European Consensus Guidelines on the Management of Respiratory Distress Syndrome: 2022 Update.

Respiratory distress syndrome (RDS) care pathways evolve slowly as new evidence emerges. We report the sixth version of "European Guidelines for the Management of RDS" by a panel of experienced European neonatologists and an expert perinatal obstetrician based on available literature up to end of 2022. Optimising outcome for babies with RDS includes prediction of risk of preterm delivery, appropriate maternal transfer to a perinatal centre, and appropriate and timely use of antenatal steroids. Evidence-based lung-protective management includes initiation of non-invasive respiratory support from birth, judicious use of oxygen, early surfactant administration, caffeine therapy, and avoidance of intubation and mechanical ventilation where possible. Methods of ongoing non-invasive respiratory support have been further refined and may help reduce chronic lung disease. As technology for delivering mechanical ventilation improves, the risk of causing lung injury should decrease, although minimising time spent on mechanical ventilation by targeted use of postnatal corticosteroids remains essential. The general care of infants with RDS is also reviewed, including emphasis on appropriate cardiovascular support and judicious use of antibiotics as being important determinants of best outcome. We would like to dedicate this guideline to the memory of Professor Henry Halliday who died on November 12, 2022.These updated guidelines contain evidence from recent Cochrane reviews and medical literature since 2019. Strength of evidence supporting recommendations has been evaluated using the GRADE system. There are changes to some of the previous recommendations as well as some changes to the strength of evidence supporting recommendations that have not changed. This guideline has been endorsed by the European Society for Paediatric Research (ESPR) and the Union of European Neonatal and Perinatal Societies (UENPS).

Late (≥ 7 days) systemic postnatal corticosteroids for prevention of bronchopulmonary dysplasia in preterm infants.

BACKGROUND: Many infants born preterm develop bronchopulmonary dysplasia (BPD), with lung inflammation playing a role. Corticosteroids have powerful anti-inflammatory effects and have been used to treat individuals with established BPD. However, it is unclear whether any beneficial effects outweigh the adverse effects of these drugs. OBJECTIVES: To examine the relative benefits and adverse effects of late (starting at seven or more days after birth) systemic postnatal corticosteroid treatment for preterm infants with evolving or established BPD. SEARCH METHODS: We ran an updated search on 25 September 2020 of the following databases: CENTRAL via CRS Web and MEDLINE via OVID. We also searched clinical trials databases and reference lists of retrieved articles for randomised controlled trials (RCTs). We did not include quasi-RCTs. SELECTION CRITERIA: We selected for inclusion in this review RCTs comparing systemic (intravenous or oral) postnatal corticosteroid treatment versus placebo or no treatment started at seven or more days after birth for preterm infants with evolving or established BPD. We did not include trials of inhaled corticosteroids. DATA COLLECTION AND ANALYSIS: We used standard Cochrane methods. We extracted and analysed data regarding clinical outcomes that included mortality, BPD, and cerebral palsy. We used the GRADE approach to assess the certainty of evidence. MAIN RESULTS: Use of the GRADE approach revealed that the certainty of evidence was high for most of the major outcomes considered, except for BPD at 36 weeks for all studies combined and for the dexamethasone subgroup, which were downgraded one level to moderate because of evidence of publication bias, and for the combined outcome of mortality or BPD at 36 weeks for all studies combined and for the dexamethasone subgroup, which were downgraded one level to moderate because of evidence of substantial heterogeneity. We included 23 RCTs (1817 infants); 21 RCTS (1382 infants) involved dexamethasone (one also included hydrocortisone) and two RCTs (435 infants) involved hydrocortisone only. The overall risk of bias of included studies was low; all were RCTs and most trials used rigorous methods. Late systemic corticosteroids overall reduce mortality to the latest reported age (risk ratio (RR) 0.81, 95% confidence interval (CI) 0.66 to 0.99; 21 studies, 1428 infants; high-certainty evidence). Within the subgroups by drug, neither dexamethasone (RR 0.85, 95% CI 0.66 to 1.11; 19 studies, 993 infants; high-certainty evidence) nor hydrocortisone (RR 0.74, 95% CI 0.54 to 1.02; 2 studies, 435 infants; high-certainty evidence) alone clearly reduce mortality to the latest reported age. We found little evidence for statistical heterogeneity between the dexamethasone and hydrocortisone subgroups (P = 0.51 for subgroup interaction). Late systemic corticosteroids overall probably reduce BPD at 36 weeks' postmenstrual age (PMA) (RR 0.89, 95% CI 0.80 to 0.99; 14 studies, 988 infants; moderate-certainty evidence). Dexamethasone probably reduces BPD at 36 weeks' PMA (RR 0.76, 95% CI 0.66 to 0.87; 12 studies, 553 infants; moderate-certainty evidence), but hydrocortisone does not (RR 1.10, 95% CI 0.92 to 1.31; 2 studies, 435 infants; high-certainty evidence) (P < 0.001 for subgroup interaction). Late systemic corticosteroids overall probably reduce the combined outcome of mortality or BPD at 36 weeks' PMA (RR 0.85, 95% CI 0.79 to 0.92; 14 studies, 988 infants; moderate-certainty evidence). Dexamethasone probably reduces the combined outcome of mortality or BPD at 36 weeks' PMA (RR 0.75, 95% CI 0.67 to 0.84; 12 studies, 553 infants; moderate-certainty evidence), but hydrocortisone does not (RR 0.98, 95% CI 0.88 to 1.09; 2 studies, 435 infants; high-certainty evidence) (P < 0.001 for subgroup interaction). Late systemic corticosteroids overall have little to no effect on cerebral palsy (RR 1.17, 95% CI 0.84 to 1.61; 17 studies, 1290 infants; high-certainty evidence). We found little evidence for statistical heterogeneity between the dexamethasone and hydrocortisone subgroups (P = 0.63 for subgroup interaction). Late systemic corticosteroids overall have little to no effect on the combined outcome of mortality or cerebral palsy (RR 0.90, 95% CI 0.76 to 1.06; 17 studies, 1290 infants; high-certainty evidence). We found little evidence for statistical heterogeneity between the dexamethasone and hydrocortisone subgroups (P = 0.42 for subgroup interaction). Studies had few participants who were not intubated at enrolment; hence, it is not possible to make any meaningful comments on the effectiveness of late corticosteroids in preventing BPD in non-intubated infants, including those who might in the present day be supported by non-invasive techniques such as nasal continuous positive airway pressure or high-flow nasal cannula oxygen/air mixture, but who might still be at high risk of later BPD. Results of two ongoing studies are awaited. AUTHORS' CONCLUSIONS: Late systemic postnatal corticosteroid treatment (started at seven days or more after birth) reduces the risks of mortality and BPD, and the combined outcome of mortality or BPD, without evidence of increased cerebral palsy. However, the methodological quality of studies determining long-term outcomes is limited, and no studies were powered to detect increased rates of important adverse long-term neurodevelopmental outcomes. This review supports the use of late systemic corticosteroids for infants who cannot be weaned from mechanical ventilation. The role of late systemic corticosteroids for infants who are not intubated is unclear and needs further investigation. Longer-term follow-up into late childhood is vital for assessment of important outcomes that cannot be assessed in early childhood, such as effects of late systemic corticosteroid treatment on higher-order neurological functions, including cognitive function, executive function, academic performance, behaviour, mental health, motor function, and lung function. Further RCTs of late systemic corticosteroids should include longer-term survival free of neurodevelopmental disability as the primary outcome.

Early (< 7 days) systemic postnatal corticosteroids for prevention of bronchopulmonary dysplasia in preterm infants.

BACKGROUND: Bronchopulmonary dysplasia (BPD) remains a major problem for infants born extremely preterm. Persistent inflammation in the lungs is important in its pathogenesis. Systemic corticosteroids have been used to prevent or treat BPD because of their potent anti-inflammatory effects. OBJECTIVES: To examine the relative benefits and adverse effects of systemic postnatal corticosteroids commenced within the first six days after birth for preterm infants at risk of developing BPD. SEARCH METHODS: We ran an updated search of the following databases on 25 September 2020: CENTRAL via CRS Web and MEDLINE via OVID. We also searched clinical trials databases and reference lists of retrieved articles for randomised controlled trials (RCTs). We did not include cluster randomised trials, cross-over trials, or quasi-RCTs. SELECTION CRITERIA: For this review, we selected RCTs examining systemic (intravenous or oral) postnatal corticosteroid treatment started within the first six days after birth (early) in high-risk preterm infants. We included studies that evaluated the use of dexamethasone, as well as studies that assessed hydrocortisone, even when the latter was used primarily for management of hypotension, rather than for treatment of lung problems. We did not include trials of inhaled corticosteroids. DATA COLLECTION AND ANALYSIS: We used standard Cochrane methods. We extracted and analysed data regarding clinical outcomes that included mortality, BPD, mortality or BPD, failure to extubate, complications during the primary hospitalisation, and long-term health and neurodevelopmental outcomes. We used the GRADE approach to assess the certainty of evidence. MAIN RESULTS: Use of the GRADE approach revealed that the certainty of evidence was high for the major outcomes considered, except for BPD at 36 weeks for all studies combined, which was downgraded one level to moderate because of evidence of publication bias. We included 32 RCTs (4395 infants). The overall risk of bias of included studies was low; all were RCTs, and most trials used rigorous methods. Early systemic corticosteroids overall have little or no effect on mortality to the latest reported age (risk ratio (RR) 0.95, 95% confidence interval (CI) 0.85 to 1.06; 31 studies, 4373 infants; high-certainty evidence), but hydrocortisone alone reduces mortality (RR 0.80, 95% CI 0.65 to 0.99; 11 studies, 1433 infants; high-certainty evidence). Early systemic corticosteroids overall probably reduce BPD at 36 weeks' postmenstrual age (PMA) (RR 0.80, 95% CI 0.73 to 0.88; 26 studies, 4167 infants; moderate-certainty evidence), as does dexamethasone (RR 0.72, 95% CI 0.63 to 0.82; 17 studies, 2791 infants; high-certainty evidence), but hydrocortisone has little to no effect (RR 0.92, 95% CI 0.81 to 1.06; 9 studies, 1376 infants; high-certainty evidence). Early systemic corticosteroids overall reduce the combined outcome of mortality or BPD at 36 weeks' PMA (RR 0.89, 95% CI 0.84 to 0.94; 26 studies, 4167 infants; high-certainty evidence), as do both dexamethasone (RR 0.88, 95% CI 0.81 to 0.95; 17 studies, 2791 infants; high-certainty evidence) and hydrocortisone (RR 0.90, 95% CI 0.82 to 0.99; 9 studies, 1376 infants; high-certainty evidence). Early systemic corticosteroids overall increase gastrointestinal perforation (RR 1.84, 95% CI 1.36 to 2.49; 16 studies, 3040 infants; high-certainty evidence), as do both dexamethasone (RR 1.73, 95% CI 1.20 to 2.51; 9 studies, 1936 infants; high-certainty evidence) and hydrocortisone (RR 2.05, 95% CI 1.21 to 3.47; 7 studies, 1104 infants; high-certainty evidence). Early systemic corticosteroids overall increase cerebral palsy (RR 1.43, 95% CI 1.07 to 1.92; 13 studies, 1973 infants; high-certainty evidence), as does dexamethasone (RR 1.77, 95% CI 1.21 to 2.58; 7 studies, 921 infants; high-certainty evidence) but not hydrocortisone (RR 1.05, 95% CI 0.66 to 1.66; 6 studies, 1052 infants; high-certainty evidence). Early systemic corticosteroids overall have little to no effect on the combined outcome of mortality or cerebral palsy (RR 1.03, 95% CI 0.91 to 1.16; 13 studies, 1973 infants; high-certainty evidence), nor does hydrocortisone (RR 0.86, 95% CI 0.71 to 1.05; 6 studies, 1052 infants; high-certainty evidence). However, early dexamethasone probably increases the combined outcome of mortality or cerebral palsy (RR 1.18, 95% CI 1.01 to 1.37; 7 studies, 921 infants; high-certainty evidence), In sensitivity analyses by primary intention for treatment with hydrocortisone (lung problems versus hypotension), there was little evidence of differences in effects on major outcomes of mortality, BPD, or combined mortality or BPD, by indication for the drug. AUTHORS' CONCLUSIONS: Early systemic postnatal corticosteroid treatment (started during the first six days after birth) prevents BPD and the combined outcome of mortality or BPD. However, it increases risks of gastrointestinal perforation, cerebral palsy, and the combined outcome of mortality or cerebral palsy. Most beneficial and harmful effects are related to early treatment with dexamethasone, rather than to early treatment with hydrocortisone, but early hydrocortisone may prevent mortality, whereas early dexamethasone does not. Longer-term follow-up into late childhood is vital for assessment of important outcomes that cannot be assessed in early childhood, such as effects of early corticosteroid treatment on higher-order neurological functions, including cognitive function, executive function, academic performance, behaviour, mental health, motor function, and lung function. Further RCTs of early corticosteroids, particularly of hydrocortisone, should include longer-term survival free of neurodevelopmental disability as the primary outcome.

Evaluation of the Quality of Perinatal Trials: Making the GRADE.

BACKGROUND: Assessing the quality of clinical research is a key evidence-based practice skill. Clinicians, guideline producers, policy makers, service commissioners, and families need to have a sense of the validity, applicability, and certainty of research evidence when determining how it should inform their decision-making and practice. METHODS: We consider the various methodological and study design factors that contribute to the validity and applicability of clinical research findings. We describe the "Grading of Recommendations Assessment, Development and Evaluation" (GRADE) methodology and discuss how this approach is used to assess and report certainty of evidence and strength of recommendations. RESULTS: The randomized controlled trial (RCT) is the gold standard method for assessing interventions because randomization balances prognostic characteristics between comparison groups. The GRADE approach considers evidence from RCTs as high quality, but acknowledges that the quality and level of certainty of trial evidence may be "downgraded" based on consideration of threats across 5 domains: risk of bias in included trials, inconsistency between trials in outcome estimates, indirectness of the evidence, imprecision of estimates, and likelihood of publication bias. CONCLUSIONS: Structured critical appraisal using GRADE methods to assess risk of bias and other threats to the internal and external validity of RCTs and systematic reviews and meta-analyses of their data facilitates transparency and consistency in using evidence to inform policy and practice.

European Consensus Guidelines on the Management of Respiratory Distress Syndrome - 2019 Update.

As management of respiratory distress syndrome (RDS) advances, clinicians must continually revise their current practice. We report the fourth update of "European Guidelines for the Management of RDS" by a European panel of experienced neonatologists and an expert perinatal obstetrician based on available literature up to the end of 2018. Optimising outcome for babies with RDS includes prediction of risk of preterm delivery, need for appropriate maternal transfer to a perinatal centre and timely use of antenatal steroids. Delivery room management has become more evidence-based, and protocols for lung protection including initiation of CPAP and titration of oxygen should be implemented immediately after birth. Surfactant replacement therapy is a crucial part of management of RDS, and newer protocols for its use recommend early administration and avoidance of mechanical ventilation. Methods of maintaining babies on non-invasive respiratory support have been further developed and may cause less distress and reduce chronic lung disease. As technology for delivering mechanical ventilation improves, the risk of causing lung injury should decrease, although minimising time spent on mechanical ventilation using caffeine and, if necessary, postnatal steroids are also important considerations. Protocols for optimising general care of infants with RDS are also essential with good temperature control, careful fluid and nutritional management, maintenance of perfusion and judicious use of antibiotics all being important determinants of best outcome.

Association Between Oxygen Saturation Targeting and Death or Disability in Extremely Preterm Infants in the Neonatal Oxygenation Prospective Meta-analysis Collaboration.

Importance: There are potential benefits and harms of hyperoxemia and hypoxemia for extremely preterm infants receiving more vs less supplemental oxygen. Objective: To compare the effects of different target ranges for oxygen saturation as measured by pulse oximetry (Spo2) on death or major morbidity. Design, Setting, and Participants: Prospectively planned meta-analysis of individual participant data from 5 randomized clinical trials (conducted from 2005-2014) enrolling infants born before 28 weeks' gestation. Exposures: Spo2 target range that was lower (85%-89%) vs higher (91%-95%). Main Outcomes and Measures: The primary outcome was a composite of death or major disability (bilateral blindness, deafness, cerebral palsy diagnosed as ≥2 level on the Gross Motor Function Classification System, or Bayley-III cognitive or language score <85) at a corrected age of 18 to 24 months. There were 16 secondary outcomes including the components of the primary outcome and other major morbidities. Results: A total of 4965 infants were randomized (2480 to the lower Spo2 target range and 2485 to the higher Spo2 range) and had a median gestational age of 26 weeks (interquartile range, 25-27 weeks) and a mean birth weight of 832 g (SD, 190 g). The primary outcome occurred in 1191 of 2228 infants (53.5%) in the lower Spo2 target group and 1150 of 2229 infants (51.6%) in the higher Spo2 target group (risk difference, 1.7% [95% CI, -1.3% to 4.6%]; relative risk [RR], 1.04 [95% CI, 0.98 to 1.09], P = .21). Of the 16 secondary outcomes, 11 were null, 2 significantly favored the lower Spo2 target group, and 3 significantly favored the higher Spo2 target group. Death occurred in 484 of 2433 infants (19.9%) in the lower Spo2 target group and 418 of 2440 infants (17.1%) in the higher Spo2 target group (risk difference, 2.8% [95% CI, 0.6% to 5.0%]; RR, 1.17 [95% CI, 1.04 to 1.31], P = .01). Treatment for retinopathy of prematurity was administered to 220 of 2020 infants (10.9%) in the lower Spo2 target group and 308 of 2065 infants (14.9%) in the higher Spo2 target group (risk difference, -4.0% [95% CI, -6.1% to -2.0%]; RR, 0.74 [95% CI, 0.63 to 0.86], P < .001). Severe necrotizing enterocolitis occurred in 227 of 2464 infants (9.2%) in the lower Spo2 target group and 170 of 2465 infants (6.9%) in the higher Spo2 target group (risk difference, 2.3% [95% CI, 0.8% to 3.8%]; RR, 1.33 [95% CI, 1.10 to 1.61], P = .003). Conclusions and Relevance: In this prospectively planned meta-analysis of individual participant data from extremely preterm infants, there was no significant difference between a lower Spo2 target range compared with a higher Spo2 target range on the primary composite outcome of death or major disability at a corrected age of 18 to 24 months. The lower Spo2 target range was associated with a higher risk of death and necrotizing enterocolitis, but a lower risk of retinopathy of prematurity treatment.

The Research Cycle: Improving Care and Outcomes for Newborn Infants.

Ensuring that policies and practice in perinatal care are informed by evidence from high-quality research is fundamental to improving outcomes for newborn infants and their families. Effective interventions in the perinatal period can have a life-long impact disproportionate to their costs. Many of the major advances in care that have transformed outcomes for preterm and sick newborn infants have been informed by empirical and applied health research. Conversely, there are examples of life-long adverse consequences for infants and families that are a legacy of practices based on poor-quality evidence. The challenge in the 21st century is to maintain the trajectory of improvements in care and outcomes. This will most likely be achieved via marginal gains from new or improved care practices underpinned by a range of research approaches, from preclinical and laboratory-based empirical studies that uncover pathogenic pathways or therapeutic mechanisms, to large-scale, applied research such as multicentre, randomised controlled trials. This will involve the coordination and collaboration of research efforts globally. Strategies to develop and prioritise research questions need to involve parents and families. Given the context in which much perinatal research is conducted, particularly in emergency situations around the time of birth, robust and transparent ethics and governance frameworks are essential to maintain the trust and engagement of communities. An ethical imperative exists to ensure that research output is disseminated effectively, and that effective and cost-effective interventions are implemented and integrated within a cycle that audits and benchmarks good practice and outcomes, and informs research evidence-based continuous quality improvement. This is the first in a series of articles on research methodology in neonatal medicine to be published in Neonatology, in response to a request from trainee researchers. We introduce the series by describing the research cycle, in particular how it is applied in neonatal medicine. Subsequent articles will cover translational research, clinical trials, diagnostic tests, global challenges, and the ethical issues relating to neonatal/perinatal research.

Interventions to prevent hypothermia at birth in preterm and/or low birth weight infants.

BACKGROUND: Newborn admission temperature is a strong predictor of outcomes across all gestations. Hypothermia immediately after birth remains a worldwide issue and, if prolonged, is associated with harm. Keeping preterm infants warm is difficult even when recommended routine thermal care guidelines are followed in the delivery room. OBJECTIVES: To assess the efficacy and safety of interventions designed for prevention of hypothermia in preterm and/or low birth weight infants applied within 10 minutes after birth in the delivery room, compared with routine thermal care or any other single/combination of intervention(s) also designed for prevention of hypothermia in preterm and/or low birth weight infants applied within 10 minutes after birth in the delivery room. SEARCH METHODS: We used the standard search strategy of Cochrane Neonatal to search the Cochrane Central Register of Controlled Trials (CENTRAL; 2016, Issue 5), MEDLINE via PubMed (1966 to 30 June 2016), Embase (1980 to 30 June 2016), and CINAHL (1982 to 30 June 2016). We also searched clinical trials databases, conference proceedings, and reference lists of retrieved articles for randomised controlled trials and quasi-randomised trials. SELECTION CRITERIA: Trials using randomised or quasi-randomised allocations to test interventions designed to prevent hypothermia (apart from 'routine' thermal care) applied within 10 minutes after birth in the delivery room for infants at < 37 weeks' gestation and/or birth weight ≤ 2500 grams. DATA COLLECTION AND ANALYSIS: We used Cochrane Neonatal methods when performing data collection and analysis. MAIN RESULTS: Twenty-five studies across 15 comparison groups met the inclusion criteria, categorised as: barriers to heat loss (18 studies); external heat sources (three studies); and combinations of interventions (four studies).Barriers to heat loss Plastic wrap or bag versus routine carePlastic wraps improved core body temperature on admission to the neonatal intensive care unit (NICU) or up to two hours after birth (mean difference (MD) 0.58°C, 95% confidence interval (CI) 0.50 to 0.66; 13 studies; 1633 infants), and fewer infants had hypothermia on admission to the NICU or up to two hours after birth (typical risk ratio (RR) 0.67, 95% CI 0.62 to 0.72; typical risk reduction (RD) -0.25, 95% CI -0.29 to -0.20; number needed to treat for an additional beneficial outcome (NNTB) 4, 95% CI 4 to 5; 10 studies; 1417 infants). Risk of hyperthermia on admission to the NICU or up to two hours after birth was increased in infants in the wrapped group (typical RR 3.91, 95% CI 2.05 to 7.44; typical RD 0.04, 95% CI 0.02 to 0.06; number needed to treat for an additional harmful outcome (NNTH) 25, 95% CI 17 to 50; 12 studies; 1523 infants), but overall, fewer infants receiving plastic wrap were outside the normothermic range (typical RR 0.75, 95% CI 0.69 to 0.81; typical RD -0.20, 95% CI -0.26 to -0.15; NNTH 5, 95% CI 4 to 7; five studies; 1048 infants).Evidence was insufficient to suggest that plastic wraps or bags significantly reduce risk of death during hospital stay or other major morbidities, with the exception of reducing risk of pulmonary haemorrhage.Evidence of practices regarding permutations on this general approach is still emerging and has been based on the findings of only one or two small studies.External heat sourcesEvidence is emerging on the efficacy of external heat sources, including skin-to-skin care (SSC) versus routine care (one study; 31 infants) and thermal mattress versus routine care (two studies; 126 infants).SSC was shown to be effective in reducing risk of hypothermia when compared with conventional incubator care for infants with birth weight ≥ 1200 and ≤ 2199 grams (RR 0.09, 95% CI 0.01 to 0.64; RD -0.56, 95% CI -0.84 to -0.27; NNTB 2, 95% CI 1 to 4). Thermal (transwarmer) mattress significantly kept infants ≤ 1500 grams warmer (MD 0.65°C, 95% CI 0.36 to 0.94) and reduced the incidence of hypothermia on admission to the NICU, with no significant difference in hyperthermia risk.Combinations of interventionsTwo studies (77 infants) compared thermal mattresses versus plastic wraps or bags for infants at ≤ 28 weeks' gestation. Investigators reported no significant differences in core body temperature nor in the incidence of hypothermia, hyperthermia, or core body temperature outside the normothermic range on admission to the NICU.Two additional studies (119 infants) compared plastic bags and thermal mattresses versus plastic bags alone for infants at < 31 weeks' gestation. Meta-analysis of these two studies showed improvement in core body temperature on admission to the NICU or up to two hours after birth, but an increase in hyperthermia. Data show no significant difference in the risk of having a core body temperature outside the normothermic range on admission to the NICU nor in the risk of other reported morbidities. AUTHORS' CONCLUSIONS: Evidence of moderate quality shows that use of plastic wraps or bags compared with routine care led to higher temperatures on admission to NICUs with less hypothermia, particularly for extremely preterm infants. Thermal mattresses and SSC also reduced hypothermia risk when compared with routine care, but findings are based on two or fewer small studies. Caution must be taken to avoid iatrogenic hyperthermia, particularly when multiple interventions are used simultaneously. Limited evidence suggests benefit and no evidence of harm for most short-term morbidity outcomes known to be associated with hypothermia, including major brain injury, bronchopulmonary dysplasia, retinopathy of prematurity, necrotising enterocolitis, and nosocomial infection. Many observational studies have shown increased mortality among preterm hypothermic infants compared with those who maintain normothermia, yet evidence is insufficient to suggest that these interventions reduce risk of in-hospital mortality across all comparison groups. Hypothermia may be a marker for illness and poorer outcomes by association rather than by causality. Limitations of this review include small numbers of identified studies; small sample sizes; and variations in methods and definitions used for hypothermia, hyperthermia, normothermia, routine care, and morbidity, along with lack of power to detect effects on morbidity and mortality across most comparison groups. Future studies should: be adequately powered to detect rarer outcomes; apply standardised morbidity definitions; focus on longer-term outcomes, particularly neurodevelopmental outcomes.

Long-Term Effects of Inhaled Budesonide for Bronchopulmonary Dysplasia.

BACKGROUND: The long-term effects on neurodevelopment of the use of inhaled glucocorticoids in extremely preterm infants for the prevention or treatment of bronchopulmonary dysplasia are uncertain. METHODS: We randomly assigned 863 infants (gestational age, 23 weeks 0 days to 27 weeks 6 days) to receive early (within 24 hours after birth) inhaled budesonide or placebo. The prespecified secondary long-term outcome was neurodevelopmental disability among survivors, defined as a composite of cerebral palsy, cognitive delay (a Mental Development Index score of <85 [1 SD below the mean of 100] on the Bayley Scales of Infant Development, Second Edition, with higher scores on the scale indicating better performance), deafness, or blindness at a corrected age of 18 to 22 months. RESULTS: Adequate data on the prespecified composite long-term outcome were available for 629 infants. Of these infants, 148 (48.1%) of 308 infants assigned to budesonide had neurodevelopmental disability, as compared with 165 (51.4%) of 321 infants assigned to placebo (relative risk, adjusted for gestational age, 0.93; 95% confidence interval [CI], 0.80 to 1.09; P=0.40). There was no significant difference in any of the individual components of the prespecified outcome. There were more deaths in the budesonide group than in the placebo group (82 [19.9%] of 413 infants vs. 58 [14.5%] of 400 infants for whom vital status was available; relative risk, 1.37; 95% CI, 1.01 to 1.86; P=0.04). CONCLUSIONS: Among surviving extremely preterm infants, the rate of neurodevelopmental disability at 2 years did not differ significantly between infants who received early inhaled budesonide for the prevention of bronchopulmonary dysplasia and those who received placebo, but the mortality rate was higher among those who received budesonide. (Funded by the European Union and Chiesi Farmaceutici; ClinicalTrials.gov number, NCT01035190 .).