(N Engl J Med. 2024;390(4):314–325) In the past 20 years, survival rates among exceedingly premature neonates have risen. There is also a documented slight decrease in neonatal illness in the same time period, although bronchopulmonary dysplasia rates have climbed. Among exceedingly premature neonates, a patent ductus arteriosus (PDA) with a diameter of at least 1.5 mm persisting beyond 72 hours after birth correlates with heightened mortality, morbidity, and a greater chance of bronchopulmonary dysplasia compared with infants without a PDA. The occurrence of PDA declines as gestational age decreases. The risk of bronchopulmonary dysplasia or death in exceedingly premature neonates also rises with PDA persisting beyond 1 to 2 weeks after birth.

Aims The management of PDA continues to be a clinical conundrum in extremely low gestational age newborns (ELGANS). Presence of a PDA at 72 hours after birth in ELGANS is associated with an increased risk of death and complications of prematurity. Functional echocardiography (fEcho) is increasingly used to assess the haemodynamic impact of PDA and can be used in the first 3 days after birth to identify babies with a large pre-symptomatic PDA. The objective of this study was to evaluate whether early targeted treatment of a large PDA (diagnosed by fEcho) in extreme preterm babies with ibuprofen within 72 hours of birth improves short term health outcomes of death or moderate to severe BPD at 36 weeks post-menstrual age (PMA). Methods Baby-OSCAR is a UK multi-centre placebo-controlled masked randomised clinical trial in babies between 23+0and 28+6weeks’ gestation. With parental consent, eligible babies admitted to tertiary NICU were screened using fEcho. Babies with a large PDA on fEcho, (diameter >1.5mm and with a pulsatile or growing pulse wave Doppler ductal flow pattern), were randomised within the first 72 hours after birth. A central secure web-based randomisation system using a probabilistic minimisation algorithm was used to allocate treatments. Babies received either i.v. ibuprofen at dose 10-5-5 mg/kg 24 hours apart or matched placebo (0.9% normal saline). The primary outcome was a composite of death or moderate to severe BPD at 36 weeks PMA. The trial was funded by the UK National Institute for Health Research. Ethics approval was obtained from East Midlands Research Ethics Committee. Statistical analysis by intention-to-treat was performed using Stata 17®. Results A total of 3848 babies were screened with fEcho from 32 tertiary NICU in the UK from July 2015–December 2020. Of these, 653 infants were randomised: 326 to ibuprofen and 327 to placebo. Infant baseline characteristics were broadly similar between the study groups (table 1). The median size of the PDA was 2.2mm in both groups. The primary outcome event rate in the ibuprofen and control groups was 220/318 (69.2%) and 202/318 (63.5%) respectively; adjusted risk ratio 1.09 (95% CI 0.98 to 1.20); p=0.104. There was no evidence of differences in secondary outcomes, except reduced need for surgical ligation (2.8% vs 9.6%; p<0.001) and a higher proportion of closed/non-significant PDA at ~3 weeks age (55.5% vs 37%; p<0.001) in ibuprofen compared to placebo respectively (table 2). Conclusion We found no evidence of a reduction in death or moderate to severe BPD with early selective treatment of a large PDA with ibuprofen within 72 hours of birth in extreme preterm infants.

Abstract Background The question of whether to treat patent ductus arteriosus (PDA) early or wait until symptoms appear remains high on the research agenda for neonatal medicine. Around 7000 extremely preterm babies under 29 weeks’ gestation are born in the UK every year. In 40% of cases the PDA will fail to close spontaneously, even by 4 months of age. Untreated PDA can be associated with several serious and life-threatening short and long-term complications. Reliable data to support clinical decisions about PDA treatment are needed to prevent serious complications in high risk babies, while minimising undue exposure of infants. With the availability of routine bedside echocardiography, babies with a large PDA can be diagnosed before they become symptomatic. Methods This is a multicentre, masked, randomised, placebo-controlled parallel group trial to determine if early-targeted treatment of a large PDA with parenteral ibuprofen in extremely preterm babies (23+ 0–28+ 6 weeks’ gestation) improves short and long-term health and economic outcomes. With parental informed consent, extremely preterm babies (born between 23+ 0–28+ 6 weeks’ gestation) admitted to tertiary neonatal units are screened using echocardiography. Babies with a large PDA on echocardiography, defined by diameter of at least 1.5 mm and unrestricted pulsatile PDA flow pattern, are randomly allocated to either ibuprofen or placebo within 72 h of birth. The primary endpoint is the composite outcome of death by 36 weeks’ postmenstrual age or moderate or severe bronchopulmonary dysplasia (BPD) at 36 weeks postmenstrual age. Discussion Prophylactic pharmacological treatment of all preterm babies unnecessarily exposes them to potentially serious side effects of drug treatment, when their PDA may have closed spontaneously. However, delaying treatment until babies become symptomatic could result in loss of treatment benefit as irreversible damage may have already been done. Targeted, early pharmacological treatment of PDA in asymptomatic babies has the potential to overcome the disadvantages of both prophylactic (overtreatment) and symptomatic approaches (potentially too late). This could result in improvements in the clinically important short-term clinical (mortality and moderate or severe BPD at 36 weeks’ postmenstrual age) and long-term health outcomes (moderate or severe neurodevelopment disability and respiratory morbidity) measured at 2 years corrected age. Trial registration ISRCTN84264977 . Date assigned: 15/09/2010.

It is every neonatologist’s aspiration to achieve “optimal postnatal growth” in preterm infants, because nutrition and growth of this population affect long-term neurodevelopmental outcomes. However, despite having this common goal, there are huge variations in the enteral feeding practices of preterm infants across the globe. One such practice is the rate of advancement of enteral feedings; there is no consensus about the optimal approach, even among international nutritional experts. In this review, we aim to provide readers with the rationale for different practices in feeding advancement and summarize the current literature.

This issue of Seminars examines respiratory distress in the term newborn. Whereas respiratory distress has a greater incidence in preterm infants, because there are nearly ten times as many term newborns, the prevalence of respiratory distress is higher. Many affected infants are born in community hospitals and their disease status comes as a surprise to both parents and providers.

Term infants with respiratory distress may have extremely varied etiologies of their illnesses. These range from anatomical malformations to infectious or inflammatory conditions to genetic, metabolic, or neurological abnormalities. This article reviews the present array of diagnostic studies available to the clinician, including the physical examination, imaging (radiography, computed tomography, magnetic resonance imaging, ultrasound, and nuclear scanning techniques), lung mechanics and function testing, evaluation of gas exchange (blood gases, pulse oximetry, transcutaneous monitoring, and end-tidal carbon monoxide measurements), and anatomical studies (bronchoscopy and lung biopsy). These tests and procedures are reviewed and a stepwise approach recommended.

AIM:This study determined current international clinical practice and opinions regarding initial fractional inspired oxygen (FiO2 ) and pulse oximetry (SpO2 ) targets for delivery room resuscitation of preterm infants of less than 29 weeks of gestation.METHODS:An online survey was disseminated to neonatal clinicians via established professional clinical networks using a web-based survey programme between March 9 and June 30, 2015.RESULTS:Of the 630 responses from 25 countries, 60% were from neonatologists. The majority (77%) would target SpO2 between the 10th to 50th percentiles values for full-term infants. The median starting FiO2 was 0.3, with Japan using the highest (0.4) and the UK using the lowest (0.21). New Zealand targeted the highest SpO2 percentiles (median 50%). Most respondents agreed or did not disagree that a trial was required that compared the higher FiO2 of 0.6 (83%), targeting the 50th SpO2 percentile (60%), and the lower FiO2 of 0.21 (80%), targeting the 10th SpO2 percentile (78%). Most (65%) would join this trial. Many considered that evidence was lacking and further research was needed.CONCLUSION:Clinicians currently favour lower SpO2 targets for preterm resuscitation, despite acknowledging the lack of evidence for benefit or harm, and 65% would join a clinical trial.

Viral infection is an important cause of upper and lower respiratory tract illness in infants and young children world wide, causing significant respiratory morbidity in affected children. Premature infants, especially those with bronchopulmonary dysplasia (BPD), chronic oxygen dependency and congenital heart disease are regarded as “high risk” infants because a higher proportion of such infants require hospitalization and admission to the pediatric intensive care units. Their problems often continue after discharge from hospital, as they may develop persistent symptoms such as cough and wheeze. This has significant impact on resource utilization, cost of care and quality of life for the infants and their families. A number of viruses such as respiratory syncytial virus (RSV) and adenoviruses are well recognized to be implicated in the pathogenesis of serious lower respiratory tract illness, but in a substantial number of symptomatic children, no virus can be identified. This may be due to a variety of reasons including insensitivity of the specific diagnostic tests at individual hospitals, or the medical profession’s unawareness of newly emerging pathogens. This was indeed the case when researchers in the Netherlands isolated human metapneumovirus (hMPV) from children for the first time in 2001 [1]. Since then, investigations in different coun-

Single-center randomized controlled trials confer certain advantages over multi-center trials, in that they are cheaper and easier to design and conduct. However, recent research suggests that single-center trials are likely to overestimate treatment effects. There are notable examples in neonatology where results from multi-center trials have contradicted results of single-center studies. In this paper we discuss issues around external generalizability of single-center studies, and methodological issues that may cause bias.

Over the last decade, more emphasis has been given to nutritional management of preterm infants than ever before. A number of basic science and clinical trials have been completed to investigate the nutritional basis of neonatal morbidities including necrotising enterocolitis (NEC), broncho-pulmonary dysplasia and long term neurodevelopmental outcomes. This edition of Gastroenterology and Nutrition in the series on Neonatal Questions and Controversies provides a comprehensive review of the various debatable issues in preterm nutrition as well as a rationale of current practices in nutritional management of preterm infants.

Respiratory distress syndrome is a disease of prematurity and is caused by a relative deficiency of endogenous surfactant production. Respiratory distress syndrome is the most common cause of mortality and morbidity in the newborn population and the standard of care is to provide exogenous surfactant therapy. This saves lives and reduces respiratory complications but, despite treatment, a significant proportion of these infants go onto develop chronic lung disease, the severest form of which is bronchopulmonary dysplasia. Once developed, this is a multisystem disease and treatment is mostly supportive by using various therapeutic adjuncts. Some of these have been proven to be safe and effective in large randomized, controlled trials but similar evidence for other drugs is lacking. The aim of this paper is to provide an overview and critically appraise the available scientific evidence for or against their use in routine practice.

Like many other organ systems, the respiratory system of a preterm infant develops in stages. The respiratory centre’s immaturity, unstable chest wall, compliant airways and surfactant deficiency altogether make it difficult for these infants to achieve effective respiration and cope with underlying lung pathology. The various modalities of non-invasive respiratory support help preterm infants in establishing their functional residual capacity and thus reduce the work of breathing. One of the other proposed mechanisms of action of non-invasive ventilation (NIV) is enhanced respiratory drive simply by stimulating the upper airways, which could be particularly useful in situations such as the immediate postextubation period. Preterm infants are also more prone to obstructive apnoea and NIV may help to prevent this by providing anchoring support to the airways. NIV in neonates is not a novel concept and its use has been reported in the literature for over half a century. Negative pressure ventilation was used as a form of NIV but without much benefit. The first report of possible use of NIV was published much before Gregory’s article on continuous positive airway pressure (CPAP). This modality lost interest among neonatologists over the next few decades because of associated complications including head moulding, cerebellar haemorrhage and gastric perforation. Newer and safer delivery devices have regenerated interest in NIV Non-invasive respiratory support in preterm infants: do we need more evidence?

Despite increased interest in continuous positive airway pressure (CPAP) and other forms of noninvasive respiratory support, mechanical ventilation remains the mainstay of treatment for babies with respiratory failure. This has been practiced since the late 1960's and enabled the survival of even smallest of babies who without this intervention would have died. However, many deleterious complications have been associated with mechanical ventilation. Much has been learnt since then about the pathophysiology of ventilator induced lung injury (VIL1) and in response, newer modes of ventilation have been introduced in the neonatal population, in order to try and minimise this. Whatever method is used, the goal of mechanical ventilation remains the same which is to optimise tidal volume delivery, reduce the work of breathing, and avoid iatrogenic complications.

Despite surfactant and mechanical ventilation being the standard of care for preterm infants with respiratory failure, non-invasive respiratory support is increasingly being employed in neonatal units. The latter can be accomplished in a variety of ways but none of them have been proven so far to be superior to intubation and mechanical ventilation. Nonetheless, they appear to be safe and effective in experienced hands. This article relates to the use of non-invasive forms of respiratory support and evidence is reviewed from the clinical trials which have evaluated the use of these techniques.

Objective: To determine if the advantages of Volume Controlled Ventilation (VCV) seen in randomised controlled trials (RCTs) are reproducible in daily clinical practice. Design: Hospital-based retrospective cohort study. Setting: James Cook University Hospital. Participants: Infants born between February 2008 and September 2009 with gestational age 24-31 weeks, weight 600-1500 g and diagnosis of respiratory distress syndrome for which they received VCV. Outcome measures: Total duration of mechanical ventilation, survival to discharge and frequency of bronchopulmonary dysplasia (BPD) were compared between the study cohort and the cohort treated with VCV in 2002-2004 RCT. Results: There was no statistically significant difference in the main outcome measures between the two cohorts (duration of ventilation: 171 hours versus 216 hours; p = 0.425, survival: 89.7% versus 91.2%; p = 1.00 and frequency of BPD 27.6% versus 28.1%; p = 1.00). Conclusion: The efficacy and safety of VCV in very preterm low birth weight babies can be maintained in routine clinical practice.