High-Dose Docosahexaenoic Acid in Newborns Born at Less Than 29 Weeks' Gestation and Behavior at Age 5 Years: Follow-Up of a Randomized Clinical Trial.

Importance: Children born at less than 29 weeks' gestation are at risk of behavioral difficulties. This may be due in part to the lack of transplacental supply of docosahexaenoic acid (DHA), a key fatty acid with structural and functional roles in the brain. Objective: To determine whether meeting the neonatal DHA requirement through supplementation is associated with improved behavioral functioning of children born at less than 29 weeks' gestation. Design, Setting and Participants: This was a follow-up of children from 10 Australian participating centers in a multi-center, blinded, parallel group randomized clinical trial of infants born at less than 29 weeks' gestation conducted from June 2012 and September 2015, excluding those with additional fatty acid supplementation or major congenital or chromosomal abnormalities. Follow-up took place from August 2018 to May 2021. Parents of surviving children who had not withdrawn from the original trial were invited to complete questionnaires when the child turned 5 years' corrected age. Interventions: Infants were randomized to receive daily enteral emulsions providing 60 mg/kg/d of DHA or a soy-oil emulsion (with no DHA) from within the first 3 days of enteral feeding until 36 weeks' postmenstrual age or discharge home, whichever occurred first. Main Outcomes and Measures: The primary outcome of this follow-up was parent-rated behavior and emotional functioning as indicated by the Total Difficulties score of the Strengths and Difficulties Questionnaire. Parents also completed questionnaires about their child's behavioral manifestations of executive functioning, as well as a range of health outcomes to assess potential longer-term side effects of DHA intervention. Results: Primary outcome data were available for 731 children (76% of 958 surviving eligible children; 361 in the intervention group and 370 in the control group). Of these 731, 452 (47%) were female, and the mean (SD) corrected age at follow-up was 5.4 (0.5) years. Following imputation for missing data, the mean Total Difficulties score was the same in both groups (intervention group, n = 465; mean [SD], 11.8 [6.3]; control group, n = 493; mean [SD], 11.8 [6.0]; mean difference adjusted for sex, gestational age stratum, and hospital, 0.01; 95% CI, -0.87 to 0.89; P = .98). There was no evidence for differences between the groups in any secondary outcomes of behavior, executive functioning, or health. Conclusions and Relevance: In this follow-up of a randomized clinical trial, enteral DHA supplementation at the equivalent of the estimated in utero dose for infants born at less than 29 weeks' gestation did not improve behavioral functioning at age 5 years. There were no indications of adverse effects with DHA supplementation. Trial Registration: Australian New Zealand Clinical Trial Registry: ACTRN12612000503820.

Neonatal Drug Formularies-A Global Scope.

Neonatal drug information (DI) is essential for safe and effective pharmacotherapy in (pre)term neonates. Such information is usually absent from drug labels, making formularies a crucial part of the neonatal clinician's toolbox. Several formularies exist worldwide, but they have never been fully mapped or compared for content, structure and workflow. The objective of this review was to identify neonatal formularies, explore (dis)similarities, and raise awareness of their existence. Neonatal formularies were identified through self-acquaintance, experts and structured search. A questionnaire was sent to all identified formularies to provide details on formulary function. An original extraction tool was employed to collect DI from the formularies on the 10 most commonly used drugs in pre(term) neonates. Eight different neonatal formularies were identified worldwide (Europe, USA, Australia-New Zealand, Middle East). Six responded to the questionnaire and were compared for structure and content. Each formulary has its own workflow, monograph template and style, and update routine. Focus on certain aspects of DI also varies, as well as the type of initiative and funding. Clinicians should be aware of the various formularies available and their differences in characteristics and content to use them properly for the benefit of their patients.

Analytical and Non-Analytical Variation May Lead to Inappropriate Antimicrobial Dosing in Neonates: An In Silico Study.

BACKGROUND: Therapeutic drug monitoring (TDM) of aminoglycosides and vancomycin is used to prevent oto- and nephrotoxicity in neonates. Analytical and nonanalytical factors potentially influence dosing recommendations. This study aimed to determine the impact of analytical variation (imprecision and bias) and nonanalytical factors (accuracy of drug administration time, use of non-trough concentrations, biological variation, and dosing errors) on neonatal antimicrobial dosing recommendations. METHODS: Published population pharmacokinetic models and the Australasian Neonatal Medicines Formulary were used to simulate antimicrobial concentration-time profiles in a virtual neonate population. Laboratory quality assurance data were used to quantify analytical variation in antimicrobial measurement methods used in clinical practice. Guideline-informed dosing recommendations based on drug concentrations were applied to compare the impact of analytical variation and nonanalytical factors on antimicrobial dosing. RESULTS: Analytical variation caused differences in subsequent guideline-informed dosing recommendations in 9.3-12.1% (amikacin), 16.2-19.0% (tobramycin), 12.2-45.8% (gentamicin), and 9.6-19.5% (vancomycin) of neonates. For vancomycin, inaccuracies in drug administration time (45.6%), use of non-trough concentrations (44.7%), within-subject biological variation (38.2%), and dosing errors (27.5%) were predicted to result in more dosing discrepancies than analytical variation (12.5%). Using current analytical performance specifications, tolerated dosing discrepancies would be up to 14.8% (aminoglycosides) and 23.7% (vancomycin). CONCLUSIONS: Although analytical variation can influence neonatal antimicrobial dosing recommendations, nonanalytical factors are more influential. These result in substantial variation in subsequent dosing of antimicrobials, risking inadvertent under- or overexposure. Harmonization of measurement methods and improved patient management systems may reduce the impact of analytical and nonanalytical factors on neonatal antimicrobial dosing.

Intermittent phototherapy versus continuous phototherapy for neonatal jaundice.

BACKGROUND: Phototherapy is a widely accepted, effective first-line therapy for neonatal jaundice. It is traditionally used continuously but intermittent phototherapy has been proposed as an equally effective alternative with practical advantages of improved maternal feeding and bonding. The effectiveness of intermittent phototherapy compared with continuous phototherapy is unknown. OBJECTIVES: To assess the safety and effectiveness of intermittent phototherapy compared with continuous phototherapy. SEARCH METHODS: Searches were conducted on 31 January 2022 in the following databases: CENTRAL via CRS Web, MEDLINE and Embase via Ovid. We also searched clinical trials databases and the reference lists of retrieved articles for randomised controlled trials (RCTs) and quasi-randomised trials. SELECTION CRITERIA: We included RCTs, cluster-RCTs and quasi-RCTs comparing intermittent phototherapy with continuous phototherapy in jaundiced infants (both term and preterm) up to the age of 30 days. We compared intermittent phototherapy with continuous phototherapy by any method and at any dose and duration as defined by the authors. DATA COLLECTION AND ANALYSIS: Three review authors independently selected trials, assessed trial quality and extracted data from included studies. We performed fixed-effect analyses and expressed treatment effects as mean difference (MD), risk ratio (RR) and risk difference (RD) with 95% confidence intervals (CIs). Our primary outcomes of interest were rate of decline of serum bilirubin, and kernicterus. We used the GRADE approach to assess the certainty of evidence. MAIN RESULTS: We included 12 RCTs (1600 infants) in the review. There is one ongoing study and four awaiting classification. There was little or no difference between intermittent phototherapy and continuous phototherapy with respect to rate of decline of bilirubin in jaundiced newborn infants (MD -0.09 micromol/L/hr, 95% CI -0.21 to 0.03; I² = 61%; 10 studies; 1225 infants; low-certainty evidence). One study involving 60 infants reported no incidence of bilirubin induced brain dysfunction (BIND). It is uncertain whether either intermittent or continuous phototherapy reduces BIND because the certainty of this evidence is very low. There was little or no difference in treatment failure (RD 0.03, 95% CI 0.08 to 0.15; RR 1.63, 95% CI 0.29 to 9.17; 1 study; 75 infants; very low-certainty evidence) or infant mortality (RD -0.01, 95% CI -0.03 to 0.01; RR 0.69, 95% CI 0.37 to 1.31 I² = 0%; 10 studies, 1470 infants; low-certainty evidence).  AUTHORS' CONCLUSIONS: The available evidence detected little or no difference between intermittent and continuous phototherapy with respect to rate of decline of bilirubin. Continuous phototherapy appears to be more effective in preterm infants, however, the risks of continuous phototherapy and the potential benefits of a slightly lower bilirubin level are unknown. Intermittent phototherapy is associated with a decrease in the total number of hours of phototherapy exposure. There are theoretical benefits to intermittent regimens but there are important safety outcomes that were inadequately addressed. Large, well designed, prospective trials are needed in both preterm and term infants before it can be concluded that intermittent and continuous phototherapy regimens are equally effective.

Individualized vancomycin dosing in infants: prospective evaluation of an online dose calculator.

BACKGROUND: Empiric vancomycin dosing regimens fail to achieve recommended target trough concentrations of 10-20 mg/L in the majority of infants. This study assessed the performance of a model-based dosing calculator (Vanc App) in achieving target vancomycin concentrations at first steady-state level. METHODS: This was a multicenter prospective study in four tertiary pediatric hospitals over an 18-month period. Infants aged 0-90 days with suspected Gram-positive sepsis requiring empiric vancomycin treatment were included if they did not meet any of the exclusion criteria: post-menstrual age (PMA) <25 weeks, weight <500 g, glycopeptide allergy, receiving extracorporeal membrane oxygenation, vancomycin use within the previous 72 h, and renal impairment. The Vanc App used a published population pharmacokinetic model to generate a dose based on the infant's PMA, weight, creatinine, and target vancomycin concentration. RESULTS: A total of 40 infants were included; 40% were female, median (range) weight was 2505 (700-4460) g and median (range) PMA was 37.4 (25.7-49.0) weeks. The median (range) vancomycin dose was 45 (24-79) mg/kg/day. All infants had trough vancomycin concentrations measured at steady-state (24-<48 hours) and 30 (75%) infants achieved target concentrations. Five infants had supratherapeutic (median 25, range 21-38 mg/L) and five had subtherapeutic (median 6, range <5-9 mg/L) concentrations. An area under the concentration-time curve (AUC0-24) of 400-650 mg/L.h was achieved in 33 (83%) infants. There were no infusion-related reactions or nephrotoxicity. CONCLUSION: Individualized intermittent vancomycin dosing using a model-based online calculator resulted in 75% and 83% of infants achieving target trough and AUC0-24, respectively, at first steady-state level. There were no vancomycin-related nephrotoxicity or infusion-related reactions.

Reference values for diaphragm electrical activity (Edi) in newborn infants.

BACKGROUND: Neurally adjusted ventilatory assist is an emerging mode of respiratory support that uses the electrical activity of the diaphragm (Edi) to provide synchronised inspiratory pressure support, proportional to an infant's changing inspiratory effort. Data on Edi reference values for neonates are limited. The objective of this study was to establish reference Edi values for preterm and term neonates who are not receiving respiratory support. METHODS: This was a prospective observational study of newborn infants breathing spontaneously in room air. The Edi waveform was monitored by a specialised naso/orogastric feeding tube with embedded electrodes positioned at the level of the diaphragm. Edi minimums and peaks were recorded continuously for 4 h without changes to routine clinical handling. RESULTS: Twenty-four newborn infants (16 preterm [< 37 weeks' gestation]; 8 term) were studied. All infants were breathing comfortably in room air at the time of study. Edi data were successfully captured in all infants. The mean (±SD) Edi minimum was 3.02 (±0.94) µV and the mean Edi peak was 10.13 (±3.50) µV. In preterm infants the mean (±SD) Edi minimum was 3.05 (±0.91) µV and the mean Edi peak was 9.36 (±2.13) µV. In term infants the mean (±SD) Edi minimum was 2.97 (±1.05) µV and the mean Edi peak was 11.66 (±5.14) µV. CONCLUSION: Reference Edi values were established for both preterm and term neonates. These values can be used as a guide when monitoring breathing support and when using diaphragm-triggered modes of respiratory support in newborn infants.

Survival prediction modelling in extreme prematurity: are days important?

OBJECTIVE: To demonstrate that days are important in extreme prematurity when creating survival prediction models based on gestation. STUDY DESIGN: Prospectively collected data were analysed for all admitted infants born 23 + 0 to 27 + 6 weeks gestation in the Australian and New Zealand Neonatal Network from 2009 to 2016. The effect of days on observed survival rates was assessed using a non-parametric test for trend. Prediction models created based on gestational age in completed weeks only or weeks plus days were compared. RESULT: Seven thousand eight hundred and thirty-six extreme preterm infants were studied. Observed survival increased with days for 23, 24, 25, and 27 weeks gestational age (P = 0.01; P < 0.001; P = 0.003; P = 0.003) but not for 26 weeks (P = 0.19). A survival prediction model based on weeks and days performed better than completed weeks only (AUC 0.722 vs 0.712; P < 0.001). CONCLUSION: In extreme prematurity, survival estimate accuracy improves when survival prediction models include days in addition to weeks.

Protocol for assessing if behavioural functioning of infants born <29 weeks' gestation is improved by omega-3 long-chain polyunsaturated fatty acids: follow-up of a randomised controlled trial.

INTRODUCTION: During the last trimester of pregnancy, the fetal brain undergoes a rapid growth spurt and accumulates essential nutrients including docosahexaenoic acid (DHA). This takes place ex-utero for infants born <29 weeks' gestation, without the in-utero provisions of DHA. Infants born <29 weeks' are more likely to experience behavioural and emotional difficulties than their term-born counterparts. It has been hypothesised that supplementing preterm infants with dietary DHA may alleviate insufficiency and subsequently prevent or minimise behavioural problems. This protocol describes a follow-up of infants born <29 weeks gestation who were enrolled in a randomised controlled trial (RCT) of DHA supplementation. We aim to determine whether DHA supplementation improves the behaviour, and general health of these infants. METHODS AND ANALYSIS: Infants born <29 weeks' gestation were enrolled in a multicentre blinded RCT of enteral DHA supplementation. Infants were randomised to receive an enteral emulsion that provided 60 mg/kg/day of DHA or a control emulsion commenced within the first 3 days of enteral feeding, until 36 weeks' postmenstrual age or discharge home, whichever occurred first. Families of surviving children (excluding those who withdrew from the study) from the Australian sites (up to 955) will be invited to complete a survey. The survey will include questions regarding child behavioural and emotional functioning, executive functioning, respiratory health and general health. We hypothesise that the DHA intervention will have a benefit on the primary outcome, parent-rated behaviour and emotional status as measured using the Total Difficulties score of the Strengths and Difficulties Questionnaire. Detecting a 2-point difference between groups (small effect size of 0.25 SD) with 90% power will require follow-up of 676 participants. ETHICS AND DISSEMINATION: The Women's and Children Health Network Human Research Ethics Committee reviewed and approved the study (HREC/16/WCHN/184). Results will be disseminated in peer-reviewed publications and conference presentations. TRIAL REGISTRATION NUMBER: ACTRN12612000503820.

Early PARacetamol (EPAR) Trial: A Randomized Controlled Trial of Early Paracetamol to Promote Closure of the Ductus Arteriosus in Preterm Infants.

INTRODUCTION: This study aimed to investigate whether early treatment with paracetamol reduces the number of infants requiring intervention for patent ductus arteriosus (PDA) and assess the safety profile of paracetamol during the early postnatal period. METHODS: This was a double-blind, parallel, randomized, placebo-controlled trial. Preterm infants born at <29-week gestation with a ductus arteriosus >0.9 mm at 6 h of life were randomized to either (1) intravenous paracetamol (15 mg/kg initially and then 7.5 mg/kg every 6 h) or (2) intravenous dextrose for 5 days. The primary outcome was the need for any intervention for PDA up to 5 days. Secondary outcomes included ductal closure at 5 days, ductal size at 48 h, ductal reopening, mortality, and significant morbidities. RESULTS: Of 58 infants randomized, 29 were allocated to the intervention and 29 to the control group. The trial was stopped for benefit at 50% recruitment after reaching the prespecified stopping criteria. Less infants in the intervention group required intervention for PDA up to 5 days (6 [21%] vs. 17 [59%] infants [p = 0.003]; relative risk reduction 0.35 [95% CI 0.16-0.77; NNT 2.6]). The intervention group had a higher rate of ductal closure (20 [69%] vs. 8 [28%] infants [p = 0.002]) and smaller ductal size (1.0 mm [±0.8] vs. 1.4 mm [±0.9]; p = 0.04). Three deaths occurred (2 in the intervention group), which were not attributed to the intervention. No other adverse events were reported. DISCUSSION/CONCLUSION: Early paracetamol treatment reduced the number of infants requiring intervention for PDA. Short-term safety data were reassuring, acknowledging the small number of infants involved in the study.

When should intensive care be provided for the extremely preterm infants born at the margin of viability? A survey of Australasian parents and clinicians.

AIM: This study aimed to explore clinician and parent opinions of risk limits on resuscitation and intensive care (IC) for extremely premature infants born at the margin of viability. METHODS: Two anonymous on-line surveys were conducted from August 2016 to January 2017. Survey participants were: (i) clinicians affiliated with neonatal intensive care units in Australia; and (ii) parents or individuals who expressed interest in premature babies through the Facebook page of Miracle Babies Foundation. RESULTS: A total of 961 responses were received. Among 204 clinicians, 52% were neonatologists, 22% obstetricians, 20% neonatal intensive care unit nurses and 4% were midwives. Among 757 parents, 98% had a premature baby. Only 75% of clinicians responded to the risk limits questions. Median mortality risk above which they would not recommend resuscitation/IC was 70% (interquartile range (IQR) 50-80%); major disability risk in survivors 60% (IQR 50-75%); and composite risk of mortality and major disability 70% (IQR 50-80%). All parents answered the risk limit questions. The median mortality risk for not planning resuscitation was 90% (IQR 60-90%); major disability risk in survivors 50% (IQR 30-90%); and composite risk 90% (IQR 50-90%). Most clinicians (82%) stated that decisions should be guided by parent opinions if there are uncertainties. Parents had varying perception of previous counselling, and 57% stated that both their viewpoint and doctor's predicted risk influenced their decision-making. CONCLUSIONS: Clinicians and parents had different views on mortality and major disability risks when deciding on resuscitation/neonatal IC treatment. When there was uncertainty, both agreed on working together.

Cholestatic jaundice in neonates: How common is biliary atresia? Experience at an Australian tertiary centre.

AIM: To (i) review the aetiologies of neonatal cholestasis among term and preterm neonates at a single tertiary centre in Australia; (ii) identify clinical variables associated with biliary atresia (BA) and non-BA aetiology of neonatal cholestasis; (iii) investigate the utility of hepatobiliary scintigraphy in predicting BA among term and preterm neonates. METHODS: A retrospective cohort study of neonates born and investigated for cholestasis at two co-located neonatal and children facilities from January 2013 to December 2017. RESULTS: Of the 139 neonates with cholestasis, BA and intestinal-failure-associated liver-disease was the most common cause of neonatal cholestasis in term (18%) and preterm (66%) cohorts, respectively. Incidence of BA was higher in term (1:6) than preterm (1:50) neonates (OR 10.29; 95% CI 2.06-49.97, P = 0.0024). Higher birthweight, acholic stool, absent or abnormal gallbladder on ultrasound was significantly associated with BA while gestational age ≤32 weeks, total parenteral nutrition ≥14 days and low albumin were associated with non-BA aetiology of cholestasis. In diagnosing BA, non-draining hepatobiliary scintigraphy demonstrated a lower specificity (73% vs. 90%) and lower positive predictive value (25% vs. 78%) in preterm compared to term neonates. CONCLUSION: Aetiology of cholestasis among preterm neonates differs from those in term neonates and currently existing diagnostic algorithm for neonatal cholestasis may need to be modified for preterm cohort, taking into account the prevalence for each aetiology, potential predictors and cost-efficiency.

FEEding DURing red cell transfusion (FEEDUR RCT): a multi-arm randomised controlled trial.

BACKGROUND: Necrotising Enterocolitis (NEC) is a devastating neonatal disease. A temporal association between red cell transfusion and NEC has been recognized and there have been concerns about the effects of feeding during transfusion. We aimed to assess the effect of different enteral feeding regimens on splanchnic oxygenation in preterm infants receiving red cell transfusions. METHODS: This was an open, multi-arm, parallel-group, randomised controlled trial conducted in a single centre in Australia. We compared three different enteral feeding regimes during a single red cell transfusion in preterm infants < 35 weeks gestational age at birth. Infants were randomised to either: (1) Withholding enteral feeds for 12 h from the start of transfusion or; (2) Continuing enteral feeds or; (3) Restriction of enteral feed volume to 120 ml/kg/day (maximum 20 kcal/30 ml) for 12 h. The primary outcome was mean splanchnic-cerebral oxygenation ratio (SCOR) and mean splanchnic fractional oxygen extraction (FOE) before (1 h prior), during (1 h into transfusion) and after (end of transfusion; 12 and 24 h post) transfusion. RESULTS: There were 60 transfusion episodes (20 transfusion episodes in each group) included in the analysis. 41 infants with a median gestational age at birth of 27 weeks (range 23-32 weeks) were enrolled. The median postnatal age was 43 days (range 19-94 days) and the median pre-transfusion haematocrit was 0.27 (range 0.22-0.32). All three groups were similar at baseline. There were no differences in mean SCOR and mean splanchnic FOE at any of the pre-specified time points. There were also no differences in clinical outcomes. There were no episodes of NEC in any infant. Across all groups the mean SCOR increased from the start to the end of each transfusion (0.97 [CI95% 0.96-0.98] vs 1.00 [CI95% 0.99-1.01]; p = 0.04) and the mean FOE decreased from the start to the end of each transfusion (0.22 [CI95% 0.21-0.23] vs 0.17 [CI95% 0.16-0.18]; p < 0.001). CONCLUSIONS: There were no differences in splanchnic oxygenation when enteral feeds were either withheld, continued or restricted during a transfusion. However, the successful conduct of this study supports the feasibility of a large trial powered to assess clinical outcomes. TRIAL REGISTRATION: ANZCTR, ACTRN12616000160437. Registered 10 February 2016, https://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=370069.

Standardised neonatal parenteral nutrition formulations - Australasian neonatal parenteral nutrition consensus update 2017.

BACKGROUND: The first consensus standardised neonatal parenteral nutrition formulations were implemented in many neonatal units in Australia in 2012. The current update involving 49 units from Australia, New Zealand, Singapore, Malaysia and India was conducted between September 2015 and December 2017 with the aim to review and update the 2012 formulations and guidelines. METHODS: A systematic review of available evidence for each parenteral nutrient was undertaken and new standardised formulations and guidelines were developed. RESULTS: Five existing preterm Amino acid-Dextrose formulations have been modified and two new concentrated Amino acid-Dextrose formulations added to optimise amino acid and nutrient intake according to gestation. Organic phosphate has replaced inorganic phosphate allowing for an increase in calcium and phosphate content, and acetate reduced. Lipid emulsions are unchanged, with both SMOFlipid (Fresenius Kabi, Australia) and ClinOleic (Baxter Healthcare, Australia) preparations included. The physicochemical compatibility and stability of all formulations have been tested and confirmed. Guidelines to standardise the parenteral nutrition clinical practice across facilities have also been developed. CONCLUSIONS: The 2017 PN formulations and guidelines developed by the 2017 Neonatal Parenteral Nutrition Consensus Group offer concise and practical instructions to clinicians on how to implement current and up-to-date evidence based PN to the NICU population.

Improving incidence trends of severe intraventricular haemorrhages in preterm infants <32 weeks gestation: a cohort study.

OBJECTIVE: To describe the trend and risk factors for severe intraventricular haemorrhage (IVH) among infants <32 weeks gestation. DESIGN: Population-based cohort study. SETTING: Australia and New Zealand. PATIENTS: All preterm infants <32 weeks gestation in the Australian and New Zealand Neonatal Network (ANZNN) from 1995 to 2012. INTERVENTIONS: Comparison of IVH incidence between 6-year epochs. MAIN OUTCOME MEASURES: Overall IVH and severe IVH incidence. RESULTS: A total of 60 068 infants were included, and overall survival to discharge increased from 89% to 93% over the three epochs. As the percentage of infants with IVH decreased from 23.6% to 21.3% and 21.4% (p<0.001) from epoch 1 to 3, respectively, fewer survivors had severe IVH (4.0%, 3.3% and 2.8%, respectively, p<0.001). Over time, there were fewer antenatal complications, higher antenatal steroid usage and more caesarean-section births. Fewer infants were intubated at birth, had low 5 min Apgar score, had sepsis or pneumothorax needing drainage. Adjusted for perinatal confounders, there was significant reduction in odds of severe IVH from epoch 1 to 3 (adjusted OR (AOR) 0.8, 95% CI 0.7 to 0.9). Factors associated with development of severe IVH include no antenatal steroids (AOR 1.7, 95% CI 1.5 to 1.9), male (AOR 1.3, 95% CI 1.2 to 1.4), 5 min Apgar score <7 (AOR 2.0, 95% CI 1.9 to 2.2), intubated at birth (AOR 2.0, 95% CI 1.8 to 2.2), extremely low gestational age (AOR 4.0, 95% CI 3.7 to 4.4), outborn (AOR 1.6, 95% CI 1.5 to 1.8) and vaginal delivery (AOR 1.4, 95% CI 1.3 to 1.6). CONCLUSIONS: Along with increased survival among infants born <32 weeks gestation, the incidence of severe IVH has decreased over the 18 years, especially in the most recent period. This coincided with reduction in rates of risk factors for severe IVH development.

Early PARacetamol (EPAR) trial: a study protocol for a randomised controlled trial of early paracetamol to promote closure of the ductus arteriosus in preterm infants.

INTRODUCTION: The optimal management of patent ductus arteriosus (PDA) remains contentious. The medications used to treat PDA are often non-steroidal anti-inflammatory drugs, which are associated with a number of unwanted adverse effects. Paracetamol is a medication with an excellent safety profile in infants and has been suggested as a safe alternative medication in situations where other medications have failed or are contraindicated. There are limited data on the use of early, intravenous paracetamol in preterm infants. METHODS AND ANALYSIS: This trial aims to address whether early treatment with paracetamol will reduce the number of infants requiring intervention for PDA. This is a randomised, double-blind, placebo-controlled trial in preterm infants <29 weeks' gestation. At 6 hours of life, infants with a ductus arteriosus >0.9 mm will be randomised to receive either (1) intravenous paracetamol at a dose of 15 mg/kg initially, followed by every 6 hours at a dose of 7.5 mg/kg for 5 days; or (2) intravenous 5% dextrose every 6 hours for 5 days. The primary outcome is the need for any intervention for management of PDA up to 5 days. Secondary outcomes include closure of the ductus arteriosus at 5 days, size of the ductus arteriosus, ductal reopening, systemic blood flow, mortality and significant morbidities. The target sample size of 100 infants yields >80% power, at the two-sided 5% level significance, to detect a 50% reduction in the need for intervention assuming that approximately 60% of infants in this study would otherwise have required intervention for PDA. ETHICS AND DISSEMINATION: A report on the results of the planned analyses will be prepared. The results of the primary analysis of all end points will be presented at medical conferences and submitted for publication in peer-reviewed journals. Separate manuscripts pertaining to the second aim of the study may be written, and these will also be submitted for publication in peer-reviewed journals. TRIAL REGISTRATION NUMBER: ACTRN12616001517460.

Continuous Versus Intermittent Vancomycin Infusions in Infants: A Randomized Controlled Trial.

BACKGROUND: In adults, continuous infusions of vancomycin (CIV) are associated with earlier attainment of target drug concentrations, require fewer blood samples for monitoring, and may reduce drug toxicity. We aimed to determine, in young infants, if CIV or intermittent infusions of vancomycin (IIV) better achieves target vancomycin concentrations at the first steady-state level and to compare the frequency of drug-related adverse effects. METHODS: In a multicenter randomized controlled trial in 2 tertiary neonatal units over a 40-month period, young infants aged 0 to 90 days requiring vancomycin therapy for at least 48 hours were randomly assigned to CIV and IIV. RESULTS: Of 111 infants randomized, 104 were included in the intention-to-treat analysis. Baseline characteristics were similar for both groups. The proportion of infants achieving target concentrations at the first steady-state level was higher for CIV compared with IIV (45 in 53 [85%] vs 21 in 51 [41%]; P < .001). Fewer dose adjustments were required in the CIV group (median 0; range 0-1) compared with the IIV group (median 1; range 0-3; P < .001). The mean daily dose required to achieve target concentrations was lower with CIV compared with IIV (40.6 [SD 10.7] vs 60.6 [SD 53.0] mg/kg per day, respectively; P = .01). No drug-related adverse effects occurred in either group. CONCLUSIONS: In young infants, CIV is associated with earlier and improved attainment of target concentrations compared with IIV. Lower total daily doses are required to achieve target levels with CIV. There is no difference in the rate of drug-related adverse effects.

Neurodevelopmental outcomes of extremely preterm infants in New South Wales and the Australian Capital Territory.

AIM: This study aimed to provide updated information on gestation-specific neurodevelopmental outcomes of extremely to very preterm infants 23-28 weeks' gestation admitted to neonatal intensive care units (NICUs). METHODS: This was a population-based retrospective cohort study of infants born between 23+0 and 28+6 weeks' gestation and admitted to a network of NICUs between 2007 and 2012 in a well-defined geographic area of New South Wales (NSW) and the Australian Capital Territory (ACT). Primary outcome was moderate to severe neurodevelopmental impairment. RESULTS: Of 2287 infants admitted to NICUs, 1914 (83.7%) survived to discharge, and 1514 (79.8% = 1514/1897) were followed up. Moderate to severe neurodevelopmental impairment was 11% overall, and the incidence decreased with increasing gestational age (GA): 25, 23, 15, 13, 9 and 7% at 23, 24, 25, 26, 27 and 28 weeks, respectively. Male gender, major intraventricular haemorrhage, late-onset sepsis, chronic lung disease and post-natal corticosteroid therapy were found to be independently associated with increased risk of moderate to severe impairment. Compared with an incidence of 16% in the 1998-2004 cohort, there was a significant reduction in moderate to severe neurodevelopmental impairment in the current cohort (unadjusted odds ratio: 0.65, 95% confidence interval: 0.52-0.80). CONCLUSIONS: We report the latest neurodevelopmental outcomes of extremely to very preterm infants in NSW and the ACT. Neurodevelopmental outcome rates based on GA alone may not provide the true estimate as these outcomes can vary based on the presence or absence of other relevant perinatal factors.

Admission temperature and hospital outcomes in extremely preterm infants.

AIM: To evaluate trends in admission temperature and its effect on mortality and short-term morbidities in extremely preterm infants. METHODS: A regional cohort study of infants born at 23-28 weeks' gestation and admitted to the 10 neonatal intensive care units in New South Wales and the Australian Capital Territory between 1994 and 2012. Hypothermia was defined as skin temperature <36°C on admission to the neonatal intensive care unit. The primary outcome was hospital mortality. RESULTS: In total, 6267 infants were included. Mean admission temperatures improved significantly from 35.6°C in 1994 to 36.4°C in 2012 (R < 0.88). The incidence of hypothermia was 29.5 and 13.9% between 1994-2005 and 2006-2012, respectively. In comparison with normothermic infants, hypothermic infants had lower gestational age at birth (26 vs. 27 weeks) and lower birthweight (800 vs. 976 g). In-hospital mortality was higher in hypothermic infants (28.5 vs. 12.9%; odds ratio (OR) 2.69, 95% confidence interval (CI) 2.37-3.06). Severe intraventricular haemorrhage (12.1 vs. 8.5%, OR 1.48, 95% CI 1.25-1.75), necrotising enterocolitis (NEC) (11.0 vs. 7.5%; OR 1.54, 95% CI 1.29-1.83) and severe retinopathy of prematurity (16.5 vs. 8.9%; OR 2.02, 95% CI 1.70-2.39) were significantly higher in hypothermic infants. Multivariate regression analysis showed hypothermia was an independent risk factor for increased mortality (AOR (adjusted odds ratio ) 1.50, 95% CI 1.29-1.74, P < 0.001) and NEC (AOR 1.28, 95% CI 1.05-1.55, P = 0.01). CONCLUSIONS: Admission temperatures improved during the time period. Hypothermia at admission was associated with a significant increase in mortality and NEC.