Child development education in the Neonatal Unit: Understanding parent developmental literacy needs, priorities and preferences.

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.

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

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 Parents of surviving children who had not withdrawn from the original trial were invited to complete questionnaires when the child turned 5 years' corrected age.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

Study protocol of the WashT Trial: transfusion with washed versus unwashed red blood cells to reduce morbidity and mortality in infants born less than 28 weeks' gestation - a multicentre, blinded, parallel group, randomised controlled trial.

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.

Enteral supplementation with high-dose docosahexaenoic acid on the risk of bronchopulmonary dysplasia in very preterm infants: a collaborative study protocol for an individual participant data meta-analysis.

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.

Mediation Analysis to Untangle Opposing Associations of High-Dose Docosahexaenoic Acid With IQ and Bronchopulmonary Dysplasia in Children Born Preterm.

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.

Growth of late preterm infants fed nutrient-enriched formula to 120 days corrected age-A randomized controlled trial.

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.

Variable preterm oral microbiome stabilizes and reflects a full-term infant profile within three months.

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.

Effect of Docosahexaenoic Acid (DHA) Supplementation of Preterm Infants on Growth, Body Composition, and Blood Pressure at 7-Years Corrected Age: Follow-Up of a Randomized Controlled Trial.

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.

Neonatal Docosahexaenoic Acid in Preterm Infants and Intelligence at 5 Years.

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.).

Breastfeeding outcomes in late preterm infants: A multi-centre prospective cohort study.

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.

Associations of Maternal Milk Feeding With Neurodevelopmental Outcomes at 7 Years of Age in Former Preterm Infants.

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.

Parent concerns for child development following admission to neonatal intensive or special care: From birth to adolescence.

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.

Diathesis-stress or differential susceptibility? Comparing the theories when determining the outcomes for children born before 33 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.

Early versus delayed introduction of human milk fortification in enterally fed preterm infants: A systematic review and meta-analysis.

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.

Avoidance of bottles during the establishment of breastfeeds in preterm infants.

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.

Consequences of using chronological age versus corrected age when testing cognitive and motor development in infancy and intelligence quotient at school age for children born preterm.

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.

A Systematic Review and Meta-Analysis of Human Milk Feeding and Short-Term Growth in Preterm and Very Low Birth Weight Infants.

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.

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

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

Protocol for assessing whether cognition of preterm infants <29 weeks' gestation can be improved by an intervention with the omega-3 long-chain polyunsaturated fatty acid docosahexaenoic acid (DHA): a follow-up of a randomised controlled trial.

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.

The Role of Long-Chain Polyunsaturated Fatty Acids in Very Preterm Nutrition.

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.