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.).

Cortical growth from infancy to adolescence in preterm and term-born children.

Early life experiences can exert a significant influence on cortical and cognitive development. Very preterm birth exposes infants to several adverse environmental factors during hospital admission, which affect cortical architecture. However, the subsequent consequence of very preterm birth on cortical growth from infancy to adolescence has never been defined; despite knowledge of critical periods during childhood for establishment of cortical networks. Our aims were to: chart typical longitudinal cortical development and sex differences in cortical development from birth to adolescence in healthy term-born children; estimate differences in cortical development between children born at term and very preterm; and estimate differences in cortical development between children with normal and impaired cognition in adolescence. This longitudinal cohort study included children born at term (≥37 weeks' gestation) and very preterm (<30 weeks' gestation) with MRI scans at ages 0, 7 and 13 years (n = 66 term-born participants comprising 34 with one scan, 18 with two scans and 14 with three scans; n = 201 very preterm participants comprising 56 with one scan, 88 with two scans and 57 with three scans). Cognitive assessments were performed at age 13 years. Cortical surface reconstruction and parcellation were performed with state-of-the-art, equivalent MRI analysis pipelines for all time points, resulting in longitudinal cortical volume, surface area and thickness measurements for 62 cortical regions. Developmental trajectories for each region were modelled in term-born children, contrasted between children born at term and very preterm, and contrasted between all children with normal and impaired cognition. In typically developing term-born children, we documented anticipated patterns of rapidly increasing cortical volume, area and thickness in early childhood, followed by more subtle changes in later childhood, with smaller cortical size in females than males. In contrast, children born very preterm exhibited increasingly reduced cortical volumes, relative to term-born children, particularly during ages 0-7 years in temporal cortical regions. This reduction in cortical volume in children born very preterm was largely driven by increasingly reduced cortical thickness rather than area. This resulted in amplified cortical volume and thickness reductions by age 13 years in individuals born very preterm. Alterations in cortical thickness development were found in children with impaired language and memory. This study shows that the neurobiological impact of very preterm birth on cortical growth is amplified from infancy to adolescence. These data further inform the long-lasting impact on cortical development from very preterm birth, providing broader insights into neurodevelopmental consequences of early life experiences.

Relationships of Severity of Bronchopulmonary Dysplasia with Adverse Neurodevelopmental Outcomes and Poor Respiratory Function at 7-8 Years of Age.

OBJECTIVE: To clarify the relationships of 3 definitions of severity of bronchopulmonary dysplasia (BPD) with adverse neurodevelopmental and respiratory outcomes at early school-age. STUDY DESIGN: Participants comprised 218 consecutive survivors to 7-8 years of age born either <28 weeks' gestation or weighing <1000 g in Victoria, Australia, in 2005. BPD was classified as none, grade 1 (mild), grade 2 (moderate), or grade 3 (severe), using 2 commonly accepted definitions: 1) Jobe2001, and 2) Higgins2018, and our own 3) Victorian Infant Collaborative Study (VICS) 2005, adapted from Jensen2019. Outcomes included major neurodevelopmental disability, low IQ and academic achievement, poor motor function, and poor respiratory function as assessed by spirometry. Outcomes for children with each grade of BPD were compared with children with no BPD. RESULTS: Of the 218 survivors, 132 (61%) had BPD on Jobe2001 criteria, and 113 (52%) had BPD on both Higgins2018 and VICS2005 criteria. Grade 1 on any criteria was not associated with any adverse neurodevelopmental outcomes. Grade 1 on both Higgins2018 and VICS2005 was associated with reduced spirometry, grade 2 on both Higgins2018 and VICS2005, and grade 3 on all criteria were associated with increased risk for both adverse neurodevelopmental and respiratory outcomes. CONCLUSIONS: Compared with no BPD, receiving additional oxygen up to 29% but no positive pressure support at 36 weeks' postmenstrual age increased the risk of abnormal respiratory function but not adverse neurodevelopment. Receiving ≥30% oxygen or any positive pressure support at 36 weeks increased the risk of both adverse outcomes.

Early Hyperoxemia and 2-year Outcomes in Infants with Hypoxic-ischemic Encephalopathy: A Secondary Analysis of the Infant Cooling Evaluation Trial.

OBJECTIVE: To determine the causal relationship between exposure to early hyperoxemia and death or major disability in infants with hypoxic-ischemic encephalopathy (HIE). STUDY DESIGN: We analyzed data from the Infant Cooling Evaluation (ICE) trial that enrolled newborns ≥35 weeks' gestation with moderate-severe HIE, randomly allocated to hypothermia or normothermia. The primary outcome was death or major sensorineural disability at 2 years. We included infants with arterial pO2 measured within 2 hours of birth. Using a directed acyclic graph, we established that markers of severity of perinatal hypoxia-ischemia and pCO2 were a minimally sufficient set of variables for adjustment in a regression model to estimate the causal relationship between arterial pO2 and death/disability. RESULTS: Among 221 infants, 116 (56%) had arterial pO2 and primary outcome data. The unadjusted analysis revealed a U-shaped relationship between arterial pO2 and death or major disability. Among hyperoxemic infants (pO2 100-500 mmHg) the proportion with death or major disability was 40/58 (0.69), while the proportion in normoxemic infants (pO2 40-99 mmHg) was 20/48 (0.42). In the adjusted model, hyperoxemia increased the risk of death or major disability (adjusted risk ratio 1.61, 95% CI 1.07-2.00, P = .03) in relation to normoxemia. CONCLUSION: Early hyperoxemia increased the risk of death or major disability among infants who had an early arterial pO2 in the ICE trial. Limitations include the possibility of residual confounding and other causal biases. Further work is warranted to confirm this relationship in the era of routine therapeutic hypothermia.

The Knowledge Translation of Early Cerebral Palsy (KiTE CP) Study: Implementing Screening Among a High-Risk Prospective Cohort of Australian Infants.

OBJECTIVE: To describe the implementation of the international guidelines for the early diagnosis of cerebral palsy (CP) and engagement in the screening process in an Australian cohort of infants with neonatal risk factors for CP. STUDY DESIGN: Prospective cohort study of infants with neonatal risk factors recruited at <6 months corrected age from 11 sites in the states of Victoria, New South Wales, and Queensland, Australia. First, we implemented a multimodal knowledge translation strategy including barrier identification, technology integration, and special interest groups. Screening was implemented as follows: infants with clinical indications for neuroimaging underwent magnetic resonance imaging and/or cranial ultrasound. The Prechtl General Movements Assessment (GMA) was recorded clinically or using an app (Baby Moves). Infants with absent or abnormal fidgety movements on GMA videos were offered further assessment using the Hammersmith Infant Neurological Examination (HINE). Infants with atypical findings on 2/3 assessments met criteria for high risk of CP. RESULTS: Of the 597 infants (56% male) recruited, 95% (n = 565) received neuroimaging, 90% (n = 537) had scorable GMA videos (2% unscorable/8% no video), and 25% (n = 149) HINE. Overall, 19% of the cohort (n = 114/597) met criteria for high risk of CP, 57% (340/597) had at least 2 normal assessments (of neuroimaging, GMA or HINE), and 24% (n = 143/597) had insufficient assessments. CONCLUSIONS: Early CP screening was implemented across participating sites using a multimodal knowledge translation strategy. Although the COVID-19 pandemic affected recruitment rates, there was high engagement in the screening process. Reasons for engagement in early screening from parents and clinicians warrant further contextualization and investigation.

School-age outcomes among IVF-conceived children: A population-wide cohort study.

BACKGROUND: In vitro fertilisation (IVF) is a common mode of conception. Understanding the long-term implications for these children is important. The aim of this study was to determine the causal effect of IVF conception on primary school-age childhood developmental and educational outcomes, compared with outcomes following spontaneous conception. METHODS AND FINDINGS: Causal inference methods were used to analyse observational data in a way that emulates a target randomised clinical trial. The study cohort comprised statewide linked maternal and childhood administrative data. Participants included singleton infants conceived spontaneously or via IVF, born in Victoria, Australia between 2005 and 2014 and who had school-age developmental and educational outcomes assessed. The exposure examined was conception via IVF, with spontaneous conception the control condition. Two outcome measures were assessed. The first, childhood developmental vulnerability at school entry (age 4 to 6), was assessed using the Australian Early Developmental Census (AEDC) (n = 173,200) and defined as scoring <10th percentile in ≥2/5 developmental domains (physical health and wellbeing, social competence, emotional maturity, language and cognitive skills, communication skills, and general knowledge). The second, educational outcome at age 7 to 9, was assessed using National Assessment Program-Literacy and Numeracy (NAPLAN) data (n = 342,311) and defined by overall z-score across 5 domains (grammar and punctuation, reading, writing, spelling, and numeracy). Inverse probability weighting with regression adjustment was used to estimate population average causal effects. The study included 412,713 children across the 2 outcome cohorts. Linked records were available for 4,697 IVF-conceived cases and 168,503 controls for AEDC, and 8,976 cases and 333,335 controls for NAPLAN. There was no causal effect of IVF-conception on the risk of developmental vulnerability at school-entry compared with spontaneously conceived children (AEDC metrics), with an adjusted risk difference of -0.3% (95% CI -3.7% to 3.1%) and an adjusted risk ratio of 0.97 (95% CI 0.77 to 1.25). At age 7 to 9 years, there was no causal effect of IVF-conception on the NAPLAN overall z-score, with an adjusted mean difference of 0.030 (95% CI -0.018 to 0.077) between IVF- and spontaneously conceived children. The models were adjusted for sex at birth, age at assessment, language background other than English, socioeconomic status, maternal age, parity, and education. Study limitations included the use of observational data, the potential for unmeasured confounding, the presence of missing data, and the necessary restriction of the cohort to children attending school. CONCLUSIONS: In this analysis, under the given causal assumptions, the school-age developmental and educational outcomes for children conceived by IVF are equivalent to those of spontaneously conceived children. These findings provide important reassurance for current and prospective parents and for clinicians.

Bronchopulmonary dysplasia and expiratory airflow at 8 years in children born extremely preterm in the post-surfactant era.

BACKGROUND: It is unclear if bronchopulmonary dysplasia (BPD) is independently associated with reduced expiratory airflow at school age. OBJECTIVE: To determine the independent associations of moderate-severe BPD, mild BPD, gestational age and birth weight z-score with expiratory airflow in children born extremely preterm (EP; <28 weeks' gestation). METHODS: All EP survivors born in Victoria, Australia, in three eras (1991-1992, n=225; 1997, n=151; and 2005, n=170) were recruited at birth and 418/546 (77%) had valid spirometry data at 8 years. BPD was classified as moderate-severe (oxygen requirement at 36 weeks' postmenstrual age), or mild (oxygen >28 days but not at 36 weeks' postmenstrual age). Expiratory airflow variables, including the forced expired volume in 1 s (FEV1), were measured and values converted to z-scores. RESULTS: Compared with no BPD (n=94), moderate-severe BPD (n=193) was associated with a substantial reduction in expiratory airflow (eg, zFEV1 mean difference -0.69, 95% CI -0.97 to -0.41; p<0.001), but mild BPD (n=131) was not (zFEV1 mean difference 0.01, 95% CI -0.28 to 0.31; p=0.93). On multivariable analysis, moderate-severe BPD remained strongly associated with reduced airflow (zFEV1 mean difference -0.63, 95% CI -0.92 to -0.33; p<0.001), but mild BPD (zFEV1 mean difference 0.04, 95% CI -0.26 to 0.34; p=0.27), gestational age (zFEV1 0.06 mean increase per week, 95% CI -0.05 to 0.17; p=0.29) and birth weight z-score (zFEV1 0.07 mean increase per SD, 95% CI -0.06 to 0.20; p=0.28) were not. CONCLUSIONS: In children born EP, moderate-severe BPD, but not mild BPD was independently associated with reduced expiratory airflow at 8 years.

Mental health in young adults born extremely preterm or extremely low birthweight with contemporary neonatal intensive care.

BACKGROUND: For infants born in the contemporary era of neonatal care, little is known about adult mental health outcomes of extremely preterm birth (EP; <28 weeks' gestation) or extremely low birthweight (ELBW; <1000 g). This study aimed to compare attention deficit hyperactivity disorder (ADHD), anxiety, mood, and substance use disorder prevalence in young adults born EP/ELBW and normal birthweight (NBW; >2499 g) controls, and to compare change in prevalence of mental health symptoms and disorders from 18 to 25 years. METHODS: Participants were a prospective geographical cohort of 297 consecutive survivors born EP/ELBW during 1991-1992 and 260 NBW controls. At age 25 years, 174 EP/ELBW and 139 NBW participants completed the Adult ADHD Rating Scale, Structured Clinical Interview for DSM-IV Disorders, Beck Anxiety Inventory, and Center for Epidemiologic Studies Depression Scale-Revised. Data from follow-up at 18 years were also utilized. Multiple imputation was used to account for attrition. RESULTS: Mental health outcomes at 25 years were similar between groups: prevalence rates were ADHD 7% v. 5%; anxiety 32% v. 27%; mood 38% v. 35%; substance use 12% v. 14% in the EP/ELBW and NBW groups, respectively. In both groups, ADHD declined between 18 and 25 years [odds ratio (OR) per year = 0.87, 95% confidence interval (CI) 0.79-0.95], and generalized anxiety disorder and major depressive episode became more common (OR 1.22, 95% CI 1.10-1.35 per year; OR 1.20, 95% CI 1.10-1.30 respectively). CONCLUSIONS: This contemporary EP/ELBW cohort has comparable young adult mental health outcomes to controls, and similar patterns of change in mental health from late adolescence.

Growth of prefrontal and limbic brain regions and anxiety disorders in children born very preterm.

BACKGROUND: Children born very preterm (VP) display altered growth in corticolimbic structures compared with full-term peers. Given the association between the cortiocolimbic system and anxiety, this study aimed to compare developmental trajectories of corticolimbic regions in VP children with and without anxiety diagnosis at 13 years. METHODS: MRI data from 124 VP children were used to calculate whole brain and corticolimbic region volumes at term-equivalent age (TEA), 7 and 13 years. The presence of an anxiety disorder was assessed at 13 years using a structured clinical interview. RESULTS: VP children who met criteria for an anxiety disorder at 13 years (n = 16) displayed altered trajectories for intracranial volume (ICV, p < 0.0001), total brain volume (TBV, p = 0.029), the right amygdala (p = 0.0009) and left hippocampus (p = 0.029) compared with VP children without anxiety (n = 108), with trends in the right hippocampus (p = 0.062) and left medial orbitofrontal cortex (p = 0.079). Altered trajectories predominantly reflected slower growth in early childhood (0-7 years) for ICV (ß = -0.461, p = 0.020), TBV (ß = -0.503, p = 0.021), left (ß = -0.518, p = 0.020) and right hippocampi (ß = -0.469, p = 0.020) and left medial orbitofrontal cortex (ß = -0.761, p = 0.020) and did not persist after adjusting for TBV and social risk. CONCLUSIONS: Region- and time-specific alterations in the development of the corticolimbic system in children born VP may help to explain an increase in anxiety disorders observed in this population.

Long-term cardiovascular consequences of adolescent anorexia nervosa.

BACKGROUND: Anorexia nervosa (AN) is associated with maladaptive cardiovascular changes. This study investigated whether individuals who recovered from AN during adolescence experience long-term cardiovascular risk in early adulthood. METHODS: Former AN patients discharged from the Royal Children's and Monash Children's Hospital Eating Disorder Services in Melbourne, Australia underwent cardiovascular testing. Measurements were performed using an oscillometric device for blood pressure and pulse wave velocity, ultrasound for carotid wall structure/function, resting electrocardiogram for heart-rate variability, and the EndoPat 2000 (Itamar) system for endothelial function. Patient measures were compared to healthy controls and/or normal thresholds. RESULTS: Ninety-one percent of the former AN patients (N = 22) and controls (N = 66) were female, aged approximately 25 years, with a healthy body mass index. The mean time interval from AN recovery to participation was 7.4 years. Pulse wave velocity was lower in the former AN patients than controls. Carotid intima-media thickness was not different; however, carotid distensibility and compliance were lower, and the elastic modulus higher in the former AN patients. Greater vagal tone was observed and endothelial dysfunction was evident in 46% of the former patients. CONCLUSIONS: Young adults who recovered from adolescent AN exhibit persistent cardiovascular adaptations. Routine cardiovascular monitoring could manage potential disease risk. IMPACT: Cardiovascular complications are common in patients with anorexia nervosa (AN) and population studies have revealed that developmental adaptations in response to undernutrition have long-term consequences for cardiovascular health. In this study of young adults treated for AN during adolescence, there was evidence of increased carotid artery stiffness, reduced aortic stiffness, vagal hyperactivity, and endothelial dysfunction in early adulthood when compared to healthy controls. It is important to consider the cardiovascular health of patients with AN beyond achieving medical stability. Interventions that monitor cardiovascular health could minimise the burden of future cardiovascular disease.

ADHD symptoms and diagnosis in adult preterms: systematic review, IPD meta-analysis, and register-linkage study.

BACKGROUND: This study examined differences in ADHD symptoms and diagnosis between preterm and term-born adults (≥18 years), and tested if ADHD is related to gestational age, birth weight, multiple births, or neonatal complications in preterm borns. METHODS: (1) A systematic review compared ADHD symptom self-reports and diagnosis between preterm and term-born adults published in PubMed, Web of Science, and PROQUEST until April 2021; (2) a one-stage Individual Participant Data(IPD) meta-analysis (n = 1385 preterm, n = 1633 term; born 1978-1995) examined differences in self-reported ADHD symptoms[age 18-36 years]; and (3) a population-based register-linkage study of all live births in Finland (01/01/1987-31/12/1998; n = 37538 preterm, n = 691,616 term) examined ADHD diagnosis risk in adulthood (≥18 years) until 31/12/2016. RESULTS: Systematic review results were conflicting. In the IPD meta-analysis, ADHD symptoms levels were similar across groups (mean z-score difference 0.00;95% confidence interval [95% CI] -0.07, 0.07). Whereas in the register-linkage study, adults born preterm had a higher relative risk (RR) for ADHD diagnosis compared to term controls (RR = 1.26, 95% CI 1.12, 1.41, p < 0.001). Among preterms, as gestation length (RR = 0.93, 95% CI 0.89, 0.97, p < 0.001) and SD birth weight z-score (RR = 0.88, 95% CI 0.80, 0.97, p < 0.001) increased, ADHD risk decreased. CONCLUSIONS: While preterm adults may not report higher levels of ADHD symptoms, their risk of ADHD diagnosis in adulthood is higher. IMPACT: Preterm-born adults do not self-report higher levels of ADHD symptoms, yet are more likely to receive an ADHD diagnosis in adulthood compared to term-borns. Previous evidence has consisted of limited sample sizes of adults and used different methods with inconsistent findings. This study assessed adult self-reported symptoms across 8 harmonized cohorts and contrasted the findings with diagnosed ADHD in a population-based register-linkage study. Preterm-born adults may not self-report increased ADHD symptoms. However, they have a higher risk of ADHD diagnosis, warranting preventive strategies and interventions to reduce the presentation of more severe ADHD symptomatology in adulthood.

Motor performance and attention outcomes in children born very preterm.

AIM: To examine the relationship between motor performance and attention in children born very preterm and at term, and investigate the presence of individual profiles of motor and attention performance. METHOD: Attention and motor performance at 7 and 13 years were assessed in 197 children born very preterm (52.5% male) and 69 children born at term (47.8% male) between 2001 and 2003. Linear regression models were fitted including an interaction term for birth group. Subgroups of children with similar attention and motor performance profiles were identified using latent profile analysis. RESULTS: Balance was positively associated with all attention outcomes at both ages (p < 0.006). There were specific birth group interactions for aiming and catching and manual dexterity with attention at 13 years, with positive associations observed only for children born very preterm (p < 0.001). At 7 years, three profiles were observed: average attention and motor functioning; average motor functioning and low attention functioning; and low attention and motor functioning. At 13 years, two profiles of average attention and motor functioning emerged, as well as one profile of below-average attention and motor functioning. Children born very preterm were overrepresented in the lower functioning profiles (born very preterm 56%; born at term 29%). INTERPRETATION: Motor functioning at age 7 years may be a useful marker of later attention skills, particularly for children born very preterm who are at greater risk of poorer long-term cognitive outcomes. WHAT THIS PAPER ADDS: Balance was positively associated with attention in children born very preterm and at term. Relationships between motor performance and attention at age 13 years differed between children born very preterm and at term. Heterogeneous motor functioning and attention outcomes were noted for children born very preterm and at term. Children born very preterm were more likely to have lower attention and motor functioning profiles than children born at term. There was greater movement in motor functioning and attention profiles between the ages of 7 and 13 years in children born very preterm.

Parental Mental Health and Parenting Behaviors Following Very Preterm Birth: Associations in Mothers and Fathers and Implications for Child Cognitive Outcome.

OBJECTIVES: To investigate the longitudinal associations between parental mental health symptoms within 4 weeks of birth, parenting behaviors at 1 year, and child general cognitive ability at 4.5-5 years in a sample of children born very preterm (VP). This study also examined whether these associations differed based on level of family social risk. METHODS: Participants were 143 children born <30 weeks' gestation and their parents. Within 4 weeks of birth, mothers' and fathers' depressive and anxiety symptoms were assessed using the Center for Epidemiologic Studies Depression Scale and Hospital Anxiety Depression Scale-Anxiety Subscale. Parents' sensitive and structuring parenting behaviors were assessed at 1 year using the Emotional Availability Scales. Child general cognitive ability was assessed at 4.5-5 years using the Wechsler Preschool & Primary Scale of Intelligence-Fourth Edition. RESULTS: Higher maternal depressive symptoms were associated with lower levels of sensitive and structuring parenting behavior, while higher maternal anxiety symptoms were associated with higher levels of structuring parenting behavior. There was weak evidence for positive associations between mothers' sensitive parenting behavior and fathers' structuring parenting behavior and child general cognitive ability. There was also weak evidence for stronger associations between mothers' mental health symptoms, parenting behaviors, and child general cognitive ability, in families of higher compared with lower social risk. CONCLUSIONS: Depressive and anxiety symptoms experienced by mothers in the initial weeks following VP birth can have long-term effects on their parenting behaviors. Enquiring about parents' mental health during their child's hospitalization in the neonatal intensive care unit is crucial.

Comparative evaluation of the health utilities index mark 3 and the short form 6D: evidence from an individual participant data meta-analysis of very preterm and very low birthweight adults.

BACKGROUND: The most appropriate preference-based health-related quality of life (HRQoL) instruments for trials or research studies that ascertain the consequences of individuals born very preterm and/or low birthweight (VP/VLBW) are not known. Agreement between the HUI3 and SF-6D multi-attribute utility measures have not been previously investigated for VP/VLBW and normal birthweight or term-born controls. This study examined the agreement between the outputs of the HUI3 and SF-6D measures among adults born VP/VLBW and normal birthweight or term born controls. METHODS: We used two prospective cohorts of individuals born VP/VLBW and controls contributing to the 'Research on European Children and Adults Born Preterm' (RECAP) consortium which assessed HRQoL using two preference-based measures. The combined dataset of individual participant data (IPD) included 407 adult VP/VLBW survivors and 367 controls, ranging in age from 18 to 26 years. Bland-Altman plots, intra-class correlation coefficients, and generalized linear mixed models in a one-step approach were used to examine agreement between the measures. RESULTS: There was significant discordance between the HUI3 and SF-6D multi-attribute utility measures in the VP/VLBW sample, controls, and in the combined samples. Agreement between the HUI3 and SF-6D multi-attribute utility measures was weaker in controls compared with VP/VLBW individuals. CONCLUSIONS AND RELEVANCE: The HUI3 and SF-6D each provide unique information on different aspects of health status across the groups. The HUI3 better captures preterm-related changes to HRQoL in adulthood compared to SF-6D. Studies focused on measuring physical or cognitive aspects of health will likely benefit from using the HUI3 instead of the SF-6D, regardless of gestational age at birth and birthweight status.

A prospective, longitudinal, case-control study to evaluate the neurodevelopment of children from birth to adolescence exposed to COVID-19 in utero.

BACKGROUND: The Coronavirus disease (COVID-19) pandemic has created unprecedented acute global health challenges. However, it also presents a set of unquantified and poorly understood risks in the medium to long term, specifically, risks to children whose mothers were infected with the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) during pregnancy. Infections during pregnancy can increase the risk of atypical neurodevelopment in the offspring, but the long-term neurodevelopmental impact of in utero COVID-19 exposure is unknown. Prospective, longitudinal studies are needed to evaluate children exposed in utero to SARS-CoV2 to define this risk. METHODS: We have designed a prospective, case-controlled study to investigate the long-term impacts of SARS-CoV2 exposure on children exposed in utero. Women infected with SARS-CoV-2 during pregnancy will be recruited from Monash Health, the Royal Women's Hospital and Western Health (Melbourne, Australia) and Londrina Municipal Maternity Hospital Lucilla Ballalai and PUCPR Medical Clinical (Londrina, Brazil). A control group in a 2:1 ratio (2 non-exposed: 1 exposed mother infant dyad) comprising women who gave birth in the same month of delivery, are of similar age but did not contract SARS-CoV-2 during their pregnancy will also be recruited. We aim to recruit 170 exposed and 340 non-exposed mother-infant dyads. Clinical and socio-demographic data will be collected directly from the mother and medical records. Biospecimens and clinical and epidemiological data will be collected from the mothers and offspring at multiple time points from birth through to 15 years of age using standardised sample collection, and neurological and behavioural measures. DISCUSSION: The mapped neurodevelopmental trajectories and comparisons between SARS-CoV-2 exposed and control children will indicate the potential for an increase in atypical neurodevelopment. This has significant implications for strategic planning in the mental health and paediatrics sectors and long-term monitoring of children globally.

Postnatal corticosteroids and developmental outcomes in extremely preterm or extremely low birth weight infants: The Victorian Infant Collaborative Study 2016-17 cohort.

AIM: Systemic postnatal corticosteroids are used to treat or prevent bronchopulmonary dysplasia (BPD) in extremely preterm (EP) or extremely low birth weight (ELBW) infants but are associated with long-term harm. We aimed to assess the relationship between cumulative postnatal corticosteroid dose and neurodevelopmental outcomes. METHODS: Longitudinal cohort study of all EP/ELBW livebirths in Victoria, Australia 2016-2017. Perinatal data were collected prospectively. Neurodevelopmental assessment was performed at 2 years' corrected age. Linear and logistic regression were used to determine relationships between cumulative corticosteroid dose and neurodevelopment, adjusted for gestational age, birth weight, sex and major intraventricular haemorrhage. RESULTS: Seventy-six EP/ELBW infants received postnatal corticosteroids to treat or prevent BPD, 62/65 survivors were seen at 2 years. Median (IQR) cumulative postnatal corticosteroid dose was 1.36 (0.92-3.45) mg/kg dexamethasone equivalent. Higher cumulative corticosteroid dose was associated with increased odds of cerebral palsy, adjusted OR (95% CI) 1.47 (1.04, 2.07). Higher cumulative corticosteroid dose was also associated with lower cognitive and motor developmental scores, however, this weakened after adjustment for confounding variables: cognitive composite score adjusted coefficient (95% CI) -1.3 (-2.7, 0.1) and motor composite score adjusted coefficient (95% CI) -1.3 (-2.8, 0.2). CONCLUSION: Higher cumulative postnatal corticosteroid dose in EP/ELBW infants is associated with increased odds of cerebral palsy at 2 years' corrected age. Adequately powered studies are needed to assess the independent effects of cumulative steroid dose on neurodevelopmental outcomes.

Be Sweet to Babies: Consumer Evaluation of a Parent-Targeted Video Aimed at Improving Pain Management Strategies in Newborn Infants Undergoing Painful Procedures.

BACKGROUND: Evidence for analgesic effects of parent-led pain management strategies during painful procedures in newborn infants exists; however, such strategies are inconsistently used in practice. A publicly available parent-targeted video demonstrates breastfeeding, skin-to-skin care, and sucrose during painful procedures. Australian parents' use and knowledge of this video and these strategies was unknown. PURPOSE: To determine parents' use of pain management strategies, and perceived acceptability and usefulness of the parent-targeted video. METHODS: A cross-sectional, online, anonymous survey with embedded video. Participants were recruited via social media channels of the Miracle Babies Foundation, an Australian parent support network. Target participants were parents or family members of infants currently or previously hospitalized in neonatal special and/or intensive care nurseries, or high dependency units. RESULTS: A total of 162 of 189 respondents provided sufficient data for analysis; all identified as mothers. Only 6 (4%) had previously seen the video; however, nearly all rated it as potentially useful and helpful (n = 124, 82%). Although most reported that sucrose had been used (n = 112, 84%), fewer reported having used skin-to-skin care (n = 50, 37%), or breastfeeding (n = 33, 25%). Most intended to advocate for skin-to-skin care (n = 108, 88%) or breastfeeding (n = 100, 81%) in future procedures. Perceived barriers to utilizing strategies included lack of information-sharing and organizational practices that excluded parent involvement. IMPLICATIONS FOR PRACTICE AND RESEARCH: The video may be valuable in supporting mothers to advocate for their involvement during painful procedures in preterm and sick hospitalized infants. Further research is recommended to explore coordinated strategies targeting parents and healthcare professionals to overcome barriers to implementing parent-led infant pain management strategies.

Variation in clinical practice guideline recommendations for medication use in pregnancy in Australia: A systematic review.

BACKGROUND: Medication use in pregnancy is common; however, it is unknown if clinical practice guideline (CPG) prescribing recommendations referred to in Australia at the state, national and international level are consistent. AIMS: This systematic review aimed to: (1) identify sources of CPGs that inform prescribing during pregnancy in Australia; (2) assess CPG quality; and (3) evaluate variation within CPG recommendations for medication use in three common conditions in pregnancy: prophylactic antibiotics following premature rupture of membranes (PROM) at term, antidepressants in pregnancy and metformin in gestational diabetes mellitus (GDM). MATERIALS AND METHODS: A literature search was conducted across PubMed, Scopus and EMBASE databases. Grey literature was identified through publicly available Australian policy statements. Prescribing recommendations for prophylactic antibiotics following PROM at term, antidepressants in pregnancy and metformin in GDM, were compared at the state, national and international levels. CPG quality was assessed using the Appraisal of Guidelines for Research and Evaluation (AGREE II) instrument. RESULTS: We identified 39 CPG sources that inform prescribing during pregnancy in Australia. CPG quality varied between resources. There was minor variation in recommendations for antibiotic prophylaxis in PROM at term. Recommendations regarding metformin use in GDM were also variable, with CPGs either recommending its use as a first-line agent when lifestyle modifications are not effective or when insulin therapy is not practicable. Recommendations for antidepressant use were consistent across CPGs analysed. CONCLUSION: Multiple CPGs exist to inform prescribing during pregnancy in Australia, with variation present within CPG quality and recommendations. These findings offer insight into potential sources of variation in maternal and neonatal health outcomes.

Two-Year Outcomes After Minimally Invasive Surfactant Therapy in Preterm Infants: Follow-Up of the OPTIMIST-A Randomized Clinical Trial.

Importance: The long-term effects of surfactant administration via a thin catheter (minimally invasive surfactant therapy [MIST]) in preterm infants with respiratory distress syndrome remain to be definitively clarified. Objective: To examine the effect of MIST on death or neurodevelopmental disability (NDD) at 2 years' corrected age. Design, Setting, and Participants: Follow-up study of a randomized clinical trial with blinding of clinicians and outcome assessors conducted in 33 tertiary-level neonatal intensive care units in 11 countries. The trial included 486 infants with a gestational age of 25 to 28 weeks supported with continuous positive airway pressure (CPAP). Collection of follow-up data at 2 years' corrected age was completed on December 9, 2022. Interventions: Infants assigned to MIST (n = 242) received exogenous surfactant (200 mg/kg poractant alfa) via a thin catheter; those assigned to the control group (n = 244) received sham treatment. Main Outcomes and Measures: The key secondary outcome of death or moderate to severe NDD was assessed at 2 years' corrected age. Other secondary outcomes included components of this composite outcome, as well as hospitalizations for respiratory illness and parent-reported wheezing or breathing difficulty in the first 2 years. Results: Among the 486 infants randomized, 453 had follow-up data available (median gestation, 27.3 weeks; 228 females [50.3%]); data on the key secondary outcome were available in 434 infants. Death or NDD occurred in 78 infants (36.3%) in the MIST group and 79 (36.1%) in the control group (risk difference, 0% [95% CI, -7.6% to 7.7%]; relative risk [RR], 1.0 [95% CI, 0.81-1.24]); components of this outcome did not differ significantly between groups. Secondary respiratory outcomes favored the MIST group. Hospitalization with respiratory illness occurred in 49 infants (25.1%) in the MIST group vs 78 (38.2%) in the control group (RR, 0.66 [95% CI, 0.54-0.81]) and parent-reported wheezing or breathing difficulty in 73 (40.6%) vs 104 (53.6%), respectively (RR, 0.76 [95% CI, 0.63-0.90]). Conclusions and Relevance: In this follow-up study of a randomized clinical trial of preterm infants with respiratory distress syndrome supported with CPAP, MIST compared with sham treatment did not reduce the incidence of death or NDD by 2 years of age. However, infants who received MIST had lower rates of adverse respiratory outcomes during their first 2 years of life. Trial Registration: anzctr.org.au Identifier: ACTRN12611000916943.

Investigating brain structural maturation in children and adolescents born very preterm using the brain age framework.

Very preterm (VP) birth is associated with an increased risk for later neurodevelopmental and behavioural challenges. Although the neurobiological underpinnings of such challenges continue to be explored, previous studies have reported brain volume and morphology alterations in children and adolescents born VP compared with full-term (FT)-born controls. How these alterations relate to the trajectory of brain maturation, with potential implications for later brain ageing, remains unclear. In this longitudinal study, we investigate the relationship between VP birth and brain development during childhood and adolescence. We construct a normative 'brain age' model to predict age over childhood and adolescence based on measures of brain cortical and subcortical volumes and cortical morphology from structural MRI of a dataset of typically developing children aged 3-21 years (n = 768). Using this model, we examined deviations from normative brain development in a separate dataset of children and adolescents born VP (<30 weeks' gestation) at two timepoints (ages 7 and 13 years) compared with FT-born controls (120 VP and 29 FT children at age 7 years; 140 VP and 47 FT children at age 13 years). Brain age delta (brain-predicted age minus chronological age) was, on average, higher in the VP group at both timepoints compared with controls, however this difference had a small to medium effect size and was not statistically significant. Variance in brain age delta was higher in the VP group compared with controls; this difference was significant at the 13-year timepoint. Within the VP group, there was little evidence of associations between brain age delta and perinatal risk factors or cognitive and motor outcomes. Under the brain age framework, our results may suggest that children and adolescents born VP have similar brain structural developmental trajectories to term-born peers between 7 and 13 years of age.