Symbiotic symphony: Understanding host-microbiota dialogues in a spatial context.

Modern precision sequencing techniques have established humans as a holobiont that live in symbiosis with the microbiome. Microbes play an active role throughout the life of a human ranging from metabolism and immunity to disease tolerance. Hence, it is of utmost significance to study the eukaryotic host in conjunction with the microbial antigens to obtain a complete picture of the host-microbiome crosstalk. Previous attempts at profiling host-microbiome interactions have been either superficial or been attempted to catalogue eukaryotic transcriptomic profile and microbial communities in isolation. Additionally, the nature of such immune-microbial interactions is not random but spatially organised. Hence, for a holistic clinical understanding of the interplay between hosts and microbiota, it's imperative to concurrently analyze both microbial and host genetic information, ensuring the preservation of their spatial integrity. Capturing these interactions as a snapshot in time at their site of action has the potential to transform our understanding of how microbes impact human health. In examining early-life microbial impacts, the limited presence of communities compels analysis within reduced biomass frameworks. However, with the advent of spatial transcriptomics we can address this challenge and expand our horizons of understanding these interactions in detail. In the long run, simultaneous spatial profiling of host-microbiome dialogues can have enormous clinical implications especially in gaining mechanistic insights into the disease prognosis of localised infections and inflammation. This review addresses the lacunae in host-microbiome research and highlights the importance of profiling them together to map their interactions while preserving their spatial context.

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.

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.

Risk for Congenital Anomalies in Children Conceived With Medically Assisted Fertility Treatment : A Population-Based Cohort Study.

BACKGROUND: More than 2 million children are conceived annually using assisted reproductive technologies (ARTs), with a similar number conceived using ovulation induction and intrauterine insemination (OI/IUI). Previous studies suggest that ART-conceived children are at increased risk for congenital anomalies (CAs). However, the role of underlying infertility in this risk remains unclear, and ART clinical and laboratory practices have changed drastically over time, particularly there has been an increase in intracytoplasmic sperm injection (ICSI) and cryopreservation. OBJECTIVE: To investigate the role of underlying infertility and fertility treatment on CA risks in the first 2 years of life. DESIGN: Propensity score-weighted population-based cohort study. SETTING: New South Wales, Australia. PARTICIPANTS: 851 984 infants (828 099 singletons and 23 885 plural children) delivered between 2009 and 2017. MEASUREMENTS: Adjusted risk difference (aRD) in CAs of infants conceived through fertility treatment compared with 2 naturally conceived (NC) control groups-those with and without a parental history of infertility (NC-infertile and NC-fertile). RESULTS: The overall incidence of CAs was 459 per 10 000 singleton births and 757 per 10 000 plural births. Compared with NC-fertile singleton control infants (n = 747 018), ART-conceived singleton infants (n = 31 256) had an elevated risk for major genitourinary abnormalities (aRD, 19.0 cases per 10 000 births [95% CI, 2.3 to 35.6]); the risk remained unchanged (aRD, 22 cases per 10 000 births [CI, 4.6 to 39.4]) when compared with NC-infertile singleton control infants (n = 36 251) (that is, after accounting for parental infertility), indicating that ART remained an independent risk. After accounting for parental infertility, ICSI in couples without male infertility was associated with an increased risk for major genitourinary abnormalities (aRD, 47.8 cases per 10 000 singleton births [CI, 12.6 to 83.1]). There was some suggestion of increased risk for CAs after fresh embryo transfer, although estimates were imprecise and inconsistent. There were no increased risks for CAs among OI/IUI-conceived infants (n = 13 574). LIMITATIONS: This study measured the risk for CAs only in those children who were born at or after 20 weeks' gestation. Observational study design precludes causal inference. Many estimates were imprecise. CONCLUSION: Patients should be counseled on the small increased risk for genitourinary abnormalities after ART, particularly after ICSI, which should be avoided in couples without problems of male infertility. PRIMARY FUNDING SOURCE: Australian National Health and Medical Research Council.

Variation in clinical practice guidelines for use of palivizumab in preventing severe respiratory syncytial viral (RSV) disease in high-risk infants.

BACKGROUND: Uniformity and compliance with clinical practice guidelines (CPGs) for use of palivizumab in preventing severe respiratory syncytial viral infection in Australian high-risk infants remain unclear. METHODS: An online survey was conducted across the Australian and New Zealand Neonatal Network (ANZNN) to determine clinical practices around palivizumab. A literature search was also performed to identify and compare national and international guidelines. RESULTS: A total of 65 of 422 ANZNN members completed the survey. Respondents included 61 senior medical staff of consultants/staff specialists (78%) and four nursing staff (6%). According to the survey, infants most likely to be recommended palivizumab included preterm infants born <29 weeks gestational age (GA) (30%), children with chronic lung diseases (CLDs) born <32 weeks GA (40%), and with hemodynamically significant heart disease (35%). Many of the respondents (53%) stated that CPGs for palivizumab were developed locally. Literature search identified 20 guidelines (10 international and 10 domestic); 16 (80%) recommended palivizumab use in preterm infants, 16 (80%) recommended use in infants with CLD, 17 (85%) in congenital heart disease and 6 (30%) in bronchopulmonary dysplasia (BPD). Eight (40%) guidelines provided specific recommendations for immunocompromised infants. Canada, Western Australia, and American Academy of Paediatrics provided recommendations for Indigenous children. Frequency and dosage of palivizumab was universal across all CPGs. None of the international guidelines obtained were from low- or middle-income countries. CONCLUSIONS: Standardization of CPGs may improve clinical decision making around use of palivizumab in high-risk infants.

Preterm Birth and Total Health Care Use and Costs in the First 5 Years of Life: A Population-based Study.

OBJECTIVES: To investigate the relationship between preterm birth and hospital/out-of-hospital care and costs over the first 5 years of life. STUDY DESIGN: Birth data from a population-based cohort of 631 532 infants born between 2007 and 2013 were linked probabilistically with data on hospitalizations, primary and secondary care, and the use of medications. We analyzed the distribution of health care use and public health care costs for infants who survived at least 5 years, comparing the outcomes of extremely preterm (<28 weeks of gestation), very preterm (28-32 weeks), moderate to late preterm (32-37 weeks), and term infants (at least 37 weeks). A linear regression model was used to investigate the effect of preterm birth on these outcomes, controlling for important confounders including pregnancy and birth complications, neonatal morbidity, survival, and maternal socioeconomic characteristics. RESULTS: Preterm birth has a statistically significant and economically relevant effect on health care use and costs in the first 5 years of life. Compared with a term infant, preterm infants born at 32-36 weeks, 28-32 weeks, and <28 weeks of gestation had, respectively, an average of 7.0 (SE 0.06), 41.6 (0.18), and 68.7 (0.35) more hospital days; 3.1 (0.04), 11.0 (0.13), and 13.2 (0.25) more outpatient specialist physician visits; and 1.2-fold (<0.01), 6.8-fold (0.01), and 10.9-fold (0.02) higher 5-year public health care costs. Preterm infants also had statistically significantly higher levels of general practitioner visits and use of medications. CONCLUSIONS: Higher levels of accessible care are needed for preterm infants across health care settings and over sustained periods. As our understanding of the impact of preterm birth on long-term clinical outcomes continues to improve, clinicians and policymakers should develop an accurate recognition of these needs to enable appropriate resource allocation toward research priorities and early intervention strategies.

Early-onset sepsis in very preterm neonates in Australia and New Zealand, 2007-2018.

OBJECTIVE: To evaluate the epidemiology and population trends of early-onset sepsis in very preterm neonates admitted to neonatal intensive care units (NICU) in Australia and New Zealand. DESIGN: Retrospective observational cohort study using a dual-nation registry database. SETTING: 29 NICUs that have contributed to the Australian and New Zealand Neonatal Network. PARTICIPANTS: Neonates born at <32 weeks' gestation born between 2007 and 2018 and then admitted to a NICU. MAIN OUTCOME MEASURES: Microorganism profiles, incidence, mortality and morbidity. RESULTS: Over the 12-year period, 614 early-onset sepsis cases from 43 178 very preterm admissions (14.2/1000 admissions) were identified. The trends of early-onset sepsis incidence remained stable, varying between 9.8 and 19.4/1000 admissions (linear trend, p=0.56). The leading causative organisms were Escherichia coli (E. coli) (33.7%) followed by group B Streptococcus (GBS) (16.1%). The incidence of E. coli increased between 2007 (3.2/1000 admissions) and 2018 (8.3/1000 admissions; p=0.02). Neonates with E. coli had higher odds of mortality compared with those with GBS (OR=2.8, 95% CI 1.2 to 6.1). Mortality due to GBS decreased over the same period (2007: 0.6/1000 admissions, 2018: 0.0/1000 admissions; p=0.01). Early-onset sepsis tripled the odds of mortality (OR=3.0, 95% CI 2.4 to 3.7) and halved the odds of survival without morbidity (OR=0.5, 95% CI 0.4 to 0.6). CONCLUSION: Early-onset sepsis remains an important condition among very preterm populations. Furthermore, E. coli is a dominant microorganism of very preterm early-onset sepsis in Australia and New Zealand. Rates of E. coli have been increasing in recent years, while GBS-associated mortality has decreased.

Reference values for diaphragm electrical activity (Edi) in newborn infants.

BACKGROUND: Neurally adjusted ventilatory assist is an emerging mode of respiratory support that uses the electrical activity of the diaphragm (Edi) to provide synchronised inspiratory pressure support, proportional to an infant's changing inspiratory effort. Data on Edi reference values for neonates are limited. The objective of this study was to establish reference Edi values for preterm and term neonates who are not receiving respiratory support. METHODS: This was a prospective observational study of newborn infants breathing spontaneously in room air. The Edi waveform was monitored by a specialised naso/orogastric feeding tube with embedded electrodes positioned at the level of the diaphragm. Edi minimums and peaks were recorded continuously for 4 h without changes to routine clinical handling. RESULTS: Twenty-four newborn infants (16 preterm [< 37 weeks' gestation]; 8 term) were studied. All infants were breathing comfortably in room air at the time of study. Edi data were successfully captured in all infants. The mean (±SD) Edi minimum was 3.02 (±0.94) µV and the mean Edi peak was 10.13 (±3.50) µV. In preterm infants the mean (±SD) Edi minimum was 3.05 (±0.91) µV and the mean Edi peak was 9.36 (±2.13) µV. In term infants the mean (±SD) Edi minimum was 2.97 (±1.05) µV and the mean Edi peak was 11.66 (±5.14) µV. CONCLUSION: Reference Edi values were established for both preterm and term neonates. These values can be used as a guide when monitoring breathing support and when using diaphragm-triggered modes of respiratory support in newborn infants.

International Variation in the Management of Patent Ductus Arteriosus and Its Association with Infant Outcomes: A Survey and Linked Cohort Study.

OBJECTIVE: To assess whether treating patients with a presymptomatic patent ductus arteriosus (PDA), based on early routine echocardiography, performed regardless of clinical signs, improved outcomes. STUDY DESIGN: This multicenter, survey-linked retrospective cohort study used an institutional-level questionnaire and individual patient-level data and included infants of <29 weeks of gestation born in 2014-2016 and admitted to tertiary neonatal intensive care units (NICUs) of 9 population-based national or regional neonatal networks. Infants in NICUs receiving treatment of presymptomatic PDA identified by routine echocardiography and those not were compared for the primary composite outcome (early death [≤7 days after birth] or severe intraventricular hemorrhage) and secondary outcomes (any in-hospital mortality and major morbidities). RESULTS: The unit survey (response rates of 86%) revealed a wide variation among networks in the treatment of presymptomatic PDA (7%-86%). Among 246 NICUs with 17 936 infants (mean gestational age of 26 weeks), 126 NICUs (51%) with 7785 infants treated presymptomatic PDA. The primary outcome of early death or severe intraventricular hemorrhage was not significantly different between the NICUs treating presymptomatic PDA and those who did not (17% vs 21%; aOR 1.00, 95% CI 0.85-1.18). The NICUs treating presymptomatic PDA had greater odds of retinopathy of prematurity treatment (13% vs 7%; aOR 1.47, 95% CI 1.01-2.12); however, it was not significant in a sensitivity analysis excluding Japanese data. CONCLUSIONS: Treating presymptomatic PDA detected by routine echocardiography was commonplace but associated with no significant benefits. Well-designed trials are needed to assess the efficacy and safety of early targeted PDA treatment.

Neurodevelopmental outcomes of preterm infants after randomisation to initial resuscitation with lower (FiO2 <0.3) or higher (FiO2 >0.6) initial oxygen levels. An individual patient meta-analysis.

OBJECTIVE: To determine the effects of lower (≤0.3) versus higher (≥0.6) initial fractional inspired oxygen (FiO2) for resuscitation on death and/or neurodevelopmental impairment (NDI) in infants <32 weeks' gestation. DESIGN: Meta-analysis of individual patient data from three randomised controlled trials. SETTING: Neonatal intensive care units. PATIENTS: 543 children <32 weeks' gestation. INTERVENTION: Randomisation at birth to resuscitation with lower (≤0.3) or higher (≥0.6) initial FiO2. OUTCOME MEASURES: Primary: death and/or NDI at 2 years of age.Secondary: post-hoc non-randomised observational analysis of death/NDI according to 5-minute oxygen saturation (SpO2) below or at/above 80%. RESULTS: By 2 years of age, 46 of 543 (10%) children had died. Of the 497 survivors, 84 (17%) were lost to follow-up. Bayley Scale of Infant Development (third edition) assessments were conducted on 377 children. Initial FiO2 was not associated with difference in death and/or disability (difference (95% CI) -0.2%, -7% to 7%, p=0.96) or with cognitive scores <85 (2%, -5% to 9%, p=0.5). Five-minute SpO2 >80% was associated with decreased disability/death (14%, 7% to 21%) and cognitive scores >85 (10%, 3% to 18%, p=0.01). Multinomial regression analysis noted decreased death with 5-minute SpO2 ≥80% (odds (95% CI) 09.62, 0.98 to 0.96) and gestation (0.52, 0.41 to 0.65), relative to children without death or NDI. CONCLUSION: Initial FiO2 was not associated with difference in risk of disability/death at 2 years in infants <32 weeks' gestation but CIs were wide. Substantial benefit or harm cannot be excluded. Larger randomised studies accounting for patient differences, for example, gestation and gender are urgently needed.

Manipulating the neonatal gut microbiome: current understanding and future perspectives.

The development of a healthy intestinal microbiome following birth contributes to the overall health of the infant during childhood and into adulthood. However, modern birth practices such as caesarean delivery, feeding, antibiotic exposure as well as maternal factors have the potential to greatly impact infant microbiome development. Aberrant microbiome development may be a key factor in the increasing incidence of inflammatory and gut diseases. This review will summarise the current understanding of how modern birth practices may contribute to deficiencies in neonatal gut microbiome development and will also present potential methods of microbiome engineering that aim to ensure the development of a healthy and robust microbiome to protect the host from disease throughout their life.

Trial of aerosolised surfactant for preterm infants with respiratory distress syndrome.

OBJECTIVE: To evaluate the safety of an aerosolised surfactant, SF-RI 1, administered via nasal continuous positive airway pressure (nCPAP) and a prototype breath synchronisation device (AeroFact), to preterm infants with respiratory distress syndrome (RDS). DESIGN: Multicentre, open-label, dose-escalation study with historical controls. SETTING: Newborn intensive care units at Mater Mothers' Hospital, Brisbane, and Royal Hospital for Women, Sydney, Australia. PATIENTS: Infants 26 weeks through 30 weeks gestation who required nCPAP 6-8 cmH2O and fraction of inspired oxygen (FiO2) <0.30 at <2 hours of age. INTERVENTIONS: In part 1, infants received a single dose of 216 mg/kg of aerosolised surfactant. In part 2, infants could receive up to four doses of aerosolised surfactant. Three historical control infants were matched for each enrolled infant. MAIN OUTCOME MEASURES: Treatment failure was defined as Respiratory Severity Score (FiO2×cmH2O nCPAP) >2.4, nCPAP >8 cmH2O, arterial carbon dioxide >65 mm Hg, pH <7.20 or three severe apnoeas within 6 hours during the first 72 hours of life. Other outcomes included tolerance of the AeroFact treatment and complications of prematurity. RESULTS: 10 infants were enrolled in part 1 and 21 in part 2 and were compared with 93 historical controls. No safety issues were identified. In part 2, 6 of 21 (29%) AeroFact-treated infants compared with 30 of 63 (48%) control infants met failure criteria. Kaplan-Meier analysis of patients in part 2 showed a trend towards decreased rate of study failure in the AeroFact-treated infants compared with historical controls (p=0.10). CONCLUSION: The AeroFact system can safely deliver aerosolised surfactant to preterm infants with RDS who are on nCPAP. TRIAL REGISTRATION NUMBER: ACTRN12617001458325.

Five-minute Apgar score and outcomes in neonates of 24-28 weeks' gestation.

OBJECTIVES: To assess associations between 5 min Apgar score and mortality and severe neurological injury (SNI) and to report test characteristics in preterm neonates. DESIGN, SETTING AND PATIENTS: Retrospective cohort study of neonates 240 to 286 weeks' gestation born between 2007 and 2016 and admitted to neonatal units in 11 high-income countries. EXPOSURE: 5 min Apgar score. MAIN OUTCOME MEASURES: In-hospital mortality and SNI defined as grade 3 or 4 periventricular/intraventricular haemorrhage or periventricular leukomalacia. Outcome rates were calculated for each Apgar score and compared after adjustment. The diagnostic characteristics and ORs for each value from 0 versus 1-10 to 0-9 versus 10, with 1-point increments were calculated. RESULTS: Among 92 412 included neonates, as 5 min Apgar score increased from 0 to 10, mortality decreased from 60% to 8%. However, no clear increasing or decreasing pattern was identified for SNI. There was an increase in sensitivity and decrease in specificity for both mortality and SNI associated with increasing scores. The Apgar score alone had an area under the curve of 0.64 for predicting mortality, which increased to 0.73 with the addition of gestational age. CONCLUSIONS: In neonates of 24-28 weeks' gestation admitted to neonatal units, higher 5 min Apgar score was associated with lower mortality in a graded manner, while the association with SNI remained relatively constant at all scores. Among survivors, low Apgar scores did not predict SNI.

Effects of delayed versus immediate umbilical cord clamping in reducing death or major disability at 2 years corrected age among very preterm infants (APTS): a multicentre, randomised clinical trial.

BACKGROUND: Very preterm infants are at increased risk of adverse outcomes in early childhood. We assessed whether delayed clamping of the umbilical cord reduces mortality or major disability at 2 years in the APTS Childhood Follow Up Study. METHODS: In this long-term follow-up analysis of the multicentre, randomised APTS trial in 25 centres in seven countries, infants (<30 weeks gestation) were randomly assigned before birth (1:1) to have clinicians aim to delay clamping for 60 s or more or clamp within 10 s of birth, both without cord milking. The primary outcome was death or major disability (cerebral palsy, severe visual loss, deafness requiring a hearing aid or cochlear implants, major language or speech problems, or cognitive delay) at 2 years corrected age, analysed in the intention-to-treat population. This trial is registered with the Australian and New Zealand Clinical Trials Registry (ACTRN12610000633088). FINDINGS: Between Oct 21, 2009, and Jan 6, 2017, consent was obtained for follow-up for 1531 infants, of whom 767 were randomly assigned to delayed clamping and 764 to immediate clamping. 384 (25%) of 1531 infants were multiple births, 862 (56%) infants were male, and 505 (33%) were born before 27 weeks gestation. 564 (74%) of 767 infants assigned to delayed clamping and 726 (96%) of 764 infants assigned to immediate clamping received treatment that fully adhered to the protocol. Death or major disability was determined in 1419 (93%) infants and occurred in 204 (29%) of 709 infants who were assigned to delayed clamping versus 240 (34%) of 710 assigned to immediate clamping, (relative risk [RR]) 0·83, 95% CI 0·72-0·95; p=0·010). 60 (8%) of 725 infants in the delayed clamping group and 81 (11%) of 720 infants in the immediate clamping group died by 2 years of age (RR 0·70, 95% CI 0·52-0·95); among those who survived, major disability at 2 years occurred in 23% (144/627) versus 26% (159/603) of infants, respectively (RR 0·88, 0·74-1·04). INTERPRETATION: Clamping the umbilical cord at least 60 s after birth reduced the risk of death or major disability at 2 years by 17%, reflecting a 30% reduction in relative mortality with no difference in major disability. FUNDING: Australian National Health and Medical Research Council.

Mortality and significant neurosensory impairment in preterm infants: an international comparison.

OBJECTIVE: To compare mortality and rates of significant neurosensory impairment (sNSI) at 18-36 months' corrected age in infants born extremely preterm across three international cohorts. DESIGN: Retrospective analysis of prospectively collected neonatal and follow-up data. SETTING: Three population-based observational cohort studies: the Australian and New Zealand Neonatal Network (ANZNN), the Canadian Neonatal and Follow-up Networks (CNN/CNFUN) and the French cohort Etude (Epidémiologique sur les Petits Ages Gestationnels: EPIPAGE-2). PATIENTS: Extremely preterm neonates of <28 weeks' gestation in year 2011. MAIN OUTCOME MEASURES: Primary outcome was composite of mortality or sNSI defined by cerebral palsy with no independent walking, disabling hearing loss and bilateral blindness. RESULTS: Overall, 3055 infants (ANZNN n=960, CNN/CNFUN n=1019, EPIPAGE-2 n=1076) were included in the study. Primary composite outcome rates were 21.3%, 20.6% and 28.4%; mortality rates were 18.7%, 17.4% and 26.3%; and rates of sNSI among survivors were 4.3%, 5.3% and 3.3% for ANZNN, CNN/CNFUN and EPIPAGE-2, respectively. Adjusted for gestational age and multiple births, EPIPAGE-2 had higher odds of composite outcome compared with ANZNN (OR 1.71, 95% CI 1.38 to 2.13) and CNN/CNFUN (OR 1.72, 95% CI 1.39 to 2.12). EPIPAGE-2 did have a trend of lower odds of sNDI but far short of compensating for the significant increase in mortality odds. These differences may be related to variations in perinatal approach and practices (and not to differences in infants' baseline characteristics). CONCLUSIONS: Composite outcome of mortality or sNSI for extremely preterm infants differed across high-income countries with similar baseline characteristics and access to healthcare.

Survival prediction modelling in extreme prematurity: are days important?

OBJECTIVE: To demonstrate that days are important in extreme prematurity when creating survival prediction models based on gestation. STUDY DESIGN: Prospectively collected data were analysed for all admitted infants born 23 + 0 to 27 + 6 weeks gestation in the Australian and New Zealand Neonatal Network from 2009 to 2016. The effect of days on observed survival rates was assessed using a non-parametric test for trend. Prediction models created based on gestational age in completed weeks only or weeks plus days were compared. RESULT: Seven thousand eight hundred and thirty-six extreme preterm infants were studied. Observed survival increased with days for 23, 24, 25, and 27 weeks gestational age (P = 0.01; P < 0.001; P = 0.003; P = 0.003) but not for 26 weeks (P = 0.19). A survival prediction model based on weeks and days performed better than completed weeks only (AUC 0.722 vs 0.712; P < 0.001). CONCLUSION: In extreme prematurity, survival estimate accuracy improves when survival prediction models include days in addition to weeks.

A bespoke data linkage of an IVF clinical quality registry to population health datasets; methods and performance.

INTRODUCTION: Assisted reproductive technologies (ART), such as in-vitro fertilisation (IVF), have revolutionised the treatment of infertility, with an estimated 8 million babies born worldwide. However, the long-term health outcomes for women and their offspring remain an area of concern. Linking IVF treatment data to long-term health data is the most efficient method for assessing such outcomes. OBJECTIVES: To describe the creation and performance of a bespoke population-based data linkage of an ART clinical quality registry to state-based and national administrative datasets. METHODS: The linked dataset was created by deterministically and probabilistically linking the Australia and New Zealand Assisted Reproduction Database (ANZARD) to New South Wales (NSW) and Australian Capital Territory (ACT) administrative datasets (performed by NSW Centre for Health Record Linkage (CHeReL)) and to national claims datasets (performed by Australian Institute of Health and Welfare (AIHW)). The CHeReL's Master Linkage Key (MLK) was used as a bridge between ANZARD's partially identifiable patient data (statistical linkage key) and NSW and ACT administrative datasets. CHeReL then provided personal identifiers to the AIHW to obtain national content data. The results of the linkage were reported, and concordance between births recorded in ANZARD and perinatal data collections (PDCs) was evaluated. RESULTS: Of the 62,833 women who had ART treatment in NSW or ACT, 60,419 could be linked to the CHeReL MLK (linkage rate: 96.2%). A reconciliation of ANZARD-recorded births among NSW residents found that 94.2% (95% CI: 93.9-94.4%) of births were also recorded in state/territory-based PDCs. A high concordance was found in plurality status and birth outcome ≥99% agreement rate, Cohen's kappa ranged: 0.78-0.98) between ANZARD and PDCs. CONCLUSION: The data linkage resource demonstrates that high linkage rates can be achieved with partially identifiable data and that a population spine, such as the CHeReL's MLK, can be successfully used as a bridge between clinical registries and administrative datasets.

Outcomes of delivery room resuscitation of bradycardic preterm infants: A retrospective cohort study of randomised trials of high vs low initial oxygen concentration and an individual patient data analysis.

OBJECTIVE: To determine whether hospital mortality (primary outcome) is associated with duration of bradycardia without chest compressions during delivery room (DR) resuscitation in a retrospective cohort study of randomized controlled trials (RCTs) in preterm infants assigned low versus high initial oxygen concentration. METHODS: Medline and EMBASE were searched from 01/01/1990 to 12/01/2020. RCTs of low vs high initial oxygen concentration which recorded serial heart rate (HR) and oxygen saturation (SpO2) during resuscitation of infants <32 weeks gestational age were eligible. Individual patient level data were requested from the authors. Newborns receiving chest compressions in the DR and those with no recorded HR in the first 2 min after birth were excluded. Prolonged bradycardia (PB) was defined as HR < 100 bpm for ≥2 min. Individual patient data analysis and pooled data analysis were conducted. RESULTS: Data were collected from 720 infants in 8 RCTs. Neonates with PB had higher odds of hospital death before [OR 3.8 (95% CI 1.5, 9.3)] and after [OR 1.7 (1.2, 2.5)] adjusting for potential confounders. Bradycardia occurred in 58% infants, while 38% had PB. Infants with bradycardia were more premature and had lower birth weights. The incidence of bradycardia in infants resuscitated with low (≤30%) and high (≥60%) oxygen was similar. Neonates with both, PB and SpO2 < 80% at 5 min after birth had higher odds of hospital mortality. [OR 18.6 (4.3, 79.7)]. CONCLUSION: In preterm infants who did not receive chest compressions in the DR, prolonged bradycardia is associated with hospital mortality.

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.

Early PARacetamol (EPAR) Trial: A Randomized Controlled Trial of Early Paracetamol to Promote Closure of the Ductus Arteriosus in Preterm Infants.

INTRODUCTION: This study aimed to investigate whether early treatment with paracetamol reduces the number of infants requiring intervention for patent ductus arteriosus (PDA) and assess the safety profile of paracetamol during the early postnatal period. METHODS: This was a double-blind, parallel, randomized, placebo-controlled trial. Preterm infants born at <29-week gestation with a ductus arteriosus >0.9 mm at 6 h of life were randomized to either (1) intravenous paracetamol (15 mg/kg initially and then 7.5 mg/kg every 6 h) or (2) intravenous dextrose for 5 days. The primary outcome was the need for any intervention for PDA up to 5 days. Secondary outcomes included ductal closure at 5 days, ductal size at 48 h, ductal reopening, mortality, and significant morbidities. RESULTS: Of 58 infants randomized, 29 were allocated to the intervention and 29 to the control group. The trial was stopped for benefit at 50% recruitment after reaching the prespecified stopping criteria. Less infants in the intervention group required intervention for PDA up to 5 days (6 [21%] vs. 17 [59%] infants [p = 0.003]; relative risk reduction 0.35 [95% CI 0.16-0.77; NNT 2.6]). The intervention group had a higher rate of ductal closure (20 [69%] vs. 8 [28%] infants [p = 0.002]) and smaller ductal size (1.0 mm [±0.8] vs. 1.4 mm [±0.9]; p = 0.04). Three deaths occurred (2 in the intervention group), which were not attributed to the intervention. No other adverse events were reported. DISCUSSION/CONCLUSION: Early paracetamol treatment reduced the number of infants requiring intervention for PDA. Short-term safety data were reassuring, acknowledging the small number of infants involved in the study.