Feasibility and acceptability of targeted salivary cytomegalovirus screening through universal newborn hearing screening.

AIM: This study aimed to determine the feasibility and parental acceptability of screening for congenital cytomegalovirus (cCMV) through saliva polymerase chain reaction in infants who did not pass their newborn hearing screening. Additionally, the utility (i.e. time to diagnosis and treatment) of this enhanced clinical pathway was evaluated. METHODS: The study was conducted through the Victorian Infant Hearing Screening Programme (VIHSP) across four maternity hospitals in Melbourne, Australia, during June 2019-March 2020. Parents were approached by VIHSP staff about obtaining a test for cytomegalovirus (CMV) at the time of their baby's second positive ('refer') result on the VIHSP screen. Participating parents collected a saliva swab for CMV polymerase chain reaction from their infants. Feasibility was determined by the proportion of 'referred' infants whose parents completed the salivary CMV screening test ≤21 days of life. Acceptability was measured through parent survey. RESULTS: Of 126 eligible families, 96 (76.0%) had salivary screening swabs taken ≤21 days of life. Most families (>92.0%) indicated that screening was acceptable, straightforward and thought testing their baby for cCMV was a good idea. One infant screened positive on day 30, was diagnosed with cCMV via confirmatory testing by day 31 and commenced valganciclovir on day 32. CONCLUSIONS: Obtaining a saliva sample to screen for cCMV in infants who do not pass their newborn hearing screen is feasible and appears acceptable to parents. This targeted cCMV screening method could be an option where mothers are rapidly discharged from hospital, especially in the context of the COVID-19 pandemic.

The severe epilepsy syndromes of infancy: A population-based study.

OBJECTIVE: To study the epilepsy syndromes among the severe epilepsies of infancy and assess their incidence, etiologies, and outcomes. METHODS: A population-based cohort study was undertaken of severe epilepsies with onset before age 18 months in Victoria, Australia. Two epileptologists reviewed clinical features, seizure videos, and electroencephalograms to diagnose International League Against Epilepsy epilepsy syndromes. Incidence, etiologies, and outcomes at age 2 years were determined. RESULTS: Seventy-three of 114 (64%) infants fulfilled diagnostic criteria for epilepsy syndromes at presentation, and 16 (14%) had "variants" of epilepsy syndromes in which there was one missing or different feature, or where all classical features had not yet emerged. West syndrome (WS) and "WS-like" epilepsy (infantile spasms without hypsarrhythmia or modified hypsarrhythmia) were the most common syndromes, with a combined incidence of 32.7/100 000 live births/year. The incidence of epilepsy of infancy with migrating focal seizures (EIMFS) was 4.5/100 000 and of early infantile epileptic encephalopathy (EIEE) was 3.6/100 000. Structural etiologies were common in "WS-like" epilepsy (100%), unifocal epilepsy (83%), and WS (39%), whereas single gene disorders predominated in EIMFS, EIEE, and Dravet syndrome. Eighteen (16%) infants died before age 2 years. Development was delayed or borderline in 85 of 96 (89%) survivors, being severe-profound in 40 of 96 (42%). All infants with EIEE or EIMFS had severe-profound delay or were deceased, but only 19 of 64 (30%) infants with WS, "WS-like," or "unifocal epilepsy" had severe-profound delay, and only two of 64 (3%) were deceased. SIGNIFICANCE: Three quarters of severe epilepsies of infancy could be assigned an epilepsy syndrome or "variant syndrome" at presentation. In this era of genomic testing and advanced brain imaging, diagnosing epilepsy syndromes at presentation remains clinically useful for guiding etiologic investigation, initial treatment, and prognostication.

Postnatal probiotics and allergic disease in very preterm infants: Sub-study to the ProPrems randomized trial.

BACKGROUND: Probiotic supplementation to mothers and/or their term-born infants has been suggested to prevent allergic disease, in particular eczema; however, no studies have investigated probiotics for prevention of allergic diseases in very preterm infants. We evaluated the effect of a postnatal probiotic combination on development of allergic diseases in very preterm infants. METHODS: This sub-study was an a priori secondary outcome of the ProPrems multi-center, double-blind, placebo-controlled randomized trial (ANZCTR:12607000144415). ProPrems randomized 1099 very preterm infants to receive a probiotic combination or placebo from soon after birth until discharge from hospital or term corrected age (CA), whichever was earlier. Allergic disease (eczema, atopic eczema, food allergy, wheeze, atopic sensitization) was assessed in a subgroup of ProPrems infants (n = 281) as close to 12 months CA as possible by questionnaire, clinical examination, and skin prick tests to common allergens. RESULTS: There was no difference in eczema incidence between the probiotic and placebo groups (35[30%] of 118 infants vs 37[27%] of 137 infants, respectively, absolute difference 2.65%, 95% CI -8.45 to 13.75). Similarly, the incidence of atopic eczema (6[5%] of 118 vs 3[2%] of 137), food allergy (4[3%] of 124 vs 2[1%] of 154), wheeze (39[31%] of 127 vs 45[29%] of 154), and atopic sensitization (14[13%] of 106 vs 13[11%] of 123) were similar between the probiotic and placebo groups. CONCLUSION: This study found no effect of postnatal administration of a probiotic combination on the incidence of allergic diseases or atopic sensitization in the first 2 years of life in children born very preterm. Evidence that probiotics are effective for prevention of allergic disease in premature infants remains lacking; adequately powered randomized controlled trials evaluating probiotic supplementation for allergy prevention in very preterm infants are needed.

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.

Towards evidence-based resuscitation of the newborn infant.

Effective resuscitation of the newborn infant has the potential to save many lives around the world and reduce disabilities in children who survive peripartum asphyxia. In this Series paper, we highlight some of the important advances in the understanding of how best to resuscitate newborn infants, which includes monitoring techniques to guide resuscitative efforts, increasing awareness of the adverse effects of hyperoxia, delayed umbilical cord clamping, the avoidance of routine endotracheal intubation for extremely preterm infants, and therapeutic hypothermia for hypoxic-ischaemic encephalopathy. Despite the challenges of performing high-quality clinical research in the delivery room, researchers continue to refine and advance our knowledge of effective resuscitation of newborn infants through scientific experiments and clinical trials.

Advising women with diabetes in pregnancy to express breastmilk in late pregnancy (Diabetes and Antenatal Milk Expressing [DAME]): a multicentre, unblinded, randomised controlled trial.

BACKGROUND: Infants of women with diabetes in pregnancy are at increased risk of hypoglycaemia, admission to a neonatal intensive care unit (NICU), and not being exclusively breastfed. Many clinicians encourage women with diabetes in pregnancy to express and store breastmilk in late pregnancy, yet no evidence exists for this practice. We aimed to determine the safety and efficacy of antenatal expressing in women with diabetes in pregnancy. METHODS: We did a multicentre, two-group, unblinded, randomised controlled trial in six hospitals in Victoria, Australia. We recruited women with pre-existing or gestational diabetes in a singleton pregnancy from 34 to 37 weeks' gestation and randomly assigned them (1:1) to either expressing breastmilk twice per day from 36 weeks' gestation (antenatal expressing) or standard care (usual midwifery and obstetric care, supplemented by support from a diabetes educator). Randomisation was done with a computerised random number generator in blocks of size two and four, and was stratified by site, parity, and diabetes type. Investigators were masked to block size but masking of caregivers was not possible. The primary outcome was the proportion of infants admitted to the NICU. We did the analyses by intention to treat; the data were obtained and analysed masked to group allocation. This trial is registered with the Australian New Zealand Clinical Trials Registry, number ACTRN12611000217909. FINDINGS: Between June 6, 2011, and Oct 29, 2015, we recruited and randomly assigned 635 women: 319 to antenatal expressing and 316 to standard care. Three were not included in the primary analysis (one withdrawal from the standard care group, and one post-randomisation exclusion and one withdrawal from the antenatal expressing group). The proportion of infants admitted to the NICU did not differ between groups (46 [15%] of 317 assigned to antenatal expressing vs 44 [14%] of 315 assigned to standard care; adjusted relative risk 1·06, 95% CI 0·66 to 1·46). In the antenatal expressing group, the most common serious adverse event for infants was admission to the NICU for respiratory support (for three [<1%] of 317. In the standard care group, the most common serious adverse event for infants was moderate to severe encephalopathy with or without seizures (for three [<1%] of 315). INTERPRETATION: There is no harm in advising women with diabetes in pregnancy at low risk of complications to express breastmilk from 36 weeks' gestation. FUNDING: Australian National Health and Medical Research Council.

Gut microbiota of preterm infants supplemented with probiotics: sub-study of the ProPrems trial.

BACKGROUND: The ProPrems trial, a multi-center, double-blind, placebo-controlled randomized trial, previously reported a 54% reduction in necrotizing enterocolitis (NEC) of Bell stage 2 or more from 4.4 to 2.0% in 1099 infants born before 32 completed weeks' gestation and weighing < 1500 g, receiving probiotic supplementation (with Bifidobacterium longum subsp. infantis BB-02, Streptococcus thermophilus TH-4 and Bifidobacterium animalis subsp. lactis BB-12). This sub-study investigated the effect of probiotic supplementation on the gut microbiota in a cohort of very preterm infants in ProPrems. RESULTS: Bifidobacterium was found in higher abundance in infants who received the probiotics (AOR 17.22; 95% CI, 3.49-84.99, p < 0.001) as compared to the placebo group, and Enterococcus was reduced in infants receiving the probiotic during the supplementation period (AOR 0.27; 95% CI, 0.09-0.82, p = 0.02). CONCLUSION: Probiotic supplementation with BB-02, TH-4 and BB-12 from soon after birth increased the abundance of Bifidobacterium in the gut microbiota of very preterm infants. Increased abundance of Bifidobacterium soon after birth may be associated with reducing the risk of NEC in very preterm infants.

Frenotomy for tongue-tie in newborn infants.

BACKGROUND: Tongue-tie, or ankyloglossia, is a condition whereby the lingual frenulum attaches near the tip of the tongue and may be short, tight and thick. Tongue-tie is present in 4% to 11% of newborns. Tongue-tie has been cited as a cause of poor breastfeeding and maternal nipple pain. Frenotomy, which is commonly performed, may correct the restriction to tongue movement and allow more effective breastfeeding with less maternal nipple pain. OBJECTIVES: To determine whether frenotomy is safe and effective in improving ability to feed orally among infants younger than three months of age with tongue-tie (and problems feeding).Also, to perform subgroup analysis to determine the following.• Severity of tongue-tie before frenotomy as measured by a validated tool (e.g. Hazelbaker Assessment Tool for Lingual Frenulum Function (ATLFF) scores < 11; scores ≥ 11) (Hazelbaker 1993).• Gestational age at birth (< 37 weeks' gestation; 37 weeks' gestation and above).• Method of feeding (breast or bottle).• Age at frenotomy (≤ 10 days of age; > 10 days to three months of age).• Severity of feeding difficulty (infants with feeding difficulty affecting weight gain (as assessed by infant's not regaining birth weight by day 14 or falling off centiles); infants with symptomatic feeding difficulty but thriving (greater than birth weight by day 14 and tracking centiles). SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, Embase and CINAHL up to January 2017, as well as previous reviews including cross-references, expert informants and journal handsearching. We searched clinical trials databases for ongoing and recently completed trials. We applied no language restrictions. SELECTION CRITERIA: Randomised, quasi-randomised controlled trials or cluster-randomised trials that compared frenotomy versus no frenotomy or frenotomy versus sham procedure in newborn infants. DATA COLLECTION AND ANALYSIS: Review authors extracted from the reports of clinical trials data regarding clinical outcomes including infant feeding, maternal nipple pain, duration of breastfeeding, cessation of breastfeeding, infant pain, excessive bleeding, infection at the site of frenotomy, ulceration at the site of frenotomy, damage to the tongue and/or submandibular ducts and recurrence of tongue-tie. We used the GRADE approach to assess the quality of evidence. MAIN RESULTS: Five randomised trials met our inclusion criteria (n = 302). Three studies objectively measured infant breastfeeding using standardised assessment tools. Pooled analysis of two studies (n = 155) showed no change on a 10-point feeding scale following frenotomy (mean difference (MD) -0.1, 95% confidence interval (CI) -0.6 to 0.5 units on a 10-point feeding scale). A third study (n = 58) showed objective improvement on a 12-point feeding scale (MD 3.5, 95% CI 3.1 to 4.0 units of a 12-point feeding scale). Four studies objectively assessed maternal pain. Pooled analysis of three studies (n = 212) based on a 10-point pain scale showed a reduction in maternal pain scores following frenotomy (MD -0.7, 95% CI -1.4 to -0.1 units on a 10-point pain scale). A fourth study (n = 58) also showed a reduction in pain scores on a 50-point pain scale (MD -8.6, 95% CI -9.4 to -7.8 units on a 50-point pain scale). All studies reported no adverse effects following frenotomy. These studies had serious methodological shortcomings. They included small sample sizes, and only two studies blinded both mothers and assessors; one did not attempt blinding for mothers nor for assessors. All studies offered frenotomy to controls, and most controls underwent the procedure, suggesting lack of equipoise. No study was able to report whether frenotomy led to long-term successful breastfeeding. AUTHORS' CONCLUSIONS: Frenotomy reduced breastfeeding mothers' nipple pain in the short term. Investigators did not find a consistent positive effect on infant breastfeeding. Researchers reported no serious complications, but the total number of infants studied was small. The small number of trials along with methodological shortcomings limits the certainty of these findings. Further randomised controlled trials of high methodological quality are necessary to determine the effects of frenotomy.

Stable rates of neonatal sepsis in a tertiary neonatal unit.

AIMS: To describe the rate of early- and late-onset sepsis in neonates admitted to the neonatal intensive care unit at the Royal Women's Hospital and to compare the rate of late-onset sepsis (LOS) with a published (2008) cohort from the same unit. The secondary aim was to examine clinicians' compliance with antibiotic guidelines. METHODS: Infants born <32 weeks' gestation or <1500 g admitted between 1 July 2011 and 31 December 2011 were included. Strict definitions of sepsis and compliance with antibiotic guidelines were applied. RESULTS: One hundred and seventy-two infants met the inclusion criteria, with 152 having blood culture evaluations for early-onset sepsis (EOS) and 58 having 109 evaluations for LOS. Definite EOS occurred in 1.3% with Escherichia coli isolated. The rate of definite LOS in 2011 of 22% was not significantly different than the 27% in 2008, with coagulase-negative staphylococcus the main isolate. Antibiotic continuation beyond 72 h in infants with negative blood cultures was the main reason for non-compliance with antibiotic guidelines. CONCLUSIONS: The rate of EOS is comparable with published reports and the rate of LOS has remained stable over a 3-year period. Discontinuation of antibiotics with negative septic markers and blood cultures at 48-72 h is encouraged.

Cooling for newborns with hypoxic ischaemic encephalopathy.

BACKGROUND: Newborn animal studies and pilot studies in humans suggest that mild hypothermia following peripartum hypoxia-ischaemia in newborn infants may reduce neurological sequelae without adverse effects. OBJECTIVES: To determine the effect of therapeutic hypothermia in encephalopathic asphyxiated newborn infants on mortality, long-term neurodevelopmental disability and clinically important side effects. SEARCH METHODS: We used the standard search strategy of the Cochrane Neonatal Review Group as outlined in The Cochrane Library (Issue 2, 2007). Randomised controlled trials evaluating therapeutic hypothermia in term and late preterm newborns with hypoxic ischaemic encephalopathy were identified by searching the Oxford Database of Perinatal Trials, the Cochrane Central Register of Controlled Trials (CENTRAL, The Cochrane Library, 2007, Issue 2), MEDLINE (1966 to June 2007), previous reviews including cross-references, abstracts, conferences, symposia proceedings, expert informants and journal handsearching. We updated this search in May 2012. SELECTION CRITERIA: We included randomised controlled trials comparing the use of therapeutic hypothermia with standard care in encephalopathic term or late preterm infants with evidence of peripartum asphyxia and without recognisable major congenital anomalies. The primary outcome measure was death or long-term major neurodevelopmental disability. Other outcomes included adverse effects of cooling and 'early' indicators of neurodevelopmental outcome. DATA COLLECTION AND ANALYSIS: Four review authors independently selected, assessed the quality of and extracted data from the included studies. Study authors were contacted for further information. Meta-analyses were performed using risk ratios (RR) and risk differences (RD) for dichotomous data, and weighted mean difference for continuous data with 95% confidence intervals (CI). MAIN RESULTS: We included 11 randomised controlled trials in this updated review, comprising 1505 term and late preterm infants with moderate/severe encephalopathy and evidence of intrapartum asphyxia. Therapeutic hypothermia resulted in a statistically significant and clinically important reduction in the combined outcome of mortality or major neurodevelopmental disability to 18 months of age (typical RR 0.75 (95% CI 0.68 to 0.83); typical RD -0.15, 95% CI -0.20 to -0.10); number needed to treat for an additional beneficial outcome (NNTB) 7 (95% CI 5 to 10) (8 studies, 1344 infants). Cooling also resulted in statistically significant reductions in mortality (typical RR 0.75 (95% CI 0.64 to 0.88), typical RD -0.09 (95% CI -0.13 to -0.04); NNTB 11 (95% CI 8 to 25) (11 studies, 1468 infants) and in neurodevelopmental disability in survivors (typical RR 0.77 (95% CI 0.63 to 0.94), typical RD -0.13 (95% CI -0.19 to -0.07); NNTB 8 (95% CI 5 to 14) (8 studies, 917 infants). Some adverse effects of hypothermia included an increase sinus bradycardia and a significant increase in thrombocytopenia. AUTHORS' CONCLUSIONS: There is evidence from the 11 randomised controlled trials included in this systematic review (N = 1505 infants) that therapeutic hypothermia is beneficial in term and late preterm newborns with hypoxic ischaemic encephalopathy. Cooling reduces mortality without increasing major disability in survivors. The benefits of cooling on survival and neurodevelopment outweigh the short-term adverse effects. Hypothermia should be instituted in term and late preterm infants with moderate-to-severe hypoxic ischaemic encephalopathy if identified before six hours of age. Further trials to determine the appropriate techniques of cooling, including refinement of patient selection, duration of cooling and method of providing therapeutic hypothermia, will refine our understanding of this intervention.

A randomised trial of two techniques for bottle feeding preterm infants.

AIM: Preterm infants begin the transition from gastric tube feeds to sucking feeds around 34 weeks' postmenstrual age. We compared physiological stability in two bottle feeding positions, cradle hold versus side lying in preterm infants. METHODS: Randomised crossover trial of infants <34 weeks' gestation at birth, ≥34 weeks' postmenstrual age at study and receiving at least two sucking feeds/day. Two feeds were studied on successive days. A pulse oximeter measured oxygen saturation (SpO2) and heart rate (HR) before, during and 30 min after feeds. Continuous data were compared using paired t-tests and proportions using chi squared. RESULTS: Twenty-five study infants were mean (standard deviation (SD)) 37 (2.4) weeks' post-menstrual age and 2740 (589) g at study. There was little difference in mean (SD) SpO2 during feeds between the cradle-hold and side-lying position 94 (6) % versus 95 (6) %, respectively (P = 0.55, confidence interval (CI) -1.4, 5.4). During feeds, 17/25 (68%) experienced a period of SpO2 <80% in the cradle-hold position compared with 14/25 (56) % in the side-lying position (P = 0.26, CI 0.68, 4.10). There were no significant differences in the mean HR or number of episodes of bradycardia HR <100 bpm. There was a trend towards infants consuming a smaller mean (SD) proportion of their feed in the cradle-hold position compared with the side-lying position, 82 (25) % versus 87 (20) % (P = 0.08, CI -0.64, 10.00). CONCLUSIONS: There was little difference in infants' physiological stability between the two bottle feeding positions. Both methods may be appropriate for the transition from gastric tube to sucking feeds in preterm infants.

Intratracheal budesonide mixed with surfactant to increase survival free of bronchopulmonary dysplasia in extremely preterm infants: statistical analysis plan for the international, multicenter, randomized PLUSS trial.

BACKGROUND: Bronchopulmonary dysplasia (BPD), an inflammatory-mediated chronic lung disease, is common in extremely preterm infants born before 28 weeks' gestation and is associated with an increased risk of adverse neurodevelopmental and respiratory outcomes in childhood. Effective and safe prophylactic therapies for BPD are urgently required. Systemic corticosteroids reduce rates of BPD in the short term but are associated with poorer neurodevelopmental outcomes if given to ventilated infants in the first week after birth. Intratracheal administration of corticosteroid admixed with exogenous surfactant could overcome these concerns by minimizing systemic sequelae. Several small, randomized trials have found intratracheal budesonide in a surfactant vehicle to be a promising therapy to increase survival free of BPD. The primary objective of the PLUSS trial is to determine whether intratracheal budesonide mixed with surfactant increases survival free of bronchopulmonary dysplasia (BPD) at 36 weeks' postmenstrual age (PMA) in extremely preterm infants born before 28 weeks' gestation. METHODS: An international, multicenter, double-blinded, randomized trial of intratracheal budesonide (a corticosteroid) mixed with surfactant for extremely preterm infants to increase survival free of BPD at 36 weeks' postmenstrual age (PMA; primary outcome). Extremely preterm infants aged < 48 h after birth are eligible if (1) they are mechanically ventilated, or (2) they are receiving non-invasive respiratory support and there is a clinical decision to treat with surfactant. The intervention is budesonide (0.25 mg/kg) mixed with poractant alfa (200 mg/kg first intervention, 100 mg/kg if second intervention), administered intratracheally via an endotracheal tube or thin catheter. The comparator is poractant alfa alone (at the same doses). Secondary outcomes include the components of the primary outcome (death, BPD prior to or at 36 weeks' PMA), and potential systemic side effects of corticosteroids. Longer-term outcomes will be published separately, and include cost-effectiveness, early childhood health until 2 years of age, and neurodevelopmental outcomes at 2 years of age (corrected for prematurity). STATISTICAL ANALYSIS PLAN: A sample size of 1038 infants (519 in each group) is required to provide 90% power to detect a relative increase in survival free of BPD of 20% (an absolute increase of 10%), from the anticipated event rate of 50% in the control arm to 60% in the intervention (budesonide) arm, alpha error 0.05. To allow for up to 2% of study withdrawals or losses to follow-up, PLUSS aimed to enroll a total of 1060 infants (530 in each arm). The binary primary outcome will be reported as the number and percentage of infants who were alive without BPD at 36 weeks' PMA for each randomization group. To estimate the difference in risk (with 95% CI), between the treatment and control arms, binary regression (a generalized linear multivariable model with an identity link function and binomial distribution) will be used. Along with the primary outcome, the individual components of the primary outcome (death, and physiological BPD at 36 weeks' PMA), will be reported by randomization group and, again, binary regression will be used to estimate the risk difference between the two treatment groups for survival and physiological BPD at 36 weeks' PMA.

Intratracheal budesonide mixed with surfactant to increase survival free of bronchopulmonary dysplasia in extremely preterm infants: study protocol for the international, multicenter, randomized PLUSS trial.

BACKGROUND: Bronchopulmonary dysplasia (BPD), an inflammatory-mediated chronic lung disease, is common in extremely preterm infants born before 28 weeks' gestation and is associated with an increased risk of adverse neurodevelopmental and respiratory outcomes in childhood. Effective and safe prophylactic therapies for BPD are urgently required. Systemic corticosteroids reduce rates of BPD in the short-term but are associated with poorer neurodevelopmental outcomes if given to ventilated infants in the first week after birth. Intratracheal administration of corticosteroid admixed with exogenous surfactant could overcome these concerns by minimizing systemic sequelae. Several small, randomized trials have found intratracheal budesonide in a surfactant vehicle to be a promising therapy to increase survival free of BPD. METHODS: An international, multicenter, double-blinded, randomized trial of intratracheal budesonide (a corticosteroid) mixed with surfactant for extremely preterm infants to increase survival free of BPD at 36 weeks' postmenstrual age (PMA; primary outcome). Extremely preterm infants aged < 48 h after birth are eligible if: (1) they are mechanically ventilated, or (2) they are receiving non-invasive respiratory support and there is a clinical decision to treat with surfactant. The intervention is budesonide (0.25 mg/kg) mixed with poractant alfa (200 mg/kg first intervention, 100 mg/kg if second intervention), administered intratracheally via an endotracheal tube or thin catheter. The comparator is poractant alfa alone (at the same doses). Secondary outcomes include the components of the primary outcome (death, BPD prior to or at 36 weeks' PMA), potential systemic side effects of corticosteroids, cost-effectiveness, early childhood health until 2 years of age, and neurodevelopmental outcomes at 2 years of age (corrected for prematurity). DISCUSSION: Combining budesonide with surfactant for intratracheal administration is a simple intervention that may reduce BPD in extremely preterm infants and translate into health benefits in later childhood. The PLUSS trial is powered for the primary outcome and will address gaps in the evidence due to its pragmatic and inclusive design, targeting all extremely preterm infants regardless of their initial mode of respiratory support. Should intratracheal budesonide mixed with surfactant increase survival free of BPD, without severe adverse effects, this readily available intervention could be introduced immediately into clinical practice. TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry ( https://www.anzctr.org.au ), ACTRN12617000322336. First registered on 28th February 2017.

Probiotics in neonatology.

Probiotics are micro-organisms that confer health benefits on the host. Postulated mechanisms include: increasing resistance of the mucosal barrier to migration of bacteria and their toxins by strengthening intestinal cell junctions, modification of host response to microbial products, augmentation of immunoglobulin A mucosal responses, enhancement of enteral nutrition to inhibit the growth of pathogens; production of antimicrobial proteins; and competitive exclusion of potential pathogens. Published meta-analyses and systematic reviews report the effects of probiotics on important clinical outcomes in neonates. This paper will review the evidence for probiotic supplementation in neonatology, with a focus on preterm infants.

Translating evidence into practice: Implementing culturally safe continuity of midwifery care for First Nations women in three maternity services in Victoria, Australia.

Background: Strategies to improve outcomes for Australian First Nations mothers and babies are urgently needed. Caseload midwifery, where women have midwife-led continuity throughout pregnancy, labour, birth and the early postnatal period, is associated with substantially better perinatal health outcomes, but few First Nations women receive it. We assessed the capacity of four maternity services in Victoria, Australia, to implement, embed, and sustain a culturally responsive caseload midwifery service. Methods: A prospective, non-randomised research translational study design was used. Site specific culturally responsive caseload models were developed by site working groups in partnership with their First Nations health units and the Victorian Aboriginal Community Controlled Health Organisation. The primary outcome was to increase the proportion of women having a First Nations baby proactively offered and receiving caseload midwifery as measured before and after programme implementation. The study was conducted in Melbourne, Australia. Data collection commenced at the Royal Women's Hospital on 06/03/2017, Joan Kirner Women's and Children's Hospital 01/10/2017 and Mercy Hospital for Women 16/04/2018, with data collection completed at all sites on 31/12/2020. Findings: The model was successfully implemented in three major metropolitan maternity services between 2017 and 2020. Prior to this, over a similar timeframe, only 5.8% of First Nations women (n = 34) had ever received caseload midwifery at the three sites combined. Of 844 women offered the model, 90% (n = 758) accepted it, of whom 89% (n = 663) received it. Another 40 women received standard caseload. Factors including ongoing staffing crises, prevented the fourth site, in regional Victoria, implementing the model. Interpretation: Key enablers included co-design of the study and programme implementation with First Nations people, staff cultural competency training, identification of First Nations women (and babies), and regular engagement between caseload midwives and First Nations hospital and community teams. Further work should include a focus on addressing cultural and workforce barriers to implementation of culturally responsive caseload midwifery in regional areas. Funding: Partnership Grant (# 1110640), Australian National Health and Medical Research Council and La Trobe University.

The ProPrems trial: investigating the effects of probiotics on late onset sepsis in very preterm infants.

BACKGROUND: Late onset sepsis is a frequent complication of prematurity associated with increased mortality and morbidity. The commensal bacteria of the gastrointestinal tract play a key role in the development of healthy immune responses. Healthy term infants acquire these commensal organisms rapidly after birth. However, colonisation in preterm infants is adversely affected by delivery mode, antibiotic treatment and the intensive care environment. Altered microbiota composition may lead to increased colonisation with pathogenic bacteria, poor immune development and susceptibility to sepsis in the preterm infant.Probiotics are live microorganisms, which when administered in adequate amounts confer health benefits on the host. Amongst numerous bacteriocidal and nutritional roles, they may also favourably modulate host immune responses in local and remote tissues. Meta-analyses of probiotic supplementation in preterm infants report a reduction in mortality and necrotising enterocolitis. Studies with sepsis as an outcome have reported mixed results to date.Allergic diseases are increasing in incidence in "westernised" countries. There is evidence that probiotics may reduce the incidence of these diseases by altering the intestinal microbiota to influence immune function. METHODS/DESIGN: This is a multi-centre, randomised, double blinded, placebo controlled trial investigating supplementing preterm infants born at < 32 weeks' gestation weighing < 1500 g, with a probiotic combination (Bifidobacterium infantis, Streptococcus thermophilus and Bifidobacterium lactis). A total of 1,100 subjects are being recruited in Australia and New Zealand. Infants commence the allocated intervention from soon after the start of feeds until discharge home or term corrected age. The primary outcome is the incidence of at least one episode of definite (blood culture positive) late onset sepsis before 40 weeks corrected age or discharge home. Secondary outcomes include: Necrotising enterocolitis, mortality, antibiotic usage, time to establish full enteral feeds, duration of hospital stay, growth measurements at 6 and 12 months' corrected age and evidence of atopic conditions at 12 months' corrected age. DISCUSSION: Results from previous studies on the use of probiotics to prevent diseases in preterm infants are promising. However, a large clinical trial is required to address outstanding issues regarding safety and efficacy in this vulnerable population. This study will address these important issues. TRIAL REGISTRATION: Australia and New Zealand Clinical Trials Register (ANZCTR): ACTRN012607000144415The product "ABC Dophilus Probiotic Powder for Infants®", Solgar, USA has its 3 probiotics strains registered with the Deutsche Sammlung von Mikroorganismen und Zellkulturen (DSMZ--German Collection of Microorganisms and Cell Cultures) as BB-12 15954, B-02 96579, Th-4 15957.

A protocol for cell therapy infusion in neonates.

Cell therapies for neonatal morbidities are progressing to early phase clinical trials. However, protocols for intravenous (IV) delivery of cell therapies to infants have not been evaluated. It has been assumed the cell dose prescribed is the dose delivered. Early in our clinical trial of human amnion epithelial cells (hAECs), we observed cells settling in the syringe and IV tubing used to deliver the suspension. The effect on dose delivery was unknown. We aimed to quantify this observation and determine an optimal protocol for IV delivery of hAECs to extremely preterm infants. A standard pediatric infusion protocol was modeled in the laboratory. A syringe pump delivered the hAEC suspension over 60 minutes via a pediatric blood transfusion set (200-µm filter and 2.2 mL IV line). The infusion protocol was varied by agitation methods, IV-line volumes (0.2-2.2 mL), albumin concentrations (2% vs 4%), and syringe orientations (horizontal vs vertical) to assess whether these variables influenced the dose delivered. The influence of flow rate (3-15 mL/h) was assessed after other variables were optimized. The standard infusion protocol delivered 17.6% ± 9% of the intended hAEC dose. Increasing albumin concentration to 4%, positioning the syringe and IV line vertically, and decreasing IV-line volume to 0.6 mL delivered 99.7% ± 13% of the intended hAEC dose. Flow rate did not affect dose delivery. Cell therapy infusion protocols must be considered. We describe the refinement of a cell infusion protocol that delivers intended cell doses and could form the basis of future neonatal cell delivery protocols.

Effects on Growth of Smell and Taste of Milk During Tube Feeding of Preterm Infants: A Randomized Clinical Trial.

Importance: Smell and taste of food increase food anticipation, activate gut motility, and stimulate digestion and metabolism. Despite poor growth of many preterm infants in neonatal intensive care units, the smell and taste of milk with tube feeding are not generally considered a regular component of care. Objective: To determine the effect of smell and taste of milk with tube feeding on weight z scores at discharge from the hospital. Design, Setting, and Participants: A randomized, controlled, nonblinded, superiority trial was conducted at 2 perinatal centers between May 9, 2017, and February 1, 2020. Eligible infants (n = 659) were born at less than 29 weeks' postmenstrual age (PMA) and/or with a birth weight of less than 1250 g. Interventions: Infants were randomly assigned to receive either the smell and taste of milk with each tube feeding or routine care without the provision of smell and taste of milk. Main Outcomes and Measures: The primary outcome was weight z score at discharge from any hospital. Secondary outcomes included anthropometric measures at predefined time points, time to full enteral feeds, and other health outcomes associated with prematurity. Results: Of the 658 infants, a total of 396 infants were randomized; some parents had not been approached for consent (n = 144) or declined participation (n = 117), and 1 infant with consent was not randomized. Of the 396 infants, 196 were assigned to the treatment group (51% male; mean [SD] PMA at birth, 27.5 [2.2] weeks) and 200 were assigned to the control group (52% male; mean [SD] PMA at birth, 27.6 (2.3) weeks). Mean weight z scores at discharge were -0.87 (95% CI, -1.02 to -0.72) for the treatment group and -0.97 (95% CI, -1.11 to -0.83) for the control group (P = .40). The mean difference in z scores between the treatment and control groups at 36 weeks' PMA was 0.21 (95% CI, 0.01 to 0.4; P = .04) for head circumference and 0.26 (95% CI, 0.05 to 0.51; P = .04) for length. There were no clinically notable differences between the study groups for any other anthropometric, feeding, or health outcomes. Conclusions and Relevance: In this randomized clinical trial, regular smell and taste of milk included with tube feeding did not improve weight at discharge in preterm infants. Secondary outcomes suggest exposure to smell and taste may improve head circumference and length at 36 weeks' PMA, but not at discharge. Regular exposure to the smell and taste of milk is a simple and inexpensive intervention with potential benefits and no apparent adverse effects. Trial Registration: anzctr.org.au Identifier: ACTRN12617000583347.

The effect of probiotic supplementation on the gut microbiota of preterm infants.

Introduction. Probiotic supplementation of preterm infants may prevent serious morbidities associated with prematurity.Aim. To investigate the impact of probiotic supplementation on the gut microbiota and determine factors associated with detection of probiotic species in the infant gut.Hypothesis/Gap Statement. Probiotic supplementation increases the long-term colonization of probiotic species in the gut of preterm infants.Methodology. Longitudinal stool samples were collected from a cohort of very preterm infants participating in a blinded randomized controlled trial investigating the impact of probiotic supplementation (containing Bifidobacterium longum subsp. infantis BB-02, Bifidobacterium animalis subsp. lactis BB-12 and Streptococcus thermophilus TH-4) for prevention of late-onset sepsis. The presence of B. longum subsp. infantis, B. animalis subsp. lactis and S. thermophilus was determined for up to 23 months after supplementation ended using real-time PCR. Logistic regression was used to investigate the impact of probiotic supplementation on the presence of each species.Results. Detection of B. longum subsp. infantis [odds ratio (OR): 53.1; 95 % confidence interval (CI): 35.6-79.1; P < 0.001], B. animalis subsp. lactis (OR: 89.1; 95 % CI: 59.0-134.5; P < 0.001) and S. thermophilus (OR: 5.66; 95 % CI: 4.35-7.37; P < 0.001) was increased during the supplementation period in infants receiving probiotic supplementation. Post-supplementation, probiotic-supplemented infants had increased detection of B. longum subsp. infantis (OR: 2.53; 95 % CI: 1.64-3.90; P < 0.001) and B. animalis subsp. lactis (OR: 1.59; 95 % CI: 1.05-2.41; P=0.030). Commencing probiotic supplementation before 5 days from birth was associated with increased detection of the probiotic species over the study period (B. longum subsp. infantis, OR: 1.20; B. animalis subsp. lactis, OR: 1.28; S. thermophilus, OR: 1.45).Conclusion. Probiotic supplementation with B. longum subsp. infantis BB-02, B. animalis subsp. lactis BB-12 and S. thermophilus TH-4 enhances the presence of probiotic species in the gut microbiota of very preterm infants during and after supplementation. Commencing probiotic supplementation shortly after birth may be important for improving the long-term colonization of probiotic species.