of LPS injection) occurred in both the fetus (ΔCVR +53%) and newborn (ΔCVR +63%); subsequently prolonged cerebral vasodilatation occurred in the fetus (ΔCVR -33%) in association with double plasma nitrate/nitrite concentrations, but not in the newborn. Abundant infiltration of activated macrophages was observed in both CN and PVWM at each age, with the extent being 2-3 times greater in the fetus (P < 0.001). In conclusion, while the fetus and newborn experience a similar acute disruption of the cerebral circulation after LPS, the fetus suffers a more prolonged circulatory disruption, a greater infiltration of activated macrophages, and an exaggerated susceptibility to brain injury.
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http://dx.doi.org/10.14814/phy2.13973DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6381816PMC
February 2019

Probiotic research in neonates with congenital gastrointestinal surgical conditions - Now is the time.

Microb Biotechnol 2019 03 21;12(2):254-258. Epub 2018 Dec 21.

Centre for Neonatal Research and Education, University of Western Australia, Perth, WA, Australia.

Neonates with congenital gastrointestinal surgical conditions (CGISC) receive parenteral nutrition, get exposed to multiple courses of antibiotics, undergo invasive procedures, and are nursed in intensive care units. They do not receive early enteral feeding and have limited opportunities for skin to skin contact with their mothers. Many of these infants receive gastric acid suppression therapies. All these factors increase the risk of gut dysbiosis in these infants. Gut dysbiosis is known to be associated with increased risk of infections and other morbidities in ICU patients. Experimental studies have shown that probiotics inhibit gut colonization with pathogenic bacteria, enhance gut barrier function, facilitate colonization with healthy commensals, protect from enteropathogenic infection through production of acetate, reduce antimicrobial resistance, enhance innate immunity, and increase the maturation of the enteric nervous system and promote gut peristalsis. Through these mechanisms, probiotics have the potential to decrease the risk of sepsis and inflammation, improve feed tolerance and minimise cholestasis in neonates with CGISC. Among preterm non-surgical infants, evidence from more than 35 RCTs and multiple observational studies have shown probiotics to be safe and beneficial. A RCT in neonates (N=24) with gastroschisis found that probiotic supplementation partially attenuated gut dysbiosis. Two ongoing RCTs (total N=168) in neonates with gastrointestinal surgical conditions are expected to provide feasibility data to enable the conduct of large RCTs. Rigorous quality assurance of the probiotic product, ongoing microbial surveillance and clinical vigilance are warranted while conducting such RCTs.
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http://dx.doi.org/10.1111/1751-7915.13358DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6389852PMC
March 2019

Prevalence of Autism Spectrum Disorder in Preterm Infants: A Meta-analysis.

Pediatrics 2018 09 3;142(3). Epub 2018 Aug 3.

Neonatal Unit, King Edward Memorial Hospital for Women and Perth Children Hospital, Nedlands, Western Australia, Australia.

Context: Evidence is emerging that preterm infants are at risk for autism spectrum disorder (ASD).

Objectives: To conduct a systematic review and meta-analysis to estimate the prevalence of ASD in preterm infants.

Data Sources: Medline (via PubMed and Ovid), Embase, PsycINFO, and relevant conference proceedings were searched in May 2017.

Study Selection: Original studies in which researchers report on the prevalence of ASD using diagnostic tests in children born preterm were included. Studies in which researchers used only ASD screening tools were excluded.

Data Extraction: Relevant data were extracted independently by 3 authors.

Results: Researchers in a total of 18 studies (3366 preterm infants) used ASD diagnostic tools. The median gestation, birth weight, and age at assessment were 28.0 weeks (range: 25.1-31.3 weeks), 1055 g (range: 719-1565 g), and 5.7 years (range: 1.5-21 years), respectively. Meta-analysis revealed that the overall prevalence rate for ASD was 7% (95% confidence interval: 4% to 9%). The funnel plot and Egger's test revealed that there was probably no evidence of publication bias.

Limitations: The limitations were significant heterogeneity and a lack of studies from middle- and low-income countries.

Conclusions: The prevalence of ASD is significantly high in the preterm population. Adequate resources are needed to improve the outcomes of these children.
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http://dx.doi.org/10.1542/peds.2018-0134DOI Listing
September 2018

Clinical Outcomes Related to the Gastrointestinal Trophic Effects of Erythropoietin in Preterm Neonates: A Systematic Review and Meta-Analysis.

Adv Nutr 2018 05;9(3):238-246

Center for Neonatal Research and Education, University of Western Australia, Perth, Australia.

Erythropoietin (EPO) plays an important role in the development and maturation of the gastrointestinal tract. Recombinant EPO (rEPO) has been used to prevent anemia of prematurity. The gastrointestinal trophic effects of EPO may reduce feeding intolerance and necrotizing enterocolitis (NEC) in preterm neonates. The aim of this systematic review of randomized controlled trials (RCTs) was to evaluate the effects of rEPO on clinical outcomes such as feeding intolerance, stage II or higher NEC, any stage NEC, sepsis, retinopathy of prematurity, and bronchopulmonary dysplasia in preterm neonates. Twenty-five RCTs (intravenous: 13; subcutaneous: 10; enteral: 2; n = 4025) were eligible for inclusion. Meta-analysis of data from 17 RCTs (rEPO compared with placebo) with the use of a fixed-effects model showed no significant effect of rEPO on stage II or higher NEC (RR: 0.87; 95% CI: 0.64, 1.19; P = 0.39). Meta-analysis of data from 25 RCTs (rEPO compared with placebo) showed that rEPO significantly decreased the risk of any stage NEC [cases/total sample: 120/2058 (5.83%) compared with 146/1967 (7.42%); RR: 0.77; 95% CI: 0.61, 0.97; P = 0.03]. Only one RCT reported on time to full feedings. Meta-analysis of data from 15 RCTs showed a significant reduction in late-onset sepsis after rEPO administration (RR: 0.81; 95% CI: 0.71, 0.94; P = 0.004). Meta-analysis of 13 RCTs showed no significant effect of rEPO on mortality, retinopathy of prematurity, and bronchopulmonary dysplasia. Prophylactic rEPO had no effect on stage II or higher NEC, but it reduced any stage NEC, probably by reducing feeding intolerance, which is often labeled as stage I NEC. Adequately powered RCTs are required to confirm these findings.
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http://dx.doi.org/10.1093/advances/nmy005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5952937PMC
May 2018

Effectiveness and safety of nasal mask versus binasal prongs for providing continuous positive airway pressure in preterm infants-A systematic review and meta-analysis.

Pediatr Pulmonol 2018 07 23;53(7):987-992. Epub 2018 Apr 23.

Department of Neonatal Paediatrics, King Edward Memorial Hospital for Women, Perth, Western Australia.

Continuous positive airway pressure (CPAP) delivered via binasal prongs has been the cornerstone of respiratory management in preterm infants. Though effective, the use of binasal prongs is associated with nasal trauma, and CPAP failure. To overcome these issues, nasal masks are increasingly used to deliver CPAP in preterm infants. The aim was to conduct a systematic review of randomized controlled trials (RCTs) comparing nasal mask versus binasal prongs to deliver CPAP in preterm infants. Medline, Embase, Cochrane Central Register of Controlled Trials, Cumulative Index of Nursing, and Allied Health Literature, and E-abstracts from the Pediatric Academic Society meetings were searched in May 2017. All RCTs comparing nasal mask versus binasal prongs for delivering CPAP in preterm infants were included. Primary outcome was CPAP failure (need for mechanical ventilation within 72 h of initiating CPAP). Secondary outcomes included duration of CPAP, moderate to severe nasal trauma, any nasal trauma, pneumothorax, severe IVH, bronchopulmonary dysplasia at 36 weeks postmenstrual age, and mortality. Five RCTs with low risk of bias were included. Nasal mask significantly decreased the risk of CPAP failure (4 RCTs [N = 459]; relative risk [RR]: 0.63; 95% confidence interval [CI]: 0.45-0.88; P=.007; I2 = 0%, NNT: 9), and the incidence of moderate to severe nasal trauma (3 RCTs [N = 275], RR: 0.41; 95%CI, 0.24-0.72; P = 0.002; I2 = 74%, NNT: 6). Other outcomes did not differ significantly between the groups. Compared to binasal prongs, nasal mask may provide a safe and effective alternative by minimizing the risk of CPAP failure in preterm infants needing CPAP support.
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http://dx.doi.org/10.1002/ppul.24014DOI Listing
July 2018

Impact of hypoglycaemia on neurodevelopmental outcomes in hypoxic ischaemic encephalopathy: a retrospective cohort study.

BMJ Paediatr Open 2017 18;1(1):e000175. Epub 2017 Sep 18.

Neonatal Intensive Care Unit, Princess Margaret Hospital for Children, Perth, Western Australia, Australia.

Background: Low blood glucose levels (BGLs) in infants are known to adversely affect neurodevelopmental outcomes. However, this risk is not well explored in infants with hypoxic ischaemic encephalopathy (HIE) that receive therapeutic hypothermia (TH). Additionally, little information is available on the optimal BGLs to target in infants with HIE.

Aim: To explore the association between hypoglycaemia and neurodevelopmental outcomes at different BGL thresholds (2.6 and 3.0 mmol/L) in neonates with HIE treated with TH.

Methods: Retrospective cohort study. Clinical information and 2-year neurodevelopmental data using Bayley Scales of Infant Development, third edition (BSID-III) and disabilities were recorded for infants born in Western Australia with HIE and treated with TH between February 2008 and February 2012. Multivariable logistic regression models explored the association between hypoglycaemia and neurodevelopmental outcomes.

Results: 122 infants underwent a total of 1616 BGL estimations before and during 72 hours of TH. Hypoglycaemia (BGL<2.6 mmol/L) occurred in 38/122 (31%) infants and 11/122 (9%) had recurrent hypoglycaemia (three or more episodes). Infants with recurrent hypoglycaemia (<2.6 mmol/L) had significantly lower mean BSID-III cognitive, language and socioemotional subscale scores. On multivariable analysis, recurrent hypoglycaemia (<2.6 mmol/L) was associated with increased odds of death or disability (adjusted OR 8.15; 95% CI 1.31 to 50.58; p=0.024). Recurrent hypoglycaemia (<3.0 mmol/L) during the first 12 hours of life was also associated with severe disability among survivors (adjusted OR 11.13; 95% CI 2.06 to 59.89; p=0.005).

Conclusions: Early recurrent hypoglycaemia was associated with increased risk of death or severe disability in neonates undergoing TH for HIE. Prospective studies are needed to identify the ideal target BGL in this population.
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http://dx.doi.org/10.1136/bmjpo-2017-000175DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5862228PMC
September 2017
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