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Context: Uncertainty exists about the benefit of dietary docosahexaenoic acid (DHA) on the neurodevelopment of preterm infants.Objective: To determine the effect of meeting the estimated DHA requirement of preterm infants on neurodevelopment at 18 months' corrected age.Design, Setting, and Participants: Randomized, double-blind controlled trial enrolling infants born at less than 33 weeks' gestation from April 2001 to October 2005 at 5 Australian tertiary hospitals, with follow-up to 18 months.Intervention: High-DHA (approximately 1% total fatty acids) enteral feeds compared with standard DHA (approximately 0.3% total fatty acids) from day 2 to 4 of life until term corrected age.Main Outcome Measures: Bayley Mental Development Index (MDI) at 18 months' corrected age. A priori subgroup analyses were conducted based on randomization strata (sex and birth weight < 1250 g vs > or = 1250 g).Results: Of the 657 infants enrolled, 93.5% completed the 18-month follow-up. Bayley MDI scores did not differ between the high- and standard-DHA groups (mean difference, 1.9; 95% confidence interval [CI], -1.0 to 4.7). The MDI among girls fed the high-DHA diet was higher than girls fed standard DHA in unadjusted and adjusted analyses (unadjusted mean difference, 4.7; 95% CI, 0.5-8.8; adjusted mean difference, 4.5; 95% CI, 0.5-8.5). The MDI among boys did not differ between groups. For infants born weighing less than 1250 g, the MDI in the high-DHA group was higher than with standard DHA in the unadjusted comparison (mean difference, 4.7; 95% CI, 0.2-9.2) but did not reach statistical significance following adjustment for gestational age, sex, maternal education, and birth order (mean difference, 3.8; 95% CI, -0.5 to 8.0). The MDI among infants born weighing at least 1250 g did not differ between groups.Conclusion: A DHA dose of approximately 1% total fatty acids in early life did not increase MDI scores of preterm infants overall born earlier than 33 weeks but did improve the MDI scores of girls.Trial Registration: anzctr.org.au Identifier: ACTRN12606000327583. [ABSTRACT FROM AUTHOR]

OBJECTIVE: We investigated the relative contribution of macronutrients to postnatal growth in preterm infants born <33 wk of gestation. METHODS: An audit of daily parenteral and enteral intakes of protein, carbohydrate, fat, energy, and growth (daily weight, weekly length, and head circumference) from birth to discharge home in 138 infants at <33 wk of gestation admitted to an Australian tertiary hospital was done. A mixed-model analysis of variance with random effects (slope and intercept) for subject and controlling for time, sex, gestational age, and total energy was used to determine the relative contribution of macronutrients to growth. RESULTS: A higher energy intake (kilocalories per day) had a positive influence on growth. With total energy held constant, the contribution of carbohydrate to total energy had a positive relation to weight, length, and head circumference gains; protein had no relation and fat was negatively associated. For every 1% increase in energy from carbohydrate, there was a 2.3-g/d increase in weight (95% confidence interval 1.6-3.0, P < 0.0001), a 0.013-cm/d increase in length (95% confidence interval 0.003-0.022, P = 0.007), and a 0.015-cm/d increase in head circumference (95% confidence interval 0.009-0.022, P < 0.0001). CONCLUSION: A re-examination of the macronutrient balance in the diet of preterm infants is required in relation to optimizing growth. [ABSTRACT FROM AUTHOR]

Pain is a frequent complication of subcutaneous cytokine injections in children. A randomized crossover trial was conducted to determine the least painful and preferred method of cytokine administration for children and young people. The current standard practice of subcutaneous injection was compared with the use of Insuflon (Maersk Medical, Roskilde, Denmark), a subcutaneous indwelling catheter. Children aged between 1 month-and 18 years undergoing treatment within the oncology/hematology unit of a single tertiary hospital and receiving cytokines were eligible for the study. Twenty children participated in the study, each child receiving both administration methods in random order during sequential cytokine treatment courses. There was a trend toward higher pain scores when using subcutaneous injections for drug administration compared to Insuflon. Seventy-five percent (n = 15) of the children who completed the trial and their families preferred using insuflon for subcutaneous drug administration. Consideration needs to be given, however, to those who refused to enter the study, withdrew, or continued because of a preference for subcutaneous injections. Current practice at the Women's and Children's Hospital is to allow the child and parents to choose their preferred treatment modality for subcutaneous drug administration. Copyright © 2004 by Association of Pediatric Oncology Nurses [ABSTRACT FROM AUTHOR]

Aims: To describe the prevalence of use of breastmilk and explore demographic characteristics and clinical outcomes associated with breastmilk provision in infants born <29 weeks' gestational age in Australia, New Zealand and Singapore., Methods: This is a secondary analysis of data from a randomised controlled trial, which enrolled 1273 infants in 13 neonatal units across Australia, New Zealand and Singapore from 2012 to 2015. Infants were classified as formula-fed, donor milk-fed or mother's milk-fed at their first enteral feed and separately, at hospital discharge., Results: The percentage of infants receiving mother's own milk differed between centres both at first feed (79% to 100%), and at hospital discharge (47.1% to 71.6%). Aboriginal, Torres Strait Islander and Southeast Asian heritage, drug use and smoking were associated with lower rates of fully breastmilk feeding at hospital discharge. There was no significant difference in growth outcomes, length of stay and feeding tolerance between feeding groups., Conclusions: Achieving high breastmilk feeding rates at hospital discharge for all preterm infants born <29 weeks' gestational age at hospital discharge is possible; however, targeted support for mothers who are Indigenous, Southeast Asian and/or using recreational drugs and/or smoking and/or experiencing social disadvantage may be needed. A better understanding and shared knowledge of practice variations within neonatal units with high breastfeeding rates could improve breastmilk access and equity for preterm infants., Australian New Zealand Clinical Trials Registry: ACTRN12612000503820., (© 2024 The Author(s). Journal of Paediatrics and Child Health published by John Wiley & Sons Australia, Ltd on behalf of Paediatrics and Child Health Division (The Royal Australasian College of Physicians).)

Genetic mutations are being thoroughly mapped in human cancers, yet a fundamental question in cancer biology is whether such mutations are functionally required for cancer initiation, maintenance of established cancer, or both. Here, we study this question in the context of human acute myeloid leukemia (AML), where DNMT3A R882 missense mutations often arise early, in pre-leukemic clonal hematopoiesis, and corrupt the DNA methylation landscape to initiate leukemia. We developed CRISPR-based methods to directly correct DNMT3A R882 mutations in leukemic cells obtained from patients. Surprisingly, DNMT3A R882 mutations were largely dispensable for disease maintenance. Replacing DNMT3A R882 mutants with wild-type DNMT3A did not impair the ability of AML cells to engraft in vivo , and minimally altered DNA methylation. Taken together, DNMT3A R882 mutations are initially necessary for AML initiation, but are largely dispensable for disease maintenance. The notion that initiating oncogenes differ from those that maintain cancer has important implications for cancer evolution and therapy., Competing Interests: Declaration of interests: R.M. is on the Advisory Boards of Kodikaz Therapeutic Solutions, Orbital Therapeutics, Pheast Therapeutics, 858 Therapeutics, Prelude Therapeutics, Mubadala Capital, and Aculeus Therapeutics. R.M. is a co-founder and equity holder of Pheast Therapeutics, MyeloGene, and Orbital Therapeutics.

The African palm weevil ( Rhynchophorus phoenicis ) is a species of high economic importance in sub-Saharan Africa, both as a culturally traditional edible insect and as an agricultural pest. Here we provide a de novo assembly and annotation for the mitochondrial genome of this species from whole-genome sequence data. The mitogenome was AT-rich and 17,161bp in length, containing 13 protein-coding, 22 transfer RNA, and two ribosomal RNA genes. Phylogenetic reconstruction showed the African palm weevil to cluster within the genus Rhynchophorus and the weevil tribe Rhynchophorini. This mitogenome will be important for future genetic research into this emerging edible insect species., Competing Interests: The authors report no conflict of interest., (© 2024 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group.)

Objective: To describe child development knowledge needs, priorities, and preferences for education to enhance developmental literacy among parents with children admitted to the neonatal unit (NNU)., Methods: Two separate cohorts completed a survey; 1) Parents with children graduated from Australian NNUs (n = 316); 2) Parents with infants' inpatient at two South Australian NNUs (n = 209)., Results: Parents considered it extremely important to understand child development (Graduates: 80%; Inpatients: 71%). Inpatient parents reported lower child development knowledge. Almost half (42%) of graduate parents described the child development education provided by neonatal staff as poor or inadequate. There was consistency in preferences for developmental literacy education provision. Parents desired education to commence during NNU and continue post discharge. Priorities included content specific to preterm birth and how to support child development over the first two years of life. Individualised education by a Neonatal Nurse/Midwife was most preferred., Conclusion: Mothers and fathers value guidance to support their child's development during NNU admission and early childhood. Our study highlights the importance of improved early developmental literacy education for parents with children admitted to the neonatal unit., Practice Implications: Our findings can be used to inform the creation of future educational resources targeting improved parent developmental literacy., Competing Interests: Declaration of Competing Interest The authors have no interests to declare., (Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.)

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.

Introduction: Severe bronchopulmonary dysplasia (BPD) is a well-known factor consistently associated with impaired cognitive outcomes. Regarding reported benefits on long-term neurodevelopmental outcomes, the potential adverse effects of high-dose docosahexaenoic acid (DHA) supplementation on this short-term neonatal morbidity need further investigations in infants born very preterm. This study will determine whether high-dose DHA enteral supplementation during the neonatal period is associated with the risk of severe BPD at 36 weeks' postmenstrual age (PMA) compared with control, in contemporary cohorts of preterm infants born at less than 29 weeks of gestation., Methods and Analysis: As part of an Australian-Canadian collaboration, we will conduct an individual participant data (IPD) meta-analysis of randomised controlled trials targeting infants born at less than 29 weeks of gestation and evaluating the effect of high-dose DHA enteral supplementation in the neonatal period compared with a control. Primary outcome will be severe grades of BPD (yes/no) at 36 weeks' PMA harmonised according to a recent definition that predicts early childhood morbidities. Other outcomes will be survival without severe BPD, death, BPD severity grades, serious brain injury, severe retinopathy of prematurity, patent ductus arteriosus and necrotising enterocolitis requiring surgery, sepsis, combined neonatal morbidities and growth. Severe BPD will be compared between groups using a multivariate generalised estimating equations log-binomial regression model. Subgroup analyses are planned for gestational age, sex, small-for-gestational age, presence of maternal chorioamnionitis and mode of delivery., Ethics and Dissemination: The conduct of each trial was approved by institutional research ethics boards and written informed consent was obtained from participating parents. A collaboration and data sharing agreement will be signed between participating authors and institutions. This IPD meta-analysis will document the role of DHA in nutritional management of BPD. Findings will be disseminated through conferences, media interviews and publications to peer-reviewed journals., Prospero Registration Number: CRD42023431063., Trial Registration Number: NCT05915806., Competing Interests: Competing interests: IsM, PML, AJM, CTC, IbM, TRS and MM were investigators of RCTs expected to be included in this IPD meta-analysis., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Introduction: Many extremely preterm newborns develop anaemia requiring a transfusion, with most receiving three to five transfusions during their admission. While transfusions save lives, the potential for transfusion-related adverse outcomes is an area of growing concern. Transfusion is an independent predictor of death and is associated with increased morbidity, length of hospital stay, risk of infection and immune modulation. The underlying mechanisms include adverse pro-inflammatory and immunosuppressive responses. Evidence supports an association between transfusion of washed red cells and fewer post-transfusion complications potentially through removal of chemokines, lipids, microaggregates and other biological response modifiers. However, the clinical and cost-effectiveness of washed cells have not been determined., Methods and Analysis: This is a multicentre, randomised, double-blinded trial of washed versus unwashed red cells. Infants <28 weeks' gestation requiring a transfusion will be enrolled. Transfusion approaches will be standardised within each study centre and will occur as soon as possible with a recommended fixed transfusion volume of 15 mL/kg whenever the haemoglobin is equal to or falls below a predefined restrictive threshold, or when clinically indicated. The primary outcome is a composite of mortality and/or major morbidity to first discharge home, defined as one or more of the following: physiologically defined bronchopulmonary dysplasia; unilateral or bilateral retinopathy of prematurity grade >2, and; necrotising enterocolitis stage ≥2. To detect a 10% absolute reduction in the composite outcome from 69% with unwashed red blood cell (RBCs) to 59% with washed RBCs with 90% power, requires a sample size of 1124 infants (562 per group). Analyses will be performed on an intention-to-treat basis with a prespecified statistical analysis plan. A cost-effectiveness analysis will also be undertaken., Ethics and Dissemination: Ethics approval has been obtained from the Women's and Children's Health Network Human Research Ethics Committee (HREC/12/WCHN/55). The study findings will be disseminated through peer-reviewed articles and conferences., Trial Registration Number: ACTRN12613000237785 Australian New Zealand Clinical Trials Registry., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Importance: High-dose omega-3 docosahexaenoic acid (DHA) supplementation of children born at less than 29 weeks' gestation has been shown to improve IQ despite increasing the risk of bronchopulmonary dysplasia (BPD). Given that BPD is associated with poorer cognitive outcomes, it is unclear whether the increased risk of BPD with DHA supplementation is associated with decreased benefit to IQ., Objective: To investigate whether the increased risk of BPD with DHA supplementation was associated with diminished IQ benefit., Design, Setting, and Participants: This cohort study used data collected from a multicenter, blinded, randomized controlled trial of DHA supplementation in children born at less than 29 weeks' gestation. Participants were recruited from 2012 to 2015 and followed up until 5 years' corrected age. Data were analyzed from November 2022 to February 2023., Interventions: Enteral DHA emulsion (60 mg/kg/d, to match the estimated in-utero requirement) or a control emulsion from the first 3 days of enteral feeds until 36 weeks' postmenstrual age or discharge home., Main Outcomes and Measures: Physiological BPD was assessed at 36 weeks' postmenstrual age. IQ was assessed at 5 years' corrected age using the Wechsler Preschool and Primary Scale of Intelligence, 4th Edition; children from the 5 highest-recruiting Australian hospitals were assessed. The total effect of DHA supplementation on IQ was divided into direct and indirect effects using mediation analysis, with BPD as the presumed mediating variable., Results: Among 656 surviving children from hospitals involved in IQ follow-up (mean [SD] gestational age at birth, 26.8 [1.4] weeks; 346 males [52.7%]), there were 323 children with DHA supplementation and 333 children in the control group. Mean IQ was 3.45 points (95% CI, 0.38 to 6.53 points) higher in the DHA group than the control group, despite an increase in the risk of BPD (160 children [49.7%] vs 143 children [42.8%] with BPD). The indirect effect of DHA on IQ via BPD was not statistically significant (-0.17 points; 95% CI, -0.62 to 0.13 points), with most of the effect of DHA on IQ occurring independently of BPD (direct effect = 3.62 points; 95% CI, 0.55 to 6.81 points)., Conclusions and Relevance: This study found that associations of DHA with BPD and IQ were largely independent. This finding suggests that if clinicians supplement children born preterm with high-dose DHA, any resulting increase in BPD risk would not be associated with meaningful reductions in the IQ benefit.

Objectives: We aimed to compare the effects of nutrient-enriched formula with standard term formula on rate of body weight gain of late preterm infants appropriately grown for gestational age., Study Design: A multi-center, randomized, controlled trial. Late preterm infants (34-37 weeks' gestation), with weight appropriate for gestational age (AGA), were randomized to nutrient enriched formula (NEF) with increased calories (22 kcal/30 ml) from protein, added bovine milk fat globule membrane, vitamin D and butyrate or standard term formula 20 kcal/30 ml (STF). Breastfed term infants were enrolled as an observational reference group (BFR). Primary outcome was rate of body weight gain from enrollment to 120 days corrected age (d/CA). Planned sample size was 100 infants per group. Secondary outcomes included body composition, weight, head circumference and length gain, and medically confirmed adverse events to 365 d/CA., Results: The trial was terminated early due to recruitment challenges and sample size was substantially reduced. 40 infants were randomized to NEF ( n  = 22) and STF ( n  = 18). 39 infants were enrolled in the BFR group. At 120 d/CA there was no evidence of a difference in weight gain between randomized groups (mean difference 1.77 g/day, 95% CI, -1.63 to 5.18, P  = 0.31). Secondary outcomes showed a significant reduction in risk of infectious illness in the NEF group at 120 d/CA [relative risk 0.37 (95% CI, 0.16-0.85), P  = 0.02]., Conclusion: We saw no difference in rate of body weight gain between AGA late preterm infants fed NEF compared to STF. Results should be interpreted with caution due to small sample size., Clinical Trial Registration: The Australia New Zealand Clinical Trials Registry (ACTRN 12618000092291). "mailto:maria.makrides@sahmri.com" maria.makrides@sahmri.com., Competing Interests: TM-P is employed by Reckitt|Mead-Johnson and TRC is a former employee of Reckitt|Mead-Johnson. All other authors declare no conflict of interest. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (© 2023 Best, Yelland, Collins, McPhee, Rogers, Choo, Gibson, Murguia-Peniche, Varghese, Cooper and Makrides.)

Background: Preterm infants suffer higher morbidity and mortality rates compared to full-term infants, but little is known about how changes to oral and respiratory tract microbiota may impact disease development., Methods: Here, very preterm neonates (n = 50) were selected to study oral and respiratory microbiota development during the first few months post-birth, where 26 individuals were diagnosed with BPD and/or sepsis. These infants were compared to 14 healthy full-term infants and 16 adults. Microbiota diversity, composition, and species abundances were calculated from 16S ribosomal RNA gene sequences in buccal swabs and tracheal aspirates at two time points (within a week and 1-3 months post-birth)., Results: Collection time point was the biggest factor to significantly influence the preterm oral microbial diversity and composition. In addition, BPD and sepsis were linked to distinct preterm oral microbiota diversity and composition, and opportunistic pathogens previously associated with these diseases were identified in the initial sample for both healthy preterm neonates and those with the disease. Compared to the full-term infant and adult dataset, preterm infant diversity and composition was initially significantly different, but resembled full-term infant diversity and composition over time., Conclusion: Overall, consequences of microbiota development need further examination in preterm infant infections and later development., Impact: Non-gut microbiota research on preterm infants is limited. At one week post-birth, preterm infants harbor distinct oral microbiota that are not shared with full-term children or adults, eventually becoming similar to full-term infants at 36 weeks postmenstrual age. DNA from potential opportunistic pathogens was observed in the mouth and lungs of preterm infants within a week of birth, and microbes associated with BPD were identified in the lungs. Oral microbiota in preterm infants over the first 2-3 months is unique and may be connected to short- and long-term health outcomes in these children., (© 2023. The Author(s).)

Aim: To determine if supplementation of infants born <33 weeks’ gestation with higher dose docosahexaenoic acid (DHA) affects growth, body composition, and blood pressure at 7 y corrected age (CA) and if treatment effects differed by infant sex at birth and birth weight strata (<1250 and ≥1250 g). Methods: Seven-year follow-up of an Australian multicenter randomized controlled trial in which 657 infants were fed high-DHA (≈1% total fatty acids) enteral feeds or standard-DHA (≈0.3% total fatty acids) from age 2−4 d until term CA. Seven-year CA outcomes were growth (weight, height), body composition (lean body mass, fat mass, waist, and hip circumference), and blood pressure. Results: There was no effect of high-DHA enteral feeds compared with standard-DHA on growth, body composition, and blood pressure at 7-year CA either overall or in subgroup analysis by sex. There was a significant interaction between high-DHA and birthweight strata on height at 7-y CA (p = 0.03). However, the post-hoc analyses by birthweight strata did not reach significance (p > 0.1). High-DHA group infants were more likely to be classified as obese (relative risk 1.6 (95% CI 1.0, 2.6); p = 0.05). Conclusions: DHA supplementation of premature infants did not affect growth, body composition, or blood pressure at 7-year CA overall by sex and birthweight strata. The finding of a higher risk of obesity in children who receive high-DHA needs to be interpreted with caution due to the small number of children classified as obese.

Background: Docosahexaenoic acid (DHA) is a component of neural tissue. Because its accretion into the brain is greatest during the final trimester of pregnancy, infants born before 29 weeks' gestation do not receive the normal supply of DHA. The effect of this deficiency on subsequent cognitive development is not well understood., Methods: We assessed general intelligence at 5 years in children who had been enrolled in a trial of neonatal DHA supplementation to prevent bronchopulmonary dysplasia. In the previous trial, infants born before 29 weeks' gestation had been randomly assigned in a 1:1 ratio to receive an enteral emulsion that provided 60 mg of DHA per kilogram of body weight per day or a control emulsion from the first 3 days of enteral feeds until 36 weeks of postmenstrual age or discharge home, whichever occurred first. Children from 5 of the 13 centers in the original trial were invited to undergo assessment with the Wechsler Preschool and Primary Scale of Intelligence (WPPSI) at 5 years of corrected age. The primary outcome was the full-scale intelligence quotient (FSIQ) score. Secondary outcomes included the components of WPPSI., Results: A total of 1273 infants underwent randomization in the original trial; of the 656 surviving children who had undergone randomization at the centers included in this follow-up study, 480 (73%) had an FSIQ score available - 241 in the DHA group and 239 in the control group. After imputation of missing data, the mean (±SD) FSIQ scores were 95.4±17.3 in the DHA group and 91.9±19.1 in the control group (adjusted difference, 3.45; 95% confidence interval, 0.38 to 6.53; P = 0.03). The results for secondary outcomes generally did not support that obtained for the primary outcome. Adverse events were similar in the two groups., Conclusions: In infants born before 29 weeks' gestation who had been enrolled in a trial to assess the effect of DHA supplementation on bronchopulmonary dysplasia, the use of an enteral DHA emulsion until 36 weeks of postmenstrual age was associated with modestly higher FSIQ scores at 5 years of age than control feeding. (Funded by the Australian National Health and Medical Research Council and Nu-Mega Ingredients; N3RO Australian New Zealand Clinical Trials Registry number, ACTRN12612000503820.)., (Copyright © 2022 Massachusetts Medical Society.)

Aim: To describe the presence and nature of parent concerns regarding the development of their children admitted to Australian neonatal units (NNUs), comprising neonatal intensive care or special care., Methods: In a cross-sectional survey, mothers and fathers provided information regarding concerns for their child's development. The self-administered survey was completed by two separate cohorts; (i) parents of child graduates from Australian NNUs (n = 381); (ii) parents of infant's inpatient in two South Australian NNUs (n = 209). Data were analysed using thematic analysis and descriptive statistics., Results: Information was provided for 730 children. Developmental concern was reported for 39% of NNU graduates and 35% of inpatients. Children born very preterm (< 32 weeks' gestation) elicited greater parent concern than those born more mature (Cohort 1: 41% vs 36%; Cohort 2: 49% vs 22%), including in multiple developmental domains (Cohort 1: 17% vs 15%; Cohort 2: 28% vs 4%). Parents with inpatient infants were predominantly concerned about general development-milestones (19.1%) and the potential impact of medical or CNS issues (13.7%). Graduate parents commonly focused on specific domains, such as their child's speech-language (13.7%) and motor (12.9%) development., Conclusion: Neurodevelopment is a substantial source of concern for mothers and fathers during NNU admission and childhood, particularly for children born very preterm. However, in the first year of life, developmental concerns are poorly defined. This highlights the need for clinical education resources detailing infant developmental expectations and supportive strategies for parents of these high-risk infants., (© 2022 The Authors. Journal of Paediatrics and Child Health published by John Wiley & Sons Australia, Ltd on behalf of Paediatrics and Child Health Division (The Royal Australasian College of Physicians).)

Objectives: To describe (1) infant feeding practices during initial hospitalisation and up to 6 months corrected age (CA) in infants born late preterm with mothers intending to breastfeed, (2) the impact of early feeding practices on hospital length of stay and (3) maternal and infant factors associated with duration of breastfeeding., Methods: We conducted a prospective cohort study of infants born at 34+0 to 36+6 weeks gestational age during 2018-2020. Families were followed up until the infant reached 6 months of age (corrected for prematurity). Feeding practices during the birth hospitalisation, length of initial hospital stay, and the prevalence of exclusive or any breastfeeding at 6 weeks, 3 months, and 6 months CA were examined. Associations between maternal and infant characteristics and breastfeeding at 6 weeks, 3 months and 6 months CA were assessed using multivariable logistic regression models., Results: 270 infants were enrolled, of these, 30% were multiple births. Overall, 78% of infants received only breastmilk as their first feed, and 83% received formula during the hospitalisation. Seventy-four per cent of infants were exclusively breastfed at discharge, 41% at 6 weeks CA, 35% at 3 months CA, and 29% at 6 months CA. The corresponding combined exclusive and partial breastfeeding rates (any breastfeeding) were 72%, 64%, and 53% of babies at 6 weeks CA, 3 months CA, and 6 months CA, respectively. The mean duration of hospitalisation was 2.9 days longer (95% confidence interval (CI) 0.31, 5.43 days) in infants who received any formula compared with those receiving only breastmilk (adjusted for GA, maternal age, multiple birth, site, and neonatal intensive care unit admission). In multivariable models, receipt of formula as the first milk feed was associated with a reduction in exclusive breastfeeding at 6 weeks CA (odds ratio = 0.22; 95% CI 0.09 to 0.53) and intention to breastfeed >6 months with an increase (odds ratio = 4.98; 95% CI 2.39 to 10.40). Intention to breastfeed >6 months remained an important predictor of exclusive breastfeeding at 3 and 6 months CA., Conclusions: Our study demonstrates that long-term exclusive breastfeeding rates were low in a cohort of women intending to provide breastmilk to their late preterm infants, with approximately half providing any breastmilk at 6 months CA. Formula as the first milk feed and intention to breastfeed >6 months were significant predictors of breastfeeding duration. Improving breastfeeding outcomes may require strategies to support early lactation and a better understanding of the ongoing support needs of this population., Competing Interests: The authors have declared that no competing interests exist.

Importance: Maternal milk feeding may have unique long-term neurodevelopmental benefits in very preterm infants., Objective: To examine the extent to which maternal milk feeding after very preterm birth is associated with cognitive, academic, and behavioral outcomes at school age., Design, Setting, and Participants: This prospective cohort study assessed 586 infants born at less than 33 weeks' gestation at 5 Australian perinatal centers and enrolled in the Docosahexaenoic Acid for Improvement of Neurodevelopmental Outcomes study (January 1, 2001, to December 31, 2005) who were evaluated at a corrected age of 7 years. The statistical analysis was completed on January 19, 2022., Exposures: Maternal milk intake, including mean volume (milliliters per kilogram per day) during neonatal hospitalization and total duration (in months)., Main Outcomes and Measures: Neurodevelopmental outcomes at 7 years of age were (1) IQ (Wechsler Abbreviated Scale of Intelligence), (2) academic achievement (Wide Range Achievement Test, Fourth Edition), (3) symptoms of attention-deficit/hyperactivity disorder (ADHD) (Conners Third Edition ADHD Index, parent reported), (4) executive function (Behavior Rating Inventory of Executive Functioning, parent reported), and (5) behavior (Strengths and Difficulties Questionnaire, parent reported)., Results: A total of 586 infants (mean [SD] gestational age at birth, 29.6 [2.3] weeks; 314 male [53.6%]) born to 486 mothers (mean [SD] age, 30.6 [5.5] years; 447 [92.0%] White) were included. Mean (SD) maternal milk intake in the neonatal intensive care unit was 99 (48) mL/kg daily, and mean (SD) maternal milk duration was 5.1 (5.4) months. Mean (SD) full-scale IQ was 98.5 (13.3) points. After covariate adjustment, higher maternal milk intake during the neonatal hospitalization was associated with higher performance IQ (0.67 points per additional 25 mL/kg daily; 95% CI, 0.10-1.23 points), reading scores (1.14 points per 25 mL/kg daily; 95% CI, 0.39-1.89 points), and math scores (0.76 points per 25 mL/kg daily; 95% CI, 0.14-1.37 points) and fewer ADHD symptoms (-1.08 points per 25 mL/kg daily; 95% CI, -1.96 to -0.20 points). Longer duration of maternal milk intake was associated with higher reading (0.33 points per additional month; 95% CI, 0.03-0.63 points), spelling (0.31 points per month; 95% CI, 0.01-0.62 points), and math (0.30 points per month; 95% CI, 0.03-0.58 points) scores. Maternal milk was not associated with improved full-scale IQ, verbal IQ, executive function, or behavior. Most associations were stronger among infants born at lower gestational ages, particularly less than 30 weeks (interaction P values <.01)., Conclusions and Relevance: In this cohort study of preterm infants, maternal milk feeding during the neonatal hospitalization and after discharge were associated with better school-age performance IQ and academic achievement and with a reduction in ADHD symptoms, particularly among infants born at less than 30 weeks' gestation.

Infants born preterm (less than 37 weeks completed gestation) have a higher risk of suboptimal cognitive and behavioral outcomes when compared with their term-born counterparts. The risk and severity of poor outcome increases as gestational age at birth decreases; however, not all children born preterm will develop deficits, and environmental influences post birth may have a role in shaping developmental outcomes. Whilst early preterm birth is not preventable, it may be possible to intervene after birth via the environment in order to improve outcomes. The diathesis-stress theory hypothesizes that vulnerable individuals will have worse outcomes after a negative environmental exposure, whereas the differential susceptibility theory posits that vulnerable (or plastic) individuals can be both adversely and positively affected by environmental factors. These two theories were compared in 535 children born <33 weeks' gestation. The interaction between the degree of prematurity and the home environment (as measured by the Home Screening Questionnaire) at 18 months on cognition (Intelligence Quotient from the Wechsler Abbreviated Scale of Intelligence) and behavior (Total Difficulties Score from the Strengths and Difficulties Questionnaire) at 7 years was explored. Evidence was not found for either theory, although a supportive/stimulating home environment appeared to contribute to a decrease in the risk or severity of suboptimal scores. Future research is needed to establish stronger evidence in order to inform interventions to improve the home environment of children born preterm., (Copyright © 2022 The Authors. Published by Elsevier B.V. All rights reserved.)

Aim: To assess effects of early versus delayed introduction of human milk fortification in preterm infants., Methods: We searched Cochrane Central Register of Controlled Trials, MEDLINE, Embase, PubMed and CINAHL for randomised controlled trials evaluating start time for human milk fortification in preterm infants (March 2020). Two authors assessed trial eligibility and risk of bias, extracted data and assessed evidence certainty., Results: We identified 1307 publications and included three trials (378 infants). Meta-analysis comparing fortification commencing at an enteral feed volume of ≤40 mL/kg/day versus ≥75 mL/kg/day, showed little to no difference in rates of necrotising enterocolitis (3 trials), sepsis (3 trials), feeding intolerance (2 trials) (low-quality evidence) and infant growth (1 trial, very low-quality evidence)., Conclusions: Whether early introduction of fortification, at an enteral feed volume of ≤40 mL versus delayed at ≥75 mL/kg/day improves growth or influences adverse feeding outcomes is very uncertain., (© 2021 Paediatrics and Child Health Division (The Royal Australasian College of Physicians).)

Background: Preterm infants often start milk feeds by gavage tube. As they mature, sucking feeds are gradually introduced. Women with preterm infants may not always be in hospital to breastfeed their baby and need an alternative approach to feeding. Most commonly, milk (expressed breast milk or formula) is given by bottle. Whether using bottles during establishment of breastfeeds is detrimental to breastfeeding success is a topic of ongoing debate., Objectives: To identify the effects of avoidance of bottle feeds during establishment of breastfeeding on the likelihood of successful breastfeeding, and to assess the safety of alternatives to bottle feeds., Search Methods: A new search strategy was developed for this update. Searches were conducted without date or language limits in September 2021 in: MEDLINE, CENTRAL, and CINAHL.  We also searched the ISRCTN trial registry and the reference lists of retrieved articles for randomised controlled trials (RCTs) and quasi-RCTs.  SELECTION CRITERIA: We included RCTs and quasi-RCTs comparing avoidance of bottles with use of bottles for preterm infants where their mothers planned to breastfeed., Data Collection and Analysis: Two review authors independently assessed trial quality and extracted data. When appropriate, we contacted study authors for additional information. We used the GRADE approach to assess the certainty of evidence. Outcomes included full breastfeeding and any breastfeeding on discharge home and at three and six months after discharge, as well as length of hospital stay and episodes of infant infection. We synthesised data using risk ratios (RR), risk differences (RD) and mean differences (MD), with 95% confidence intervals (CI). We used the GRADE approach to assess the certainty of the evidence., Main Results: We included seven trials with 1152 preterm infants in this updated review. There are three studies awaiting classification. Five included studies used a cup feeding strategy, one used a tube feeding strategy and one used a novel teat when supplements to breastfeeds were needed. We included the novel teat study in this review as the teat was designed to closely mimic the sucking action of breastfeeding. The trials were of small to moderate size, and two had high risk of attrition bias. Adherence with cup feeding was poor in one of the studies, indicating dissatisfaction with this method by staff or parents (or both); the remaining four cup feeding studies provided no such reports of dissatisfaction or low adherence. Avoiding bottles may increase the extent of full breastfeeding on discharge home (RR 1.47, 95% CI 1.19 to 1.80; 6 studies, 1074 infants; low-certainty evidence), and probably increases any breastfeeding (full and partial combined) on discharge (RR 1.11, 95% CI 1.06 to 1.16; studies, 1138 infants; moderate-certainty evidence). Avoiding bottles probably increases the occurrence of full breastfeeding three months after discharge (RR 1.56, 95% CI 1.37 to 1.78; 4 studies, 986 infants; moderate-certainty evidence), and may also increase full breastfeeding six months after discharge (RR 1.64, 95% CI 1.14 to 2.36; 3 studies, 887 infants; low-certainty evidence). Avoiding bottles may increase the occurrence of any breastfeeding (full and partial combined) three months after discharge (RR 1.31, 95% CI 1.01 to 1.71; 5 studies, 1063 infants; low-certainty evidence), and six months after discharge (RR 1.25, 95% CI 1.10 to 1.41; 3 studies, 886 infants; low-certainty evidence). The effects on breastfeeding outcomes were evident at all time points for the tube alone strategy and for all except any breastfeeding three months after discharge for cup feeding, but were not present for the novel teat. There were no other benefits or harms including for length of hospital stay (MD 2.25 days, 95% CI -3.36 to 7.86; 4 studies, 1004 infants; low-certainty evidence) or episodes of infection per infant (RR 0.70, 95% CI 0.35 to 1.42; 3 studies, 500 infants; low-certainty evidence)., Authors' Conclusions: Avoiding the use of bottles when preterm infants need supplementary feeds probably increases the extent of any breastfeeding at discharge, and may improve any and full breastfeeding (exclusive) up to six months postdischarge. Most of the evidence demonstrating benefit was for cup feeding. Only one study used a tube feeding strategy. We are uncertain whether a tube alone approach to supplementing breastfeeds improves breastfeeding outcomes; further studies of high certainty are needed to determine this., (Copyright © 2021 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.)

Background: Children born preterm (<37 weeks' gestation) have an increased risk of poor neurodevelopment, including lower intelligence quotient (IQ) scores compared with their term-born counterparts., Objective: To explore the differences in psychometric scores for cognition and motor skills when they are age-standardized according to chronological age instead of corrected age for children born preterm., Methods: We assessed = 554 children born <33 weeks' gestation with the Bayley Scales of Infant Development, 2nd edition (mental and motor scores) at 18 months and the Weschler Abbreviated Scale of Intelligence (IQ score) at seven years of age. Scores were standardized according to chronological age and corrected age and differences between mean chronological and corrected scores were compared, along with the proportion of children whose scores could be classified as impaired., Results: When scores were standardized according to chronological age instead of corrected age there was a large significant difference of 17.3 points on the mental scale (79.5 vs. 96.8, respectively) and 11.8 points on the motor scale (84.8 vs. 96.6, respectively) at 18 months. By seven years, the difference in IQ scores remained, although of a smaller magnitude at 1.9 points between mean chronological and corrected age scoring (97.2 vs. 99.1, respectively)., Conclusion: Consistent with previous literature, outcome assessments for preterm infants consistently differed according to use of chronological or corrected age to standardized scores. Cognitive scores were impacted more severely than motor scores, and differences were more substantial in early childhood than later in childhood. For clinical purposes, correction for preterm birth is only likely to have an impact during early childhood, however assessments for research purposes should continue to correct into childhood to account for the persistent bias due to preterm birth., Competing Interests: Professor Makrides reports serving on board for Trajan Nutrition until Nov 2020. No other authors reported any financial disclosures.

Human milk (HM) is the gold standard for feeding infants but has been associated with slower growth in preterm infants compared with preterm formula. This systematic review and meta-analysis summarises the post-1990 literature to examine the effect of HM feeding on growth during the neonatal admission of preterm infants with birth weight ≤1500 g and/or born ≤28 weeks' gestation. Medline, PubMed, CINAHL, and Scopus were searched, and comparisons were grouped as exclusive human milk (EHM) vs. exclusive preterm formula (EPTF), any HM vs. EPTF, and higher vs. lower doses of HM. We selected studies that used fortified HM and compared that with a PTF; studies comparing unfortified HM and term formula were excluded. Experimental and observational studies were pooled separately. The GRADE system was used to evaluate risk of bias and certainty of evidence. Forty-four studies were included with 37 ( n = 9963 infants) included in the meta-analyses. In general, due to poor quality studies, evidence of the effect of any HM feeds or higher versus lower doses of HM was inconclusive. There was a possible effect that lower doses of HM compared with higher doses of HM improved weight gain during the hospital admission, and separately, a possible effect of increased head circumference growth in infants fed EPTF vs. any HM. The clinical significance of this is unclear. There was insufficient evidence to determine the effects of an exclusive HM diet on any outcomes.

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., Competing Interests: Competing interests: Study product for the original trial was donated by Clover Corporation Limited (Melbourne, Australia). MM and RAG report holding a patent relating to methods and compositions for promoting the neurological development for preterm infants (2009201540), owned by the South Australian Health and Medical Research Institute and licensed to Clover Corporation Limited. MM is supported by an Australian NHMRC Senior Research Fellowship ID: 1061704 and CTC is supported by a NHMRC Translating Research into Practice (TRIP) Fellowship ID 1132596. TS is supported by a NHMRC Emerging Leadership Investigator Grant ID: 1173576. KPB is supported by a Women’s and Children’s Hospital MS McLeod Postdoctoral Fellowship. PGD is supported by an Australian NHMRC Practitioner Fellowship ID: 1157782. JC is supported by a MRFF Career Development Fellowship ID: 1354. Honoraria have been paid to JFG’s institution to support conference travel by Fonterra. MM and RAG report serving on the board for Trajan Nutrition. No other authors reported any financial disclosures. The contents of the published material are solely the responsibility of the authors and do not reflect the views of the NHMRC., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Objective: To conduct a systematic review and meta-analysis of the efficacy and safety of fortification of human milk with human milk-based fortifier versus cow's milk-based fortifier for use in preterm and/or very low birthweight infants., Design: Randomised or quasi-randomised controlled trials comparing the effect of human milk fortification with human milk-based milk fortifier versus cow's milk-based fortifier in infants born <34 weeks' gestation and/or with birth weight <1500 g were identified by searching databases, clinical trial registries and reference lists until 5 November 2019. Two authors independently extracted data and assessed evidence quality. Meta-analyses were conducted using fixed or random effects models, as appropriate., Main Outcome Measures: Necrotising enterocolitis (Bell's stage II or higher) and late-onset sepsis., Results: Of 863 unique records identified, 16 full-text trials were screened and 2 trials involving 334 infants were included. Primary outcome data were available for 332 infants. Use of human milk-based fortifier compared with cow's milk-based fortifier reduced the risk of necrotising enterocolitis (risk ratio 0.47, 95% CI 0.22 to 0.98). There was no clear evidence of an effect on late-onset sepsis or any other outcomes. The quality of evidence was low to very low due to imprecision and lack of blinding in one study., Conclusions: Findings suggest that there is a reduction in the incidence of necrotising enterocolitis with human milk-based fortifiers compared with cow's milk-based fortifiers. The overall quality of evidence is low. Further appropriately powered trials are required before this intervention can be routinely recommended for preterm infants., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2021. No commercial re-use. See rights and permissions. Published by BMJ.)

Infants born preterm miss out on the peak period of in utero DHA accretion to the brain during the last trimester of pregnancy which is hypothesised to contribute to the increased prevalence of neurodevelopmental deficits in this population. This study aimed to determine whether DHA supplementation in infants born preterm improves attention at 18 months' corrected age. This is a follow-up of a subset of infants who participated in the N3RO randomised controlled trial. Infants were randomised to receive an enteral emulsion of high-dose DHA (60 mg/kg per d) or no DHA (soya oil - control) from within the first days of birth until 36 weeks' post-menstrual age. The assessment of attention involved three tasks requiring the child to maintain attention on toy/s in either the presence or absence of competition or a distractor. The primary outcome was the child's latency of distractibility when attention was focused on a toy. The primary outcome was available for seventy-three of the 120 infants that were eligible to participate. There was no evidence of a difference between groups in the latency of distractibility (adjusted mean difference: 0·08 s, 95 % CI -0·81, 0·97; P = 0·86). Enteral DHA supplementation did not result in improved attention in infants born preterm at 18 months' corrected age.

Introduction: Docosahexaenoic acid (DHA) is an omega-3 (n-3) fatty acid that accumulates into neural tissue during the last trimester of pregnancy, as the fetal brain is undergoing a growth spurt. Infants born <29 weeks' gestation are deprived the normal in utero supply of DHA during this period of rapid brain development. Insufficient dietary DHA postnatally may contribute to the cognitive impairments common among this population. This follow-up of the N-3 fatty acids for improvement in respiratory outcomes (N3RO) randomised controlled trial aims to determine if enteral DHA supplementation in infants born <29 weeks' gestation during the first months of life improves cognitive development at 5 years of age corrected for prematurity., Methods and Analysis: N3RO was a randomised controlled trial of enteral DHA supplementation (60 mg/kg/day) or a control emulsion (without DHA) in 1273 infants born <29 weeks' gestation to determine the effect on bronchopulmonary dysplasia (BPD). We showed that DHA supplementation did not reduce the risk of BPD and may have increased the risk.In this follow-up at 5 years' corrected age, a predefined subset (n=655) of children from five Australian sites will be invited to attend a cognitive assessment with a psychologist. Children will be administered the Wechsler Preschool and Primary Scale of Intelligence (fourth edition) and a measure of inhibitory control (fruit stroop), while height, weight and head circumference will be measured.The primary outcome is full-scale IQ. To ensure 90% power, a minimum of 592 children are needed to detect a four-point difference in IQ between the groups.Research personnel and families remain blinded to group assignment., Ethics and Dissemination: The Women's and Children Health Network Human Research Ethics Committee reviewed and approved the study (HREC/17/WCHN/187). Caregivers will give informed consent prior to taking part in this follow-up study. Findings of this study will be disseminated through peer-reviewed publications and conference presentations., Trial Registration Number: ACTRN12612000503820., Competing Interests: Competing interests: Study product for the original trial was donated by Clover (Melbourne, Australia). MM and RAG report holding a patent relating to methods and compositions for promoting the neurological development for preterm infants (2009201540), owned by the South Australian Health and Medical Research Institute and licensed to Clover Corporation Limited. MM is supported by an Australian NHMRC Senior Research Fellowship ID: 1061704 and CC is supported by an NHMRC Translating Research into Practice (TRIP) Fellowship ID 1132596. TS is supported by an NHMRC Emerging Leadership Investigator Grant ID: 1173576. KPB is supported by a Women’s and Children’s Hospital MS McLeod Postdoctoral Fellowship. PGD is supported by an Australian NHMRC Practitioner Fellowship ID: 1157782. JC is supported by an MRFF Career Development Fellowship ID: 1141354. Honoraria have been paid to Dr JFG’s institution to support conference travel by Fonterra. MM and RAG report serving on the board for Trajan Nutrition. No other authors reported any financial disclosures., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Infants born very preterm miss out on the in utero transfer of the omega-3 and omega-6 long-chain polyunsaturated fatty acids that occurs during the third trimester. A number of studies have explored the impact of increasing the enteral intakes of omega-3 +/- omega-6 long-chain polyunsaturated fatty acids to match fetal accretion rates in such infants. These studies have shown early transient improvements in vision and development with both strategies, but with the use of omega-3 supplementation alone appearing to increase the incidence of bronchopulmonary dysplasia. A recent study of omega-3 + omega-6 supplementation demonstrated a significant reduction in the incidence of severe retinopathy of prematurity in a high-risk population, without apparent adverse effects; a larger study is needed to confirm the observed benefits, to assess safety, and to determine long-term developmental outcomes of this strategy., (© 2022 S. Karger AG, Basel.)

Objective: Oxylipins synthesized by oxidation of long-chain polyunsaturated fatty acids (LCPUFAs) are bioactive downstream lipid mediators. The aim of this study was to describe oxylipin levels in preterm infants born 30 to 33 weeks' gestation who were enrolled in a randomized controlled trial in which peripheral parenteral nutrition (P-PN), including lipid emulsion (containing soy, medium chain triglyceride, olive and fish oil), was compared with 10% glucose on growth during the transition to enteral feeds., Methods: Of the 92 infants randomized to the P-PN study, the first 72 (P-PN n = 34, control n = 38) had blood taken for fatty acid analyses. P-PN infants received parenteral nutrition including 3% protein, 8% glucose and 17% SMOFlipid® lipid (containing soy, medium chain triglyceride, olive and fish oil), and control infants 10% glucose. Both groups commenced enteral feeds when clinically stable. 32 oxylipins and 5 free fatty acids were screened (using ultra-high-performance liquid chromatography-tandem mass spectrometry), and 5 total LCPUFA were measured (using gas chromatography), on study days 1 (baseline), 2, 4, 7, 14 and 21., Results: Both total and free LA, ALA and EPA were significantly higher in the P-PN group compared with control over the first week of life. Whereas total AA was significantly lower and free DHA significantly higher over the same time period. All LA, ALA, EPA and four DHA derived oxylipins detected were significantly higher in the P-PN group compared with the control group during the first week of life, with three AA derived oxylipins significantly lower and one significantly higher., Conclusions: Parenteral lipid emulsion resulted in a change in total and free fatty acids and related oxylipins with the profiles suggesting increased omega-6 driven inflammation. Further studies to investigate the association between the oxylipin levels and nutrition and to determine whether the oxylipin profiles influence the clinical outcome in preterm infants are warranted., (Copyright © 2020. Published by Elsevier Ltd.)

Background: Human milk alone may provide inadequate amounts of protein to meet the growth requirements of preterm infants because of restrictions in the amount of fluid they can tolerate. It has become common practice to feed preterm infants with breast milk fortified with protein and other nutrients but there is debate about the optimal concentration of protein in commercially available fortifiers., Objectives: To compare the effects of different protein concentrations in human milk fortifier, fed to preterm infants, on growth and neurodevelopment., Search Methods: We used the standard search strategy of Cochrane Neonatal to search CENTRAL (2019, Issue 8), Ovid MEDLINE and CINAHL on 15 August 2019. We also searched clinical trials databases and the reference lists of retrieved articles for randomised controlled trials and quasi-randomised trials., Selection Criteria: We included all published and unpublished randomised, quasi-randomised and cluster-randomised trials comparing two different concentrations of protein in human milk fortifier. We included preterm infants (less than 37 weeks' gestational age). Participants may have been exclusively fed human milk or have been supplemented with formula. The concentration of protein was classified as low (< 1g protein/100 mL expressed breast milk (EBM)), moderate (≥ 1g to < 1.4g protein/100 mL EBM) or high (≥ 1.4g protein/100 mL EBM). We excluded trials that compared two protein concentrations that fell within the same category., Data Collection and Analysis: We undertook data collection and analyses using the standard methods of Cochrane Neonatal. Two review authors independently evaluated trials. Primary outcomes included growth, neurodevelopmental outcome and mortality. Data were synthesised using risk ratios (RR), risk differences and mean differences (MD), with 95% confidence intervals (CI). We used the GRADE approach to assess the certainty of the evidence., Main Results: We identified nine trials involving 861 infants. There is one trial awaiting classification, and nine ongoing trials. The trials were mostly conducted in infants born < 32 weeks' gestational age or < 1500 g birthweight, or both. All used a fortifier derived from bovine milk. Two trials fed infants exclusively with mother's own milk, three trials gave supplementary feeds with donor human milk and four trials supplemented with preterm infant formula. Overall, trials were small but generally at low or unclear risk of bias. High versus moderate protein concentration of human milk fortifier There was moderate certainty evidence that a high protein concentration likely increased in-hospital weight gain compared to moderate concentration of human milk fortifier (MD 0.66 g/kg/day, 95% CI 0.51 to 0.82; trials = 6, participants = 606). The evidence was very uncertain about the effect of high versus moderate protein concentration on length gain (MD 0.01 cm/week, 95% CI -0.01 to 0.03; trials = 5, participants = 547; very low certainty evidence) and head circumference gain (MD 0.00 cm/week, 95% CI -0.01 to 0.02; trials = 5, participants = 549; very low certainty evidence). Only one trial reported neonatal mortality, with no deaths in either group (participants = 45). Moderate versus low protein concentration of human milk fortifier A moderate versus low protein concentration fortifier may increase weight gain (MD 2.08 g/kg/day, 95% CI 0.38 to 3.77; trials = 2, participants = 176; very low certainty evidence) with little to no effect on head circumference gain (MD 0.13 cm/week, 95% CI 0.00 to 0.26; I² = 85%; trials = 3, participants = 217; very low certainty evidence), but the evidence is very uncertain. There was low certainty evidence that a moderate protein concentration may increase length gain (MD 0.09 cm/week, 95% CI 0.05 to 0.14; trials = 3, participants = 217). Only one trial reported mortality and found no difference between groups (RR 0.48, 95% CI 0.05 to 5.17; participants = 112). No trials reported long term growth or neurodevelopmental outcomes including cerebral palsy and developmental delay., Authors' Conclusions: Feeding preterm infants with a human milk fortifier containing high amounts of protein (≥ 1.4g/100 mL EBM) compared with a fortifier containing moderate protein concentration (≥ 1 g to < 1.4 g/100 mL EBM) results in small increases in weight gain during the neonatal admission. There may also be small increases in weight and length gain when infants are fed a fortifier containing moderate versus low protein concentration (< 1 g protein/100 mL EBM). The certainty of this evidence is very low to moderate; therefore, results may change when the findings of ongoing studies are available. There is insufficient evidence to assess the impact of protein concentration on adverse effects or long term outcomes such as neurodevelopment. Further trials are needed to determine whether modest increases in weight gain observed with higher protein concentration fortifiers are associated with benefits or harms to long term growth and neurodevelopment., (Copyright © 2020 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.)

Objectives: To compare the classification of preterm postnatal poor growth using healthy preterm vs fetal growth references and to examine associations with neurodevelopmental impairment in infancy and childhood., Study Design: We included 613 infants born at <33 weeks of gestation. Using the INTERGROWTH-21 st (healthy-preterm growth) reference and the Fenton and Olsen (fetal growth) references, we classified poor growth as a decline in z-score from birth to term-equivalent >0.8 SD (weight), >1 SD (head), and >2 SD (length). We used generalized estimating equations to estimate aOR for neurodevelopmental impairment at 18 months and 7 years of corrected age, comparing infants with and without poor growth by each reference, accounting for multiple births and covariates., Results: The prevalence of poor growth was higher with INTERGROWTH-21 st than with fetal references for all measurements. Agreement was higher between the Fenton and Olsen (fetal) growth references (0.72-0.81) than between INTERGROWTH-21 st and fetal references (0.41-0.59). Poor growth by fetal references (but not by INTERGROWTH-21 st ) was associated with low neurodevelopmental scores in infancy and childhood. Poor weight gain using the Fenton reference was associated with 18-month Mental Developmental Index <85 (aOR 1.6, 95%CI: 1.1, 2.4) whereas poor weight gain by the INTERGROWTH-21 st reference was not (aOR 1.0, 95%CI: 0.6, 1.7). Poor linear growth by the Olsen reference, but not INTERGROWTH-21 st , was associated with 7-year verbal intelligence quotient <70 (aOR 3.5, 95%CI: 1.1, 12.7)., Conclusions: Poor neonatal growth categorized using fetal references showed stronger associations with long term neurodevelopment than poor growth categorized using the INTERGROWTH-21 st standards., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Background: Preterm infants born 30 to 33 weeks' gestation often require early support with intravenous fluids because of respiratory distress, hypoglycemia or feed intolerance. When full feeds are anticipated to be reached within the first week, risks associated with intravenous delivery mode and type must be carefully considered. Recommendations are for parenteral nutrition to be infused via central venous lines (because of the high osmolarity), however, given the risks associated with central lines, clinicians may opt for 10% glucose via peripheral venous catheter when the need is short-term. We therefore compare a low osmolarity peripheral intravenous parenteral nutrition (P-PN) solution with peripheral intravenous 10% glucose on growth rate in preterm infants born 30 to 33 weeks' gestation., Methods: In this parallel group, single centre, superiority, non-blinded, randomised controlled trial, 92 (P-PN 42, control 50) infants born 30 + 0 to 33 + 6 weeks' gestation, were randomised within 24 h of age, to receive either P-PN (8% glucose, 30 g/L amino acids, 500 IU/L heparin and SMOFlipid®) or a control of peripheral intravenous 10% glucose. Both groups received enteral feeds according to hospital protocol. The primary outcome was rate of weight gain from birth to 21 days of age., Results: The rate of weight gain was significantly increased in P-PN infants compared with control (P-PN, n = 42, 18.7, SD 6.6 g/d vs control, n = 50, 14.8, SD 6.0 g/d; adjusted mean difference 3.9 g/d, 95% CI 1.3 to 6.6; P = 0.004), with the effect maintained to discharge home. Days to regain birthweight were significantly reduced and length gain significantly increased in P-PN infants. One infant in the P-PN group had a stage 3 extravasation which rapidly resolved. Blood urea nitrogen and triglyceride levels were significantly higher in the P-PN group in the first week of life, but there were no instances of abnormally high levels. There were no significant differences in any other clinical or biochemical outcomes., Conclusion: P-PN improves the rate of weight gain to discharge home in preterm infants born 30 to 33 weeks gestation compared with peripheral intravenous 10% glucose., Trial Registration: Australian New Zealand Clinical Trials Registry ACTRN12616000925448 . Registered 12 July 2016.

Aim: This study sought to establish research priorities in human milk banking and use of pasteurised donor human milk. It aimed to (i) collaborate with national stakeholders, including parents of preterm infants, human milk donors and health-care professionals, to identify evidence uncertainties and (ii) agree by consensus on a consolidated prioritised list of research questions., Methods: A consensus approach modelled on the James Lind Alliance was used. A steering group was formed, and key stakeholder organisations identified. Evidence uncertainties were gathered through an online survey and literature search. An iterative process was used to consolidate and rank questions. A final workshop was held to identify the top 10 research priorities., Results: A total of 391 evidence uncertainties were gathered from 202 respondents (38% parents of preterm infants/milk donors, 50% health-care professionals, 12% who identified as both a parent of preterm and health professional) and a further 15 were identified from literature. The steering group consolidated these to 39 evidence uncertainties, which were ranked via another survey. The top 24 questions were workshopped by 13 participants (four parents and nine clinicians) to determine the top 10 research priorities. These included the risks and benefits of using donor milk, optimum techniques for processing and the effects of these on the properties of milk, the nutrient profile of the milk and clinical criteria for prioritising receipt of milk., Conclusion: The top 10 research priorities in human milk banking and use of donor milk were identified and can be used to guide researchers., (© 2019 Paediatrics and Child Health Division (The Royal Australasian College of Physicians).)

Objective: Oxylipins are biologically active signaling molecules that initiate and resolve inflammation; they are synthesized by oxidation of polyunsaturated fatty acids (PUFAs) and reflect PUFA intake and status. The PUFA intake in preterm infants differs between countries because of the type of lipid emulsions used and the PUFA content of breast milk. We compared total blood PUFA, free PUFA and their oxylipin levels in dried whole blood samples from preterm infants born in Australia and Japan., Methods: We enrolled 30 and 14 preterm infants born less than 31 weeks' gestation, from Adelaide and Japan respectively. Blood samples were obtained from cord blood, and on postnatal days 4, 7, 14 and 28. Total PUFAs were measured using gas chromatography, while free fatty acids and oxylipins were screened using ultra high-performance liquid chromatography mass spectroscopy., Results: Differences in the levels of blood PUFA between the centres were found which were in line with the timing and type of lipid emulsion administration. Significant differences in longitudinal levels were seen more often in free PUFA and their oxylipins than in total blood PUFA. This was particularly true for AA and DHA. In contrast, differences in the levels could be seen in total blood EPA, as well as in free EPA and its oxylipins. Further, levels of many free PUFA and their oxylipins were higher in Japanese infants than in Australian infants., Conclusion: Differences in total and free fatty acids and unesterified oxylipins, were observed during the first weeks of life and between preterm infants born in Australia and Japan, which were likely a reflection of the type of lipid emulsion and timing of administration. The clinical significance of these changes remains to be explored., Competing Interests: Declaration of Competing Interest RAG served on the Fonterra Scientific Advisory Board (to September 2018), honorarium was paid to support travel and consulting time. In addition, RAG has a patent 'Stabilising and analysing Fatty Acids in a biological sample stored on solid media' licensed to Adelaide Research and Innovation, University of Adelaide. Other authors have no conflicts of interest to declare., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Growth patterns are known to differ between breastfed and formula-fed infants, but little is known about the relative impact of maternal smoking in pregnancy v. feeding mode on growth trajectory in infancy. We conducted a secondary analysis of a trial, the Tolerance of Infant Goat Milk Formula and Growth Assessment trial involving 290 healthy infants, to examine whether smoking in pregnancy modified the association between feeding mode and body composition of infants. Fat mass (FM) and fat-free mass (FFM) were estimated at 1, 2, 3, 4, 6 and 12 months of age using bioimpedance spectroscopy. Formula-fed infants (n 190) had a higher mean FFM at 4 months (mean difference (MD) 160 g, 95 % CI 50·4, 269·5 g, P < 0·05)) and 6 months (MD 179 g, 95 % CI 41·5, 316·9 g, P < 0·05) compared with the breastfed infants (n 100). Sub-group analysis of breastfed v. formula-fed infants by maternal smoking status in pregnancy showed that there were no differences in the FM and FFM between the breastfed and formula-fed infants whose mothers did not smoke in pregnancy. Formula-fed infants whose mothers smoked in pregnancy were smaller at birth and had a lower FM% and higher FFM% at 1 month compared with infants of non-smoking mothers regardless of feeding mode, but the differences were not significant at other time points. Adequately powered prospective studies with an appropriate design are warranted to better understand the relative impact of maternal smoking, feeding practice and the growth trajectory of infants.