Romantic and sexual relationships of young adults born very preterm: An individual participant data meta-analysis.

AIM: To compare romantic and sexual relationships between adults born very preterm (VP; <32 weeks of gestation) or with very low birth weight (VLBW; <1500 g) and at term, and to evaluate potential biological and environmental explanatory factors among VP/VLBW participants. METHODS: This individual participant data (IPD) meta-analysis included longitudinal studies assessing romantic and sexual relationships in adults (mean sample age ≥ 18 years) born VP/VLBW compared with term-born controls. Following PRISMA-IPD guidelines, 11 of the 13 identified cohorts provided IPD from 1606 VP/VLBW adults and 1659 term-born controls. IPD meta-analyses were performed using one-stage approach. RESULTS: Individuals born VP/VLBW were less likely to be in a romantic relationship (OR 0.49; 95% CI 0.31-0.76), to be married/cohabiting (OR 0.70, 95% CI 0.53-0.92), or to have had sexual intercourse (OR 0.21, 95% CI 0.09-0.36) than term-born adults. If sexually active, VP/VLBW participants were more likely to experience their first sexual intercourse after the age of 18 years (OR 1.93, 95% CI 1.24-3.01) than term-born adults. Among VP/VLBW adults, males, and those with neurosensory impairment were least likely to experience romantic relationships. CONCLUSIONS: These findings reflect less optimal social functioning and may have implications for socioeconomic and health outcomes of adults born VP/VLBW.

Twenty four-hour blood pressure and cognitive outcomes in adolescents born extremely preterm and at term.

AIM: To explore the impact of blood pressure on cognitive outcomes at 18 years of age in individuals born extremely preterm (<28 weeks' gestation) and at term (≥37 weeks' gestation). METHODS: Prospective longitudinal cohort comprising 136 young adults born extremely preterm and 120 matched term controls born in Victoria, Australia in 1991 and 1992. Using linear regression, we analysed the relationships between 24-h mean ambulatory blood pressure, systolic and diastolic hypertension with cognitive outcomes. RESULTS: For both birth groups combined, higher 24-h mean ambulatory blood pressure and systolic hypertension were associated with similar or worse cognitive outcomes. The strongest relationships were between higher 24-h mean ambulatory blood pressure and systolic hypertension with poorer general intellect, visual learning and visual memory. We found little evidence that relationships between ambulatory blood pressure and cognitive outcomes differed by birth group. CONCLUSION: Higher 24-h mean ambulatory blood pressure and systolic hypertension were associated with poorer cognitive outcomes in individuals born extremely preterm and at term, particularly in general intelligence and visual memory.

Improving accuracy of outcome prediction for infants born extremely preterm using a digital tool: Translating 'NIC-PREDICT' into clinical practice, the first steps.

BACKGROUND: Many clinicians overestimate mortality and disability rates in infants born extremely preterm. We developed a digital tool ('NIC-PREDICT') that predicts infant mortality and survival with and without major disability in infants born 23-27 weeks' gestation. AIMS: To determine if clinicians could use NIC-PREDICT accurately, and if their perceptions of infant outcomes improved after its release in 2021. MATERIALS AND METHODS: Midwives, nurses, obstetricians, neonatologists and paediatricians working in tertiary and non-tertiary hospitals in Victoria were asked to use NIC-PREDICT to estimate three mutually exclusive outcomes: (i) mortality; (ii) survival free of major disability; and (iii) survival with major disability for six different scenarios where a liveborn infant was offered survival-focused care after birth. The proportions who completed the survey (responded to all six scenarios) and the proportions able to provide 100% accurate results for all scenarios were determined. Estimates of the three outcomes were compared with true rates. RESULTS: A total of 85 clinicians responded: 70 (82%) completed the survey, with an overall accuracy of 76%. Overall, predictions of mortality were accurate (mean difference from true value 0.7% (95% confidence interval (CI) -0.7, 2.1) P = 0.33), as were predictions of survival without major disability (mean difference - 0.7 (95% CI -3.0, 1.7) P = 0.58). However, survival with major disability was overestimated by 4.9% ((95% CI 1.7, 8.0) P = 0.003). CONCLUSIONS: Most perinatal clinicians who responded used NIC-PREDICT correctly to estimate expected outcomes in infants born extremely preterm who are offered intensive care. Undue pessimism about survival with major disability remains an ongoing concern.

Brain volume and neurodevelopment at 13 years following sepsis in very preterm infants.

BACKGROUND: Associations of neonatal infection with brain growth and later neurodevelopmental outcomes in very preterm (VP) infants are unclear. This study aimed to assess associations of neonatal sepsis in VP infants with (1) brain growth from term-equivalent age to 13 years; and (2) 13-year brain volume and neurodevelopmental outcomes. METHODS: 224 infants born VP ( < 30 weeks' gestation/<1250 g birthweight) were recruited. Longitudinal brain volumes for 68 cortical and 14 subcortical regions were derived from MRI at term-equivalent, 7 and/or 13 years of age for 216 children (79 with neonatal sepsis and 137 without). 177 children (79%) had neurodevelopmental assessments at age 13. Of these, 63 with neonatal sepsis were compared with 114 without. Brain volumetric growth trajectories across time points were compared between sepsis and no-sepsis groups using mixed effects models. Linear regressions compared brain volume and neurodevelopmental outcome measures at 13 years between sepsis and no sepsis groups. RESULTS: Growth trajectories were similar and there was little evidence for differences in brain volumes or neurodevelopmental domains at age 13 years between those with or without sepsis. CONCLUSIONS: Neonatal sepsis in children born VP does not appear to disrupt subsequent brain development, or to have functional consequences in early adolescence. IMPACT STATEMENT: Neonatal sepsis has been associated with poorer short-term neurodevelopmental outcomes and reduced brain volumes in very preterm infants. This manuscript provides new insights into the long-term brain development and neurodevelopmental outcomes of very preterm-born children who did or did not have neonatal sepsis. We found that regional brain volumes up to 13 years, and neurodevelopmental outcomes at age 13, were similar between those with and without neonatal sepsis. The links between neonatal sepsis and long-term neurodevelopment remain unclear.

Parent screening questionnaires to detect cognitive and language delay at 2 years in high-risk infants: an analysis from the Victorian Infant Collaborative Study 2016-2017 cohort.

OBJECTIVE: To determine the accuracy of two developmental screening questionnaires to detect cognitive or language delay, defined using the Bayley Scales of Infant and Toddler Development-Third Edition (Bayley-III), in children born extremely preterm (EP: <28 weeks' gestation) or extremely low birth weight (ELBW: <1000 g). DESIGN: Prospective cohort study. SETTING: State of Victoria, Australia. PATIENTS: 211 infants born EP/ELBW assessed at 2 years' corrected age (mean 2.2, SD 0.2). MAIN OUTCOME MEASURES: Cognitive and language delay (<-1 SD) on the Bayley-III. The screening questionnaires were the Parent Report of Children's Abilities-Revised (PARCA-R) and the Ages & Stages Questionnaires Third Edition (ASQ-3). RESULTS: The PARCA-R performed better than the ASQ-3, but neither questionnaire had substantial agreement with the Bayley-III to detect cognitive delay; kappa (95% CI): PARCA-R 0.43 (0.23, 0.63); ASQ-3 0.15 (-0.05, 0.35); sensitivity (95% CI): PARCA-R 70% (53%, 84%) ASQ-3 62% (47%, 76%); specificity (95% CI): PARCA-R 73% (60%, 84%) ASQ-3 53% (38%, 68%). When both tools were used in combination (below cut-off on at least one assessment), sensitivity increased to 78% (60%, 91%) but specificity fell to 45% (29%, 62%). Similar trends were noted for language delay on the Bayley-III, although kappa values were better than for cognitive delay. CONCLUSIONS: Neither screening questionnaire identified cognitive delay well, but both were better at identifying language delay. The PARCA-R detects delay on the Bayley-III more accurately than the ASQ-3. Sensitivity for detecting delay is greatest when the PARCA-R and ASQ-3 were used in combination, but resulted in lower specificity.

Updates to the Melbourne Children's Regional Infant Brain Software Package (M-CRIB-S).

The delineation of cortical areas on magnetic resonance images (MRI) is important for understanding the complexities of the developing human brain. The previous version of the Melbourne Children's Regional Infant Brain (M-CRIB-S) (Adamson et al. Scientific Reports, 10(1), 10, 2020) is a software package that performs whole-brain segmentation, cortical surface extraction and parcellation of the neonatal brain. Available cortical parcellation schemes in the M-CRIB-S are the adult-compatible 34- and 31-region per hemisphere Desikan-Killiany (DK) and Desikan-Killiany-Tourville (DKT), respectively. We present a major update to the software package which achieves two aims: 1) to make the voxel-based segmentation outputs derived from the Freesurfer-compatible M-CRIB scheme, and 2) to improve the accuracy of whole-brain segmentation and cortical surface extraction. Cortical surface extraction has been improved with additional steps to improve penetration of the inner surface into thin gyri. The improved cortical surface extraction is shown to increase the robustness of measures such as surface area, cortical thickness, and cortical volume.

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.

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.

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.

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.

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.

Childhood outcomes after maternal antenatal sildenafil treatment for severe early-onset fetal growth restriction: a randomized trial (STRIDER NZAus).

In this follow-up at 2.5 years of children from the STRIDER NZAus Trial (N = 112), in which women with singleton pregnancies affected by severe early fetal growth restriction were randomized to sildenafil citrate 75 mg daily or placebo until 32 weeks, there was no difference between groups in survival without neurosensory impairment, defined as any of cerebral palsy, deafness, blindness, cognitive delay (Bayley III cognition or language score >1 SD below mean) or motor delay: 30/56[54%] vs. 34/56[61%]; aOR = 0.74, 95%CI: 0.31, 1.77. However, children exposed to sildenafil appeared to be more likely to have cognitive delay (13/45[29%] vs. 4/40[10%]; aOR = 3.71, 95% CI: 1.01, 13.63) but less likely to have emotional-behavioural difficulties (2/43[5%] vs. 8/38[21%]; aOR = 0.19, 95%CI: 0.03, 1.00). Conclusion: maternal sildenafil treatment for severe early-onset FGR was not associated with altered survival free of neurosensory impairment at 2.5 years' corrected age.

Transition to Adulthood for Extremely Preterm Survivors.

OBJECTIVE: To compare transition into adulthood of survivors born extremely preterm (EP; <28 weeks' gestation) or extremely low birth weight (ELBW; <1000 g) in the postsurfactant era with term-born controls. METHODS: Prospective longitudinal cohort study of all EP/ELBW survivors born in the State of Victoria, Australia between January 1, 1991 and December 31, 1992 and matched term-born controls. Outcomes include educational attainment, employment, financial status, romantic partnering, living arrangements, parenthood, physical health and mental health, risk-taking behaviors, life satisfaction, and interpersonal relationships at 25 years. RESULTS: Data were available from 165 EP/ELBW and 127 control participants. Overall, there was little evidence for differences between the EP/ELBW and control groups on most comparisons after adjustment for social risk and multiple births. However, compared with controls, the EP/ELBW group was more likely to have their main source of income from government (adjusted odds ratio [aOR] 2.49, 95% confidence interval [CI] 1.21-5.13; P = .01) and to have never moved out of the parental home (aOR 2.13, 95% CI 1.27-3.58; P = .01), and fewer had ever engaged in smoking (aOR 0.52, 95% CI 0.28-0.98; P = .04), binge drinking (aOR 0.41, 95% CI 0.18-0.93; P = .03), or street drugs (aOR 0.56, 95% CI 0.32-0.98; P = .04). CONCLUSIONS: Aside from clinically important differences in main income source, leaving the parental home, and reduced risk-taking behavior, survivors born EP/ELBW in the era since surfactant was introduced are transitioning into adulthood similarly to term-born controls in some areas assessed but not all.

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.

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

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

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.

Study protocol: Generation Victoria (GenV) special care nursery registry.

Introduction: Newborn babies who require admission for specialist care can experience immediate and sometimes lasting impacts. For babies admitted to special care nurseries (SCN), there is no dataset comparable to that of the Australian and New Zealand Neonatal Network (ANZNN), which has helped improve the quality and consistency of neonatal intensive care through standardised data collection. Objectives: We aim to establish a proof-of-concept, Victoria-wide registry of babies admitted to SCN, embedded within the whole-of-Victoria Generation Victoria (GenV) cohort. Methods: This prototype registry is a depth sub-cohort nested within GenV, targeting all babies born in Victoria from Oct-2021 to Oct-2023. Infants admitted to SCN are eligible. The minimum dataset will be harmonised with ANZNN for common constructs but also include SCN-only items, and will cover maternal, antenatal, newborn, respiratory/respiratory support, cardiac, infection, nutrition, feeding, cerebral and other items. As well as the dataset, this protocol outlines the anticipated cohort, timeline for this registry, and how this will serve as a resource for longitudinal research through its integration with the GenV longitudinal cohort and linked datasets. Conclusion: The registry will provide the opportunity to better understand the health and future outcomes of the large and growing cohort of children that require specialist care after birth. The data would generate translatable evidence and could lay the groundwork for a stand-alone ongoing clinical quality registry post-GenV.

Relationship Between Parental Postnatal Distress and 5-Year Mental Health Outcomes of Children Born at <30 Weeks and at Term.

OBJECTIVE: The purpose of this study was to compare mental health symptoms and diagnoses at age 5 years between children born <30 weeks' gestation and their term-born peers and associations with postnatal symptoms of depression and anxiety in their mothers and fathers. METHODS: Parents of children born <30 weeks' gestation (n = 106) and at term (n = 105) completed measures of anxiety and depression symptoms within 4 weeks of birth and questionnaires assessing child socioemotional symptoms and mental health/neurodevelopmental diagnostic criteria at age 5 years. RESULTS: At age 5 years, children born <30 weeks' gestation were more likely to show clinically concerning levels of total difficulties (odds ratio [OR] = 3.97, 95% confidence interval [CI], 1.21-13.05), emotional problems (OR = 3.71, 95% CI, 1.14-12.15), and inattention/hyperactivity problems (OR = 4.34, 95% CI, 1.51-12.47) than term-born peers. They also showed higher rates of mental health/neurodevelopmental diagnoses than their term-born peers (18% vs 9%), although evidence for the group difference was weak ( p = 0.08). Maternal postnatal anxiety and depression symptoms were related to poorer child mental health outcomes in many domains. There was little evidence that paternal postnatal anxiety/depression symptoms were related to child outcomes or that any associations varied by birth group. CONCLUSION: Children born <30 weeks' gestation showed more mental health symptoms than their term-born peers at age 5 years. Maternal postnatal distress was associated with poorer child mental health across both groups, reinforcing the need for early identification and support of mental health distress in the postnatal period to improve longer-term child well-being.

Expiratory airflow at 7-8 years of age in children born extremely low birthweight from 14 years before to 14 years after the introduction of exogenous surfactant.

Background: It is unclear if expiratory airflow in survivors born extremely low birth weight (ELBW; 500-999 g) has improved after the introduction of exogenous surfactant into clinical practice in 1991. The primary aim of this study was to describe the changes in airflow at 7-8 years of age of survivors born ELBW in five discrete cohorts from 14 years before to 14 years after the introduction of exogenous surfactant into clinical practice. Methods: The cohorts comprised consecutive survivors born ELBW in 1977-82 and 1985-87 at the Royal Women's Hospital, Melbourne, and in 1991-92, 1997 and 2005 in the state of Victoria, Australia. Survival rates to 2-years of age for infants born ELBW in the state of Victoria rose from approximately 1-in-4 to 3-in-4 over the time of this study. Expiratory airflow measurements at 7-8 years included the forced expired volume in 1 s (FEV1), converted to z-scores for age, height, sex, and race. Findings: There were 596 ELBW participants with expiratory flow data, 280 (47%) of whom had bronchopulmonary dysplasia (BPD). Overall, there was little change in zFEV1 over the 28-year period (mean change per year; 0.003, 95% CI -0.010, 0.015, P = 0.67). There was, however, evidence of an interaction between BPD and year; zFEV1 in those who had BPD fell over time (mean change per year -0.019, 95% CI -0.037, -0.009, P = 0.035), whereas zFEV1 improved in those who did not have BPD (mean change per year 0.021, 95% CI 0.006, 0.037, P = 0.007). Interpretation: Contrary to recent evidence, expiratory airflow of children born ELBW has not improved with the introduction of surfactant, and may be deteriorating in those who had BPD. Funding: National Health and Medical Research Council (Australia); Victorian Government's Operational Infrastructure Support Program.

Growth from infancy to adulthood and associations with cardiometabolic health in individuals born extremely preterm.

Background: Few studies have tracked growth in children born extremely preterm (EP, <28 weeks' gestation) beyond late adolescence. The relationships between growth parameters (including weight and BMI) through childhood and adolescence with later cardiometabolic health, are unclear in those born EP. We aimed to (i) compare growth from 2 to 25 years between EP and controls; and in the EP group (ii) determine the associations of growth parameters with cardiometabolic health. Methods: Prospective state-wide cohort of all EP livebirths in Victoria, Australia, in 1991-1992 and contemporaneous term-born controls. Z-scores for weight (z-weight), height (z-height) and BMI (z-BMI) at 2, 5, 8, 18 and 25 years, and cardiometabolic health at 25 years (body composition, glucose tolerance, lipid profiles, blood pressure, exercise capacity) were measured. Growth trajectories were compared between groups using mixed models. The relationships between z-BMI changes/year, and being overweight at different ages, with cardiometabolic health were explored using linear regression. Findings: Z-weight and z-BMI were lower in EP than controls, but the gap decreased with age due to a more rapid rate of rise in z-weight and a decrease in z-height in the EP group compared with controls. Greater increases in z-BMI/year in the EP group were associated with poorer cardiometabolic health [coefficient (95% CI) per 0.1 z-BMI increase/year: visceral fat volume (cm3) 217.8 (160.9, 274.7), triglycerides (mmol/L) 0.45 (0.20, 0.71), systolic blood pressure (mmHg) 8.9 (5.8, 12.0), and exercise capacity (BEEP test maximum level -1.2 (-1.7, -0.7)), all p < 0.001]. The association between being overweight with poorer cardiometabolic health strengthened with age. Interpretation: The catch-up in weight and BMI by young adulthood in survivors born EP may not be desirable as it is associated with poorer cardiometabolic health. The associations of being overweight from mid-childhood with poorer cardiometabolic health may provide a window for intervention. Funding: National Health and Medical Research Council of Australia.