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

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

Airway obstruction in young adults born extremely preterm or extremely low birth weight in the postsurfactant era.

BACKGROUND: It is unknown if adults born <28 weeks or <1000 g since surfactant has been available are reaching their full airway growth potential. OBJECTIVE: To compare expiratory airflow at 25 years and from 8 to 25 years of participants born <28 weeks or <1000 g with controls, and within the preterm group to compare those who had bronchopulmonary dysplasia with those who did not. METHODS: All survivors born <28 weeks or <1000 g in 1991-1992 in Victoria, Australia, were eligible. Controls were born contemporaneously, weighing >2499 g. At 8, 18 and 25 years, expiratory airflows were measured and the results converted to z-scores. Outcomes were compared between groups at age 25 years, and trajectories (change in z-scores per year) from childhood were contrasted between groups. RESULTS: Expiratory airflows were measured at 25 years on 164 of 297 (55%) preterm survivors and 130 of 260 (50%) controls. Preterm participants had substantially reduced airflow compared with controls at age 25 years (eg, zFEV1; mean difference -0.97, 95% CI -1.23 to -0.71; p<0.001). Preterm participants had lower airflow trajectories than controls between 8 and 18 years, but not between 18 and 25 years. Within the preterm group, those who had bronchopulmonary dysplasia had worse airflows and trajectories than those who did not. CONCLUSIONS: Young adults born <28 weeks or <1000 g in the surfactant era, particularly those who had bronchopulmonary dysplasia, have substantially reduced airway function compared with controls. Some are destined to develop COPD in later adult life.

Very preterm birth before arrival at hospital.

BACKGROUND: Our aim was to report perinatal characteristics of very preterm births before arrival (BBAs) at a hospital, and perinatal and infant mortality rates up to one year, comparing BBAs with births in a hospital. MATERIALS AND METHODS: A population-based cohort study of 22-31 weeks' gestation births in the state of Victoria, Australia from 1990-2009. BBAs were defined as unintentional births at home or on route to hospital. Perinatal data were obtained from the Department of Health and Human Services, Victoria. Perinatal and infant mortality data comparing BBAs with births in hospitals were analysed by logistic regression, adjusted for gestational age, birthweight and sex. RESULTS: One hundred and thirty-three BBAs were recorded: 51 (38%) stillbirths and 82 (62%) livebirths. Compared with births in a hospital, BBAs were less mature (26.3 weeks (SD 2.9) vs 27.7 weeks (SD 2.8), P < 0.001) and a higher proportion were born to teenagers: 13% versus 5% (adjusted odds ratio (aOR) 2.86, P < 0.001). BBAs were significantly more likely to be stillborn (aOR 2.13, 95% confidence interval (CI) 1.41, 3.23, P < 0.001) die within 28 days of livebirth (aOR 2.97, 95% CI 1.54, 5.73, P = 0.001) or die within a year of livebirth (aOR 2.87, 95% CI 1.51, 5.46, P = 0.001) compared with hospital births. Overall, 54 BBAs survived to one year (41% all BBAs, 67% liveborn BBAs), compared with 69% of hospital births (87% of livebirths). CONCLUSIONS: Very preterm birth before arrival is more common in teenagers and is associated with significantly increased risks of perinatal and infant mortality compared with birth in a hospital.

What are we telling the parents of extremely preterm babies?

BACKGROUND: Parent counselling and decision-making regarding the management of preterm labour and birth are influenced by information provided by healthcare professionals regarding potential infant outcomes. AIM: The aim of this study was to determine whether perinatal healthcare providers had accurate perceptions of survival and major neurosensory disability rates of very preterm infants born in non-tertiary hospitals ('outborn') and tertiary perinatal centres ('inborn'). MATERIALS AND METHODS: A web-based survey was distributed to midwives, nurses, obstetricians and neonatologists working in non-tertiary and tertiary maternity hospitals, and the perinatal/neonatal emergency transport services in Victoria, Australia. MAIN OUTCOME MEASURES: Estimates of survival rates at 24 and 28-weeks' gestation were compared with actual survival rates of a population-based cohort of 24 and 28-weeks' gestation infants, born free of lethal anomalies in Victoria in 2001-2009. Estimates of major neurosensory disability rates in 24 and 28-week survivors were compared with actual disability rates in 24 and 28-week children born in Victoria averaged over three eras: 1991-1992, 1997 and 2005. RESULTS: Response rates varied as follows: 83% of non-tertiary midwives, 4% of obstetricians, 55% of tertiary centre staff and 68% of transport team staff responded (total of 30%). Overall, respondents underestimated survival and overestimated major neurosensory disability rates in both outborn and inborn 24 and 28-week infants. Outborn infants were perceived to have much worse prospects for survival and for survival with major disability compared with inborn peers. CONCLUSION: Many clinicians overestimated rates of adverse outcomes. These clinicians may be misinforming parents about their child's potential for a favourable outcome.

Why birthplace still matters for infants born before 32 weeks: Infant mortality associated with birth at 22-31 weeks' gestation in non-tertiary hospitals in Victoria over two decades.

BACKGROUND: Very preterm infants born in non-tertiary hospitals ('outborn') are known to have higher mortality rates compared with infants 'inborn' in tertiary centres. AIM: The aim of this study was to report changes over time in the incidence of outborn livebirths, 22-31 weeks and infant mortality rates for outborn compared with inborn births. METHODS: We conducted a population-based cohort study of consecutive livebirths, 22-31 weeks' gestation in Victoria from 1990 to 2009. The relationship between birthplace, gestational age, birthweight, sex and infant mortality were analysed by logistic regression. RESULTS: There were 13,760 livebirths, 22-31 weeks: 14% were outborn. The proportion of outborn livebirths fell from 19% in 1991 to a nadir of 9% in 1997, but climbed to 17% by 2009. At all times, outborns had higher mortality rates compared with inborns. The overall infant mortality rate was 250.6 per 1000 outborn compared with 113.3 per 1000 inborn livebirths (adjusted odds ratio (aOR) 2.76 (95% CI 2.32, 3.27, P < 0.001). There were no differences between outborn and inborn mortality risks for 22-week livebirths (OR 7.04, 95% CI 0.87, 56.8, P = 0.067), but there were at 23-27 weeks (aOR 3.16, 95% CI 2.52, 3.96, P < 0.001) and at 28-31 weeks (aOR 1.66, 95% CI 1.19, 2.31, P = 0.003). Over time, mortality rates fell for inborn 23-27 week infants. Mortality rates fell for outborn 23-27 week infants in 1990-2005, but rose in 2006-2009. CONCLUSIONS: Outborn livebirths at 22-31 weeks' gestation occur too frequently and are associated with a significantly increased risk of mortality. Strategies to reduce outborn livebirths are required.

Early developmental screening and intervention for high-risk neonates - From research to clinical benefits.

With advances in neonatal care there has been an increase in survival rates for infants born very preterm and/or with complex needs, such as those who require major surgery, who may not have survived decades ago. Despite advances in survival, these infants remain at high-risk for a range of neurodevelopmental delays and/or impairments including motor, cognitive and emotional/behavioural challenges. Research has improved our ability to identify which infants are at high-risk of developmental delay and/or impairments, and there is mounting evidence that early interventions can improve outcomes of these infants. However, clinical practice varies throughout the world regarding recommendations for developmental screening. Moreover, intervention, when available, is often not commenced early enough in development. Given limited resources, those infants most at risk of developmental impairments and their families should be targeted, with further research needed on the cost-effectiveness of surveillance and early interventions.

Impact of moderate and late preterm birth on neurodevelopment, brain development and respiratory health at school age: protocol for a longitudinal cohort study (LaPrem study).

INTRODUCTION: Children born moderate to late preterm (MLP, 32-36 weeks' gestation) account for approximately 85% of all preterm births globally. Compared with children born at term, children born MLP are at increased risk of poor neurodevelopmental outcomes. Despite making up the largest group of preterm children, developmental outcomes of children born MLP are less well studied than in other preterm groups. This study aimed to (1) compare neurodevelopmental, respiratory health and brain magnetic resonance imaging (MRI) outcomes between children born MLP and term at 9 years of age; (2) examine the differences in brain growth trajectory from infancy to 9 years between children born MLP and term; and in children born MLP; (3) examine the relationship between brain development and neurodevelopment at 9 years; and (4) identify risk factors for poorer outcomes at 9 years. METHODS AND ANALYSIS: The "LaPrem" (Late Preterm MRI Study) study is a longitudinal cohort study of children born MLP and term controls, born at the Royal Women's Hospital in Melbourne, Australia, between 2010 and 2013. Participants were recruited in the neonatal period and were previously followed up at 2 and 5 years. This 9-year school-age follow-up includes neuropsychology, motor and physical activities, and lung function assessments, as well as brain MRI. Outcomes at 9 years will be compared between birth groups using linear and logistic regressions. Trajectories of brain development will be compared between birth groups using mixed effects models. The relationships between MRI and neurodevelopmental outcomes, as well as other early predictors of poor 9-year outcomes, will be explored using linear and logistic regression. ETHICS AND DISSEMINATION: This study was approved by the human research ethics committee at the Royal Children's Hospital, Melbourne, Australia. Study outcomes will be disseminated through peer-reviewed publications, conference presentations and social media.

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

INTRODUCTION: Docosahexaenoic acid (DHA) is an omega-3 (n-3) fatty acid that accumulates into neural tissue during the last trimester of pregnancy, as the fetal brain is undergoing a growth spurt. Infants born <29 weeks' gestation are deprived the normal in utero supply of DHA during this period of rapid brain development. Insufficient dietary DHA postnatally may contribute to the cognitive impairments common among this population. This follow-up of the N-3 fatty acids for improvement in respiratory outcomes (N3RO) randomised controlled trial aims to determine if enteral DHA supplementation in infants born <29 weeks' gestation during the first months of life improves cognitive development at 5 years of age corrected for prematurity. METHODS AND ANALYSIS: N3RO was a randomised controlled trial of enteral DHA supplementation (60 mg/kg/day) or a control emulsion (without DHA) in 1273 infants born <29 weeks' gestation to determine the effect on bronchopulmonary dysplasia (BPD). We showed that DHA supplementation did not reduce the risk of BPD and may have increased the risk.In this follow-up at 5 years' corrected age, a predefined subset (n=655) of children from five Australian sites will be invited to attend a cognitive assessment with a psychologist. Children will be administered the Wechsler Preschool and Primary Scale of Intelligence (fourth edition) and a measure of inhibitory control (fruit stroop), while height, weight and head circumference will be measured.The primary outcome is full-scale IQ. To ensure 90% power, a minimum of 592 children are needed to detect a four-point difference in IQ between the groups.Research personnel and families remain blinded to group assignment. ETHICS AND DISSEMINATION: The Women's and Children Health Network Human Research Ethics Committee reviewed and approved the study (HREC/17/WCHN/187). Caregivers will give informed consent prior to taking part in this follow-up study. Findings of this study will be disseminated through peer-reviewed publications and conference presentations. TRIAL REGISTRATION NUMBER: ACTRN12612000503820.

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.

Long-term effects of postnatal corticosteroids to prevent or treat bronchopulmonary dysplasia: Balancing the risks and benefits.

Postnatal corticosteroids are effective in preventing or treating bronchopulmonary dysplasia (BPD) in preterm newborns, but their benefits need to exceed their risks. Several types of corticosteroids, and different timing and administration modes have been trialed. Systemic corticosteroids, given either early or late, have proven efficacy for reducing BPD and the combined outcome of death or BPD. Inhaled corticosteroids are less effective. However, systemic dexamethasone given early is associated with more neurosensory disability and cerebral palsy in survivors. The risk of adverse neurodevelopment is highest if dexamethasone is given to preterm infants at low risk of BPD. Current trials focus on corticosteroids, mixed with surfactant, delivered intratracheally directly to the lung, which may avoid some systemic adverse effects of corticosteroids. Early trials of intratracheal corticosteroids are encouraging, but more data are needed to determine whether this method of administration is preferable to systemic corticosteroids for preventing or treating BPD.

Outcomes of infants born at 22-27 weeks' gestation in Victoria according to outborn/inborn birth status.

OBJECTIVES: To compare mortality and serious morbidity rates between outborn and inborn livebirths at 22-27 weeks' gestation. DESIGN: Population-based cohort study. SETTING: Victoria, Australia. PATIENTS: Livebirths at 22-27 weeks' gestation free of major malformations in 2010-2011. INTERVENTIONS: Outcome data for outborn (born outside a tertiary perinatal centre) infants compared with inborn (born in a tertiary perinatal centre) infants were analysed by logistic regression, adjusted for gestational age, birth weight and sex. MAIN OUTCOME MEASURES: Infant mortality and serious morbidity rates to hospital discharge. RESULTS: 541 livebirths free of major malformations were recorded. By 1 year, 49 (58%) outborns and 140 (31%) inborns died (adjusted OR (aOR) 2.78, 95% CI 1.52 to 5.09, p=0.001). In total, 445 infants were admitted to neonatal intensive care unit (NICU); 93 died by 1 year (14/49 outborns and 79/396 inborns), (aOR 1.75, 95% CI 0.87 to 3.55, p=0.12). There were no significant differences in rates of necrotising enterocolitis, intraventricular haemorrhage, retinopathy of prematurity, bronchopulmonary dysplasia (BPD) or the combined outcome of death or BPD in outborn infants compared with inborn infants. Outborns had an increased risk of cystic periventricular leukomalacia (cPVL) compared with inborns (12.2% vs 2.8%, respectively; aOR 5.34, 95% CI 1.84 to 15.54, p=0.002). CONCLUSIONS: Mortality rates remained higher for outborn livebirths at 22-27 weeks' gestation compared with inborn peers in 2010-2011. Outborn infants admitted to NICU did not have substantially different rates of mortality or serious morbidity compared with inborns, with the exception of cPVL. Longer-term health consequences of outborn birth before 28 weeks' gestation need to be determined.