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Background Individuals born very low birthweight (VLBW) are at increased risk of impaired cardiovascular and respiratory function in adulthood. To identify markers to predict future risk for VLBW individuals, we analyzed DNA methylation at birth and at 28 years in the New Zealand (NZ) VLBW cohort (all infants born Results Genomic DNA from archived newborn heel-prick blood (n = 109 VLBW, 51 controls) and from peripheral blood at ~ 28 years (n = 215 VLBW, 96 controls) was analyzed on Illumina Infinium MethylationEPIC 850 K arrays. Following quality assurance and normalization, methylation levels were compared between VLBW cases and controls at both ages by linear regression, with genome-wide significance set to p p = 3.44E−11). The top 20 CpGs that differed most between VLBW cases and controls featured clusters in ARID3A, SPATA33, and PLCH1 and these 3 genes, along with MCF2L, TRBJ2-1 and SRC, led the list of 15,000 differentially methylated regions (DMRs) reaching FDR-adj significance. Fifteen of the 20 top CpGs in the neonate EWAS showed associations between methylation at birth and adult cardiovascular traits (particularly LnRHI). In 28-year-old adults, twelve CpGs differed between VLBW cases and controls at FDR-adjusted significance, including hypermethylation in EBF4 (four CpGs), CFI and UNC119B and hypomethylation at three CpGs in HIF3A and one in KCNQ1. DNA methylation GrimAge scores at 28 years were significantly greater in VLBW cases versus controls and weakly associated with cardiovascular traits. Four CpGs were identified where methylation differed between VLBW cases and controls in both neonates and adults, three reversing directions with age (two CpGs in EBF4, one in SNAI1 were hypomethylated in neonates, hypermethylated in adults). Of these, cg16426670 in EBF4 at birth showed associations with several cardiovascular traits in adults. Conclusions These findings suggest that methylation patterns in VLBW neonates may be informative about future adult cardiovascular and respiratory outcomes and have value in guiding early preventative care to improve adult health.

Climate change and population growth will increase vulnerability to natural and human-made disasters or pandemics. Longitudinal research studies may be adversely impacted by a lack of access to study resources, inability to travel around the urban environment, reluctance of sample members to attend appointments, sample members moving residence and potentially also the destruction of research facilities. One of the key advantages of longitudinal research is the ability to assess associations between exposures and outcomes by limiting the influence of sample selection bias. However, ensuring the validity and reliability of findings in longitudinal research requires the recruitment and retention of respondents who are willing and able to be repeatedly assessed over an extended period of time. This study examined recruitment and retention strategies of 11 longitudinal cohort studies operating during the Christchurch, New Zealand earthquake sequence which began in September 2010, including staff perceptions of the major impediments to study operations during/after the earthquakes and respondents’ barriers to participation. Successful strategies to assist recruitment and retention after a natural disaster are discussed. With the current COVID-19 pandemic, longitudinal studies are potentially encountering some of the issues highlighted in this paper including: closure of facilities, restricted movement of research staff and sample members, and reluctance of sample members to attend appointments. It is possible that suggestions in this paper may be implemented so that longitudinal studies can protect the operation of their research programmes.

Executive function difficulties are common among children born very preterm and/or very low birthweight (1500 g; VLBW), but little is known about whether they persist into adulthood.Examine the nature and pattern of self-reported executive functioning at 23 and 28 years of age using data from a national cohort study of adults born VLBW and a comparison group of same-age full-term (FT) born adults. Also examined were associations between executive function difficulties and socio-economic outcomes.All infants born VLBW in New Zealand during 1986 were prospectively included in an audit of retinopathy of prematurity (n = 413), with 250 (77% of survivors) followed to median age 28 years. A comparison group of FT adults was also recruited at age 23 and followed to 28 years (n = 100). Across both adult assessments, executive functioning was assessed using the Behaviour Rating Inventory of Executive Function-Adult Version (BRIEF-A) and analysed with semi-parametric models to examine the effects of age and group on executive function.At 23 and 28 years, VLBW adults had increased risk of executive function impairment compared with FT adults in behaviour regulation (relative risk [CI] 2.37, 95% confidence interval (CI)1.27, 4.45), meta-cognition (RR 6.03, 95% CI 2.18, 16.78) and global functioning (RR 3.20, 95% CI 1.40, 7.28). Impaired global executive functioning was associated with lower socio-economic status (regression estimate [b] = -0.43, 95% CI -0.59, -0.27) and a reduced likelihood of home ownership by age 28 years (RR 0.98, 95% CI 0.96, 1.00), even after controlling for sex, ethnicity and parental socio-economic backgrounds for both groups.VLBW-born adults continue to experience more executive function difficulties in their everyday life relative to term controls at age 28 years. These difficulties were negatively associated with their socio-economic opportunities as young adults.

Antenatal corticosteroids (ACS) given to mothers with anticipated very preterm delivery are widely used and improve infant outcomes. Follow-up studies of the first trials of ACS have shown no adverse effects, but recently there have been concerns about possible longer-term harms.We aimed to assess the relationship of ACS therapy to a range of physical health and welfare measures in a cohort of very low birthweight (VLBW;1500 g) young adults.Population-based cohort follow-up study. All VLBW infants born in New Zealand in 1986 were included in a prospective audit of retinopathy of prematurity. Perinatal data collection included information on ACS. At 26-30 years, 250 of 323 (77%) survivors participated, 58% having received ACS, with 229 assessed in one centre, including cardiovascular, metabolic, respiratory and neurocognitive measures. Differences in outcome between those receiving/not receiving ACS were summarised by the mean difference for continuous outcomes supplemented by Cohen's d as a standardised measure of effect size (ES), and risk ratios (RRI) for dichotomous outcomes, adjusted for relevant covariates using generalised linear regression methods.There were no or minimal adverse effects of receipt of ACS versus no receipt across a range of health and welfare outcomes, both for the full cohort (adjusted ES range d = 0.01-0.23; adjusted RR range 0.78-2.03) and for individuals with gestation28 weeks (extremely preterm; EP), except for a small increase in rates of major depression. In EP adults, receipt of ACS was associated with a higher incidence of hypertension, but might have a small benefit for IQ.In this population-based VLBW cohort, we detected minimal adverse outcomes associated with exposure to ACS by the third decade of life, a similar result to the 30-year follow-up of participants in the first ACS trial. However, further follow-up is warranted.

OBJECTIVES Little is known about the oral health of very low birthweight (

Summary Background Very low birthweight or preterm infants are at increased risk of adverse outcomes including sepsis, necrotising enterocolitis, and death. We assessed whether supplementing the enteral diet of very low-birthweight infants with lactoferrin, an antimicrobial protein, reduces all-cause mortality or major morbidity. Methods We did a multicentre, double-blind, pragmatic, randomised superiority trial in 14 Australian and two New Zealand neonatal intensive care units. Infants born weighing less than 1500 g and aged less than 8 days, were eligible and randomly assigned (1:1) using minimising web-based randomisation to receive once daily 200 mg/kg pasteurised bovine lactoferrin supplements or no lactoferrin supplement added to breast or formula milk until 34 weeks' post-menstrual age (or for 2 weeks, if longer), or until discharge from the study hospital if that occurred first. Designated nurses preparing the daily feeds were not masked to group assignment, but other nurses, doctors, parents, caregivers, and investigators were unaware. The primary outcome was survival to hospital discharge or major morbidity (defined as brain injury, necrotising enterocolitis, late-onset sepsis at 36 weeks' post-menstrual age, or retinopathy treated before discharge) assessed in the intention-to-treat population. Safety analyses were by treatment received. We also did a prespecified, PRISMA-compliant meta-analysis, which included this study and other relevant randomised controlled trials, to estimate more precisely the effects of lactoferrin supplementation on late-onset sepsis, necrotising enterocolitis, and survival. This trial is registered with the Australian and New Zealand Clinical Trials Registry, ACTRN12611000247976. Findings Between June 27, 2014, and Sept 1, 2017, we recruited 1542 infants; 771 were assigned to the intervention group and 771 to the control group. One infant who had consent withdrawn before beginning lactoferrin treatment was excluded from analysis. In-hospital death or major morbidity occurred in 162 (21%) of 770 infants in the intervention group and in 170 (22%) of 771 infants in the control group (relative risk [RR] 0·95, 95% CI 0·79–1·14; p=0·60). Three suspected unexpected serious adverse reactions occurred; two in the lactoferrin group, namely unexplained late jaundice and inspissated milk syndrome, but were not attributed to the intervention and one in the control group had fatal inspissated milk syndrome. Our meta-analysis identified 13 trials completed before Feb 18, 2020, including this Article, in 5609 preterm infants. Lactoferrin supplements significantly reduced late-onset sepsis (RR 0·79, 95% CI 0·71–0·88; p Interpretation Lactoferrin supplementation did not improve death or major morbidity in this trial, but might reduce late-onset sepsis, as found in our meta-analysis of over 5000 infants. Future collaborative studies should use products with demonstrated biological activity, be large enough to detect moderate and clinically important effects reliably, and assess greater doses of lactoferrin in infants at increased risk, such as those not exclusively receiving breastmilk or infants of extremely low birthweight. Funding Australian National Health and Medical Research Council.

BACKGROUND There is individual variation in physiological ageing. Former very low birthweight (VLBW; birthweight

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 p z-score (RR = 0.88, 95% CI 0.80, 0.97, p 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.

Being born preterm (PT, &lt, 37 weeks gestation) or at very low birth weight (VLBW, &lt, 1500 g) is associated with increased rates of cardiopulmonary disorders in childhood. As survivors age, late cardiac effects, including right ventricular (RV) remodelling and occult pulmonary hypertension are emerging. In this population-based study, we aimed to investigate right heart structure and function in young adults born PT at VLBW compared to normal-weight term-born controls. The New Zealand VLBW Study has followed all infants born in 1986 with birth weight &lt, 1500 g. All were born preterm from 24 to 37 weeks. A total of 229 (71% of survivors) had echocardiograms aged 26–30 years which were compared to age-matched, term-born, normal-weight controls (n = 100). Young adults born preterm at very low birth weight exhibited smaller RV dimensions compared to term-born peers. Standard echocardiographic measures of RV function did not differ, but mildly reduced function was detected by RV longitudinal strain. This difference was related to birth weight and gestational age but not lung function or left ventricular function. Echocardiographic strain imaging may be an important tool to detect differences in RV function preterm and VLBW.

Rationale: Population-based data regarding the consequences of very low birth weight (VLBW) and bronchopulmonary dysplasia (BPD) on adult exercise capacity is limited. Objectives: To compare exerci...

Introduction: The availability of and variability in healthcare professionals in neonatal units in different countries has not been well characterized. Our objective was to identify variations in the healthcare professionals for preterm neonates in 10 national or regional neonatal networks participating in the International Network for Evaluating Outcomes (iNeo) of neonates. Method: Online, pre-piloted questionnaires about the availability of healthcare professionals were sent to the directors of 390 tertiary neonatal units in 10 international networks: Australia/New Zealand, Canada, Finland, Illinois, Israel, Japan, Spain, Sweden, Switzerland, and Tuscany. Results: Overall, 325 of 390 units (83%) responded. About half of the units (48%; 156/325) cared for 11–30 neonates/day and had team-based (43%; 138/325) care models. Neonatologists were present 24 h a day in 59% of the units (191/325), junior doctors in 60% (194/325), and nurse practitioners in 36% (116/325). A nurse-to-patient ratio of 1:1 for infants who are unstable and require complex care was used in 52% of the units (170/325), whereas a ratio of 1:1 or 1:2 for neonates requiring multisystem support was available in 59% (192/325) of the units. Availability of a respiratory therapist (15%, 49/325), pharmacist (40%, 130/325), dietitian (34%, 112/325), social worker (81%, 263/325), lactation consultant (45%, 146/325), parent buddy (6%, 19/325), or parents’ resource personnel (11%, 34/325) were widely variable between units. Conclusions: We identified variability in the availability and organization of the healthcare professionals between and within countries for the care of extremely preterm neonates. Further research is needed to associate healthcare workers’ availability and outcomes.

Importance: Birth before 32 weeks’ gestation (very preterm [VPT]) and birth weight below 1500 g (very low birth weight [VLBW]) have been associated with lower cognitive performance in childhood. However, there are few investigations of the association of neonatal morbidities and maternal educational levels with the adult cognitive performance of individuals born VPT or VLBW (VPT/VLBW). Objective: To assess differences in adult IQ between VPT/VLBW and term-born individuals and to examine the association of adult IQ with cohort factors, neonatal morbidities, and maternal educational level among VPT/VLBW participants. Data Sources: Systematic review of published data from PubMed and meta-analysis of individual participant data (IPD) of cohorts from 2 consortia (Research on European Children and Adults Born Preterm [RECAP] and Adults Born Preterm International Collaboration [APIC]). Study Selection: The meta-analysis included prospective longitudinal cohort studies that assessed the full-scale IQ of adults born VPT or VLBW and respective control groups comprising term-born adults. Data Extraction And Synthesis: The study followed the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) reporting guideline for analyses of individual participant data and identified 8 studies that provided data from 2135 adults (1068 VPT/VLBW and 1067 term-born participants) born between 1978 and 1995. Meta-analyses of IPD were performed using a 1-stage approach, treating VPT birth or VLBW and cohort as random effects. Main Outcomes And Measures: Full-scale IQ scores were converted to z scores within each cohort using the combined SD of VPT/VLBW participants and a control group of term-born participants, with scores centered on the mean of the control group. Results: A total of 426 records were identified and screened. After exclusions, 13 studies were included in the aggregate meta-analysis. The IPD meta-analysis included 8 of the 9 RECAP and APIC cohorts with adult IQ data. The mean (SD) age among the 8 IPD cohorts was 24.6 (4.3) years, and 1163 participants (54.5%) were women. In unadjusted analyses, VPT/VLBW participants had mean adult IQ scores that were 0.78 SD (95% CI, −0.90 to −0.66 SD) lower than term-born participants, equivalent to a difference of 12 IQ points. Among VPT/VLBW participants, lower gestational age (score difference per week of gestation, 0.11; 95% CI, 0.07-0.14), lower birth weight z scores (score difference per 1.0 SD, 0.21; 95% CI, 0.14-0.28), the presence of neonatal bronchopulmonary dysplasia (score difference, −0.16; 95% CI, −0.30 to −0.02) or any grade of intraventricular hemorrhage (score difference, −0.19; 95% CI, −0.33 to −0.05), and lower maternal educational level (score difference, 0.26; 95% CI, 0.17-0.35) were all significantly associated with lower IQ scores in adulthood. Conclusions And Relevance: In this IPD meta-analysis, lower gestational age, lower weight for gestational age, neonatal morbidities, and lower maternal educational levels were all important risk factors associated with lower IQ among young adults born VPT or VLBW.

Of all newborns, 1%-2% are born very preterm (VP

ObjectiveTo compare mortality and rates of significant neurosensory impairment (sNSI) at 18–36 months’ corrected age in infants born extremely preterm across three international cohorts.DesignRetrospective analysis of prospectively collected neonatal and follow-up data.SettingThree 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).PatientsExtremely preterm neonates of Main outcome measuresPrimary outcome was composite of mortality or sNSI defined by cerebral palsy with no independent walking, disabling hearing loss and bilateral blindness.ResultsOverall, 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).ConclusionsComposite outcome of mortality or sNSI for extremely preterm infants differed across high-income countries with similar baseline characteristics and access to healthcare.

Collaboration and cooperation of clinicians and neonatal units at regional, national, and international levels are key features of many networks or systems that aim to improve neonatal outcomes. Network performance is typically assessed by comparing individual, unit-level outcomes. In this paper, we provide insight into another dimension, i.e., inter-center outcome variation in 10 national/regional neonatal collaborations from 11 high-income countries. We illustrate the use of coefficients of variation for evaluation of mortality and a composite outcome of mortality, severe neurological injury, treated retinopathy of prematurity, and bronchopulmonary dysplasia, as a measure of inter-center variation. These inter-center variation estimates could help to identify areas of opportunities and challenges for each country/region; they also provide "macro"-level evaluations that can be useful for clinicians, administrators, managers and policy makers.

Background Children commonly report gastrointestinal symptoms. Limited evidence suggests that children with type 1 diabetes mellitus (T1DM) report more gastrointestinal symptoms than healthy children without diabetes. The aim of this study was to ascertain the pattern and severity gastrointestinal symptoms reported by children with diabetes and healthy children without diabetes. Methods After recruitment, children (less than 16 years of age) with type 1 diabetes and healthy control children reported their recent gastrointestinal symptoms using a short questionnaire. A five-point Likert scale was utilised to grade the severity of each symptom and an overall symptom score for each child was derived. Results One hundred and fifty cases (88% of eligible population) and 94 controls completed the questionnaire. Both groups had similarly high rates of any gastrointestinal symptom [80% of controls vs. 85% cases, OR 1.5 (95% CI: 0.7-3.1)]. Children with diabetes had higher mean scores for abdominal pain (1.3 vs. 1.0, P=0.02) and reflux (0.4 vs. 0.20, P=0.02). Cases also had a higher overall mean score than controls (4.9 vs. 3.4, P=0.02). Conclusions Overall, gastrointestinal symptoms were reported at the same frequency by both groups of children. However, the children with diabetes had more severe symptoms, especially those of reflux and abdominal pain. The reasons for these differences remain to be elucidated.

Introduction Being born at very low birth weight (VLBW, Purpose To assess differences in right heart function using strain in young adults born at VLBW, compared to normal weight term born controls. Methods The New Zealand Very Low Birth Weight Study has followed all infants born in 1986 with birth weight Results VLBW subjects were smaller than their peers as young adults (Table 1). Strain measurement showed reduced myocardial deformation among VLBW subjects (RV myocardial GLS: −22.4% vs −23.5%, p=0.008; RV endocardial GLS: −23.6% vs −24.9%, p=0.005; free wall myocardial GLS −25.2% vs −26.1%, p=0.039; free wall endocardial GLS −26.7% vs −27.9%, p=0.009). TR velocity was higher in VLBW: 224 cm/s v 210 cm/s (p=0.002). RV S', and FAC were not different. Conclusion Young adults born at VLBW have impaired myocardial strain despite preserved RV function as assessed by standard techniques. Echocardiographic strain imaging may be an important tool to detect subclinical RV dysfunction. Graph 1 Funding Acknowledgement Type of funding source: None

Objective To compare length of stay (LOS) in neonatal care for babies born extremely preterm admitted to networks participating in the International Network for Evaluating Outcomes of Neonates (iNeo). Study design Data were extracted for babies admitted from 2014 to 2016 and born at 24 to 28 weeks of gestational age (n = 28 204). Median LOS was calculated for each network for babies who survived and those who died while in neonatal care. A linear regression model was used to investigate differences in LOS between networks after adjusting for gestational age, birth weight z score, sex, and multiplicity. A sensitivity analysis was conducted for babies who were discharged home directly. Results Observed median LOS for babies who survived was longest in Japan (107 days); this result persisted after adjustment (20.7 days more than reference, 95% CI 19.3-22.1). Finland had the shortest adjusted LOS (−4.8 days less than reference, 95% CI –7.3 to −2.3). For each week's increase in gestational age at birth, LOS decreased by 12.1 days (95% CI –12.3 to −11.9). Multiplicity and male sex predicted mean increases in LOS of 2.6 (95% CI 2.0-3.2) and 2.1 (95% CI 1.6-2.6) days, respectively. Conclusions We identified between-network differences in LOS of up to 3 weeks for babies born extremely preterm. Some of these may be partly explained by differences in mortality, but unexplained variations also may be related to differences in clinical care practices and healthcare systems between countries.

AIM To determine IQ at 26 to 30 years in very-low-birthweight (VLBW) adults compared with term-born controls; and to examine the stability of IQ in VLBW individuals between 7 to 8 years and 26 to 30 years, identify perinatal and social predictors of IQ, and assess the contribution of brain volume to IQ. METHOD At 26 to 30 years, 229 VLBW adults (71% survivors of prospectively enrolled national cohort) and 100 term-born controls were tested on the Wechsler Abbreviated Scale of Intelligence. For VLBW, IQ at 7 to 8 years, perinatal and social data were extracted from the data set, and 150 adults underwent volumetric cranial magnetic resonance imaging (MRI). RESULTS At 26 to 30 years, the mean adjusted difference between VLBW and controls for total IQ was 9.4 (95% CI 6.5-12.4) points. In VLBW individuals the correlation between IQ scores at 7 to 8 years and 26 to 30 years was 0.78. On multiple regression analysis, parental education was the strongest predictor of verbal and total IQ at both ages. Birthweight was a strong predictor of perceptual and total IQ. In VLBW individuals with MRI scans, the addition of brain volume as a variable increased the variance explained for perceptual and total IQ. INTERPRETATION VLBW adults have mean IQ scores 9 to 11 points below controls. Parental education and birthweight are the strongest predictors of IQ.

BACKGROUND: Much remains unknown about the consequences of very low birth weight (VLBW) and bronchopulmonary dysplasia (BPD) on adult lungs. We hypothesized that VLBW adults would have impaired lung function compared with controls, and those with a history of BPD would have worse lung function than those without. METHODS: At age 26 to 30 years, 226 VLBW survivors of the New Zealand VLBW cohort and 100 term controls born in 1986 underwent lung function tests including spirometry, plethysmographic lung volumes, diffusing capacity of the lung for carbon monoxide, and single-breath nitrogen washout (SBN2). RESULTS: An obstructive spirometry pattern was identified in 35% VLBW subjects versus 14% controls, with the majority showing mild obstruction. Compared with controls, VLBW survivors demonstrated significantly lower forced expiratory volume in 1 second (FEV1), FEV1/forced vital capacity (FVC) ratio (FEV1/FVC), forced expiratory flow at 25% to 75% of FVC and higher residual volume (RV), RV/total lung capacity (TLC) ratio (RV/TLC), decreased diffusing capacity of the lung for carbon monoxide, and increased phase III slope for SBN2. The differences persisted after adjustment for sex and smoking status. Within the VLBW group, subjects with BPD showed significant reduction in FEV1, FEV1/FVC, and forced expiratory flow at 25% to 75% of FVC, and increase in RV, RV/TLC, and phase III slope for SBN2, versus subjects without. The differences remained after adjustment for confounders. CONCLUSIONS: Adult VLBW survivors showed a higher incidence of airflow obstruction, gas trapping, reduced gas exchange, and increased ventilatory inhomogeneity versus controls. The findings suggest pulmonary effects due to VLBW persist into adulthood, and BPD is a further insult on small airway function.

ObjectiveInfant boys have worse outcomes than girls. In twins, the ‘male disadvantage’ has been reported to extend to female co-twins via a ‘masculinising’ effect. We studied the association between sex pairing and neonatal outcomes in extremely preterm twins.DesignRetrospective cohort studySettingEleven countries participating in the International Network for Evaluating Outcomes of Neonates.PatientsLiveborn twins admitted at 23–29 weeks’ gestation in 2007–2015.Main outcome measuresWe examined in-hospital mortality, grades 3/4 intraventricular haemorrhage or cystic periventricular leukomalacia (IVH/PVL), bronchopulmonary dysplasia (BPD), retinopathy of prematurity requiring treatment and a composite outcome (mortality or any of the outcomes above).ResultsAmong 20 924 twins, 38% were from male-male pairs, 32% were from female-female pairs and 30% were sex discordant. We had no information on chorionicity. Girls with a male co-twin had lower odds of mortality, IVH/PVL and the composite outcome than girl-girl pairs (reference group): adjusted OR (aOR) (95% CI) 0.79 (0.68 to 0.92), 0.83 (0.72 to 0.96) and 0.88 (0.79 to 0.98), respectively. Boys with a female co-twin also had lower odds of mortality: aOR 0.86 (0.74 to 0.99). Boys from male-male pairs had highest odds of BPD and composite outcome: aOR 1.38 (1.24 to 1.52) and 1.27 (1.16 to 1.39), respectively.ConclusionsSex-related disparities in outcomes exist in extremely preterm twins, with girls having lower risks than boys and opposite-sex pairs having lower risks than same-sex pairs. Our results may help clinicians in assessing risk in this large segment of extremely preterm infants.

Aim: Delayed gastric emptying (GE) has been demonstrated in adults with type 1 diabetes mellitus (T1DM). Little is known about GE in children with T1DM. Most methods to measure GE are invasive, that is, scintigraphy, or are only indirectly related to GE, that is, electrogastrography. Carbon-13 breath testing is a non-invasive, very low-risk procedure that accurately correlates with GE time. This was a pilot study to determine the feasibility of using carbon-13 breath testing to measure GE in children with T1DM and healthy controls. Methods: Cases were recruited from children aged 7–15 years presenting to the paediatric diabetic clinic at Christchurch Hospital. Controls were peers of the cases. Children with known gastrointestinal disease were excluded. After an overnight fast, each child ate a standardised pancake labelled with carbon-13 sodium octanoate. Samples of breath were collected over a 4-h period. Samples were analysed by mass spectrometry. GE half time (GET1/2) and GE coefficients (GEC) were calculated by linear regression to obtain a measure of GE. Results: A total of 19 cases and 15 age- and gender-matched controls underwent testing. The mean GEC in the cases was 3.19 (±0.38) and 2.90 (±0.29) in controls (P = 0.03), with an effect size = 0.86. Mean GET1/2 in the cases was 99 (52.1) min and 103 (27.5) in controls (P = 0.8), with an effect size = 0.1. Conclusion: The study generated results suggesting that a larger study will be worthwhile to investigate the relationship between GE and T1DM Refereed/Peer-reviewed

The ‘Every Newborn Action Plan’ envisions to end preventable newborn deaths and stillbirths by 2035. One important objective to realize this vision is improvement in quality of maternal and neonatal healthcare. Monitoring the performance of the healthcare systems and conducting quality improvement activities need reliable systems for data collection, analysis and interpretation. Measures chosen to monitor quality are about problems accounting for a significant health burden, for which effective interventions are available, there is evidence of variable or substandard care, and for which improvement can be undertaken by stakeholders. Data can be collected about safety, effectiveness, efficiency, equity, patient-centeredness and timeliness of care. These data can be collected by direct observation, from existing records, and by interview of the involved stakeholders. Healthcare facilities and governments need to identify core sets of quality of care indicators, regularly measure and track their performance and carry out informed quality assurance and quality improvement efforts.

Neonatal intensive care for infants born extremely preterm (

ObjectiveThere are few data on visual outcomes in adulthood of former very low birthweight (VLBW; MethodsThe cohort and controls attended a 2-day assessment in Christchurch as part of a larger study. Visual assessment included glasses prescription measured by focimeter, logarithm of the minimum angle of resolution (logMAR) distance visual acuity (VA), contrast sensitivity, autorefraction, retinal photographs and a questionnaire on vision-related everyday activities. Rates of reduced VA and myopia in the VLBW cohort at 27–29 were compared with the results of vision testing at 7–8 years.Results250 VLBW adults (77% those alive) gave study consent and 229 (45 with a history of ROP) were assessed in Christchurch, plus 100 term born controls. VLBW adults with ROP had reduced VA compared with no ROP and controls (mean logMAR score (SD); 0.003 (0.19), –0.021 (0.16), –0.078 (0.09), P=0.001). There were no differences in myopia (>2 D) between the groups but high myopia (>5 D) was confined to those with ROP. VLBW adults with ROP drove a car less often and had higher difficulties with everyday activities scores due to eyesight. Between 7–8 and 27–29 years rates of reduced VA were stable but myopia increased.ConclusionFormer VLBW young adults with ROP have ongoing problems with vision affecting daily living and should continue in regular ophthalmological review.Trial registration numberACTRN12612000995875, Pre-results .

OBJECTIVE: To explore population characteristics, organization of health services and comparability of available information for very low birth weight or very preterm neonates born before 32 weeks' gestation in 11 high-income countries contributing data to the International Network for Evaluating Outcomes of Neonates (iNeo). STUDY DESIGN: We obtained population characteristics from public domain sources, conducted a survey of organization of maternal and neonatal health services and evaluated the comparability of data contributed to the iNeo collaboration from Australia, Canada, Finland, Israel, Italy, Japan, New Zealand, Spain, Sweden, Switzerland and UK. RESULTS: All countries have nationally funded maternal/neonatal health care with >90% of women receiving prenatal care. Preterm birth rate, maternal age, and neonatal and infant mortality rates were relatively similar across countries. Most (50 to >95%) between-hospital transports of neonates born at non-tertiary units were conducted by designated transport teams; 72% (8/11 countries) had designated transfer and 63% (7/11 countries) mandate the presence of a physician. The capacity of 'step-down' units varied between countries, with capacity for respiratory care available in < 10% to >75% of units. Heterogeneity in data collection processes for benchmarking and quality improvement activities were identified. CONCLUSIONS: Comparability of healthcare outcomes for very preterm low birth weight neonates between countries requires an evaluation of differences in population coverage, healthcare services and meta-data.

ObjectivesTo compare necrotising enterocolitis (NEC) prevention practices and NEC associated factors between units from eight countries of the International Network for Evaluation of Outcomes of Neonates, and to assess their association with surgical NEC rates.DesignProspective unit-level survey combined with retrospective cohort study.SettingNeonatal intensive care units in Australia/New Zealand, Canada, Finland, Israel, Spain, Sweden, Switzerland and Tuscany (Italy).PatientsExtremely preterm infants born between 240to 286weeks’ gestation, with birth weightsExposuresNEC prevention practices (probiotics, feeding, donor milk) using responses of an on-line pre-piloted questionnaire containing 10 questions and factors associated with NEC in literature (antenatal steroids, c-section, indomethacin treated patent ductus arteriosus and sepsis) using cohort data.Outcome measuresSurgical NEC rates and death following NEC using cohort data.ResultsThe survey response rate was 91% (153 units). Both probiotic provision and donor milk availability varied between 0%–100% among networks whereas feeding initiation and advancement rates were similar in most networks. The 9792 infants included in the cohort study to link survey results and cohort outcomes, revealed similar baseline characteristics but considerable differences in factors associated with NEC between networks. 397 (4.1%) neonates underwent NEC surgery, ranging from 2.4%–8.4% between networks. Standardised ratios for surgical NEC were lower for Australia/New Zealand, higher for Spain, and comparable for the remaining six networks.ConclusionsThe variation in implementation of NEC prevention practices and in factors associated with NEC in literature could not be associated with the variation in surgical NEC incidence. This corroborates the current lack of consensus surrounding the use of preventive strategies for NEC and emphasises the need for research.

Reducing the burden of visual morbidity from retinopathy of prematurity (ROP) begins with primary prevention, and improvements in neonatal care with a positive impact on ROP are possible in all settings. Strategies range from rigorous adoption of inexpensive evidence-based protocols, for example on temperature control, prevention of sepsis and support for breast-milk feeding, through to comprehensive quality improvement programmes, and fostering team work and camaraderie. Oxygen monitoring is essential for very preterm infants receiving supplementary oxygen. The Neonatal Oxygenation Prospective Meta-analysis (NeOProM) collaboration has reported analysis of five trials of oxygen saturation (SpO2) targeting in very preterm infants and shown that a SpO2 target of 85-89% compared to 91-95% was associated with increased mortality (on average 28 extra deaths for every 1000 infants treated). Adopting a SpO2 target higher than 85-89% might increase the risk of ROP for some infants, highlighting the importance of pursuing all other means of prevention.

The availability of and variability in healthcare professionals in neonatal units in different countries has not been well characterized. Our objective was to identify variations in the healthcare professionals for preterm neonates in 10 national or regional neonatal networks participating in the International Network for Evaluating Outcomes (iNeo) of neonates.Online, pre-piloted questionnaires about the availability of healthcare professionals were sent to the directors of 390 tertiary neonatal units in 10 international networks: Australia/New Zealand, Canada, Finland, Illinois, Israel, Japan, Spain, Sweden, Switzerland, and Tuscany.Overall, 325 of 390 units (83%) responded. About half of the units (48%; 156/325) cared for 11-30 neonates/day and had team-based (43%; 138/325) care models. Neonatologists were present 24 h a day in 59% of the units (191/325), junior doctors in 60% (194/325), and nurse practitioners in 36% (116/325). A nurse-to-patient ratio of 1:1 for infants who are unstable and require complex care was used in 52% of the units (170/325), whereas a ratio of 1:1 or 1:2 for neonates requiring multisystem support was available in 59% (192/325) of the units. Availability of a respiratory therapist (15%, 49/325), pharmacist (40%, 130/325), dietitian (34%, 112/325), social worker (81%, 263/325), lactation consultant (45%, 146/325), parent buddy (6%, 19/325), or parents' resource personnel (11%, 34/325) were widely variable between units.We identified variability in the availability and organization of the healthcare professionals between and within countries for the care of extremely preterm neonates. Further research is needed to associate healthcare workers' availability and outcomes.

AIM We surveyed care practices for critically ill very preterm infants admitted to neonatal intensive care units (NICUs) in the International Network for Evaluating Outcomes in Neonates (iNeo) to identify differences relevant to outcome comparisons. METHODS We conducted an online survey on care practices for critically ill very preterm infants and infants with severe intracranial haemorrhage (ICH). The survey was distributed in 2015 to representatives of 390 NICUs in 11 countries. Survey replies were compared with network incidence of death and severe ICH for infants born between 23$^{0/7}$ and 28$^{6/7}$ weeks of gestation from January 1, 2015, to December 31, 2015. RESULTS Most units in Israel, Japan and Tuscany, Italy, favoured withholding care when care was considered futile, whereas most units in other networks favoured redirection of care. For infants with bilateral grade 4 ICH, redirection of care was very frequently (≥90% of cases) offered in the majority of units in Australia and New Zealand and Switzerland, but rarely in other networks. Networks where redirection of care was frequently offered for severe ICH had lower rates of survivors with severe ICH. CONCLUSION We identified marked inter-network differences in care approaches that need to be considered when comparing outcomes.

Importance To facilitate drug and device development for neonates, the International Neonatal Consortium brings together key stakeholders, including pharmaceutical companies, practitioners, regulators, funding agencies, scientists, and families, to address the need for objective, standardized clinical trial outcome measurements to fulfill regulatory requirements. Retinopathy of prematurity (ROP) is a disease that affects preterm neonates. The current International Classification of Retinopathy of Prematurity does not take into account all of the characteristics of ROP and does not adequately discriminate small changes in disease after treatment. These factors are critical for evaluating outcomes in clinical trials. Observations There is need for an updated ROP acute disease activity and structure scale as well as end-stage structure and ophthalmologic outcome measures designed for use at different ages. The scale and measures, based on current diagnostic methods and treatments, could be used as a guideline for clinical intervention trials. The scale is intended to be validated against retrospective data and revised for use in future trials. An iterative revision process can be accomplished if new measures are added to clinical trials and evaluated at the end of each trial for prognostic value. The new measures would then be incorporated into a new version of the activity scale and the outcome measures revised. Conclusions and relevance An ROP activity scale and outcome measures to obtain the most robust and discriminatory data for clinical trials are needed. The scales should be dynamic and modified as knowledge and imaging modalities improve and then validated using data from well-documented clinical trials. This approach is relevant to improving clinical trial data quality.

To examine the relationship between hypertensive disorders of pregnancy (HDPs) and mortality and major morbidities in preterm neonates born at 24 to 28 weeks of gestation.Using an international cohort, we retrospectively studied 27 846 preterm neonates born at 24The incidence of HDP in the entire cohort was 13% (range 11 to 16% across countries). HDP was associated with reduced odds of mortality (adjusted odds ratio (aOR) 0.77; 95% confidence interval (CI) 0.67 to 0.88), severe brain injury (aOR 0.74; 95% CI 0.62 to 0.89) and treated retinopathy (aOR 0.82; 95% CI 0.70 to 0.96), but increased odds of bronchopulmonary dysplasia (aOR 1.16; 95% CI 1.05 to 1.27).In comparison with neonates born to mothers without HDP, neonates of HDP mothers had lower odds of mortality, severe brain injury and treated retinopathy, but higher odds of bronchopulmonary dysplasia. The impact of maternal HDP on newborn outcomes was inconsistent across outcomes and among countries; therefore, further international collaboration to standardize terminology, case definition and data capture is warranted.

Neonatal care during the first hours and weeks of life determines a preterm baby’s chances of avoiding retinopathy of prematurity and its complications. Oxygen management and low-cost interventions make all the difference.

Objectives To evaluate the proportion of neonatal intensive care units with facilities supporting parental presence in their infants’ rooms throughout the 24-hour day (ie, infant-parent rooms) in high-income countries and to analyze the association of this with outcomes of extremely preterm infants. Study design In this survey and linked cohort study, we analyzed unit design and facilities for parents in 10 neonatal networks of 11 countries. We compared the composite outcome of mortality or major morbidity, length of stay, and individual morbidities between neonates admitted to units with and without infant-parent rooms by linking survey responses to patient data from 2015 for neonates of less than 29 weeks of gestation. Results Of 331 units, 13.3% (44/331) provided infant-parent rooms. Patient-level data were available for 4662 infants admitted to 159 units in 7 networks; 28% of the infants were cared for in units with infant-parent rooms. Neonates from units with infant-parent rooms had lower odds of mortality or major morbidity (aOR, 0.76; 95% CI, 0.64-0.89), including lower odds of sepsis and bronchopulmonary dysplasia, than those from units without infant-parent rooms. The adjusted mean length of stay was 3.4 days shorter (95%, CI –4.7 to −3.1) in the units with infant-parent rooms. Conclusions The majority of units in high-income countries lack facilities to support parents' presence in their infants' rooms 24 hours per day. The availability vs absence of infant-parent rooms was associated with lower odds of composite outcome of mortality or major morbidity and a shorter length of stay.

The 'Every Newborn Action Plan' envisions to end preventable newborn deaths and stillbirths by 2035. One important objective to realize this vision is improvement in quality of maternal and neonatal healthcare. Monitoring the performance of the healthcare systems and conducting quality improvement activities need reliable systems for data collection, analysis and interpretation. Measures chosen to monitor quality are about problems accounting for a significant health burden, for which effective interventions are available, there is evidence of variable or substandard care, and for which improvement can be undertaken by stakeholders. Data can be collected about safety, effectiveness, efficiency, equity, patient-centeredness and timeliness of care. These data can be collected by direct observation, from existing records, and by interview of the involved stakeholders. Healthcare facilities and governments need to identify core sets of quality of care indicators, regularly measure and track their performance and carry out informed quality assurance and quality improvement efforts.