Expectant Management or Early Ibuprofen for Patent Ductus Arteriosus.

BACKGROUND: Cyclooxygenase inhibitors are commonly used in infants with patent ductus arteriosus (PDA), but the benefit of these drugs is uncertain. METHODS: In this multicenter, noninferiority trial, we randomly assigned infants with echocardiographically confirmed PDA (diameter, >1.5 mm, with left-to-right shunting) who were extremely preterm (<28 weeks' gestational age) to receive either expectant management or early ibuprofen treatment. The composite primary outcome included necrotizing enterocolitis (Bell's stage IIa or higher), moderate to severe bronchopulmonary dysplasia, or death at 36 weeks' postmenstrual age. The noninferiority of expectant management as compared with early ibuprofen treatment was defined as an absolute risk difference with an upper boundary of the one-sided 95% confidence interval of less than 10 percentage points. RESULTS: A total of 273 infants underwent randomization. The median gestational age was 26 weeks, and the median birth weight was 845 g. A primary-outcome event occurred in 63 of 136 infants (46.3%) in the expectant-management group and in 87 of 137 (63.5%) in the early-ibuprofen group (absolute risk difference, -17.2 percentage points; upper boundary of the one-sided 95% confidence interval [CI], -7.4; P<0.001 for noninferiority). Necrotizing enterocolitis occurred in 24 of 136 infants (17.6%) in the expectant-management group and in 21 of 137 (15.3%) in the early-ibuprofen group (absolute risk difference, 2.3 percentage points; two-sided 95% CI, -6.5 to 11.1); bronchopulmonary dysplasia occurred in 39 of 117 infants (33.3%) and in 57 of 112 (50.9%), respectively (absolute risk difference, -17.6 percentage points; two-sided 95% CI, -30.2 to -5.0). Death occurred in 19 of 136 infants (14.0%) and in 25 of 137 (18.2%), respectively (absolute risk difference, -4.3 percentage points; two-sided 95% CI, -13.0 to 4.4). Rates of other adverse outcomes were similar in the two groups. CONCLUSIONS: Expectant management for PDA in extremely premature infants was noninferior to early ibuprofen treatment with respect to necrotizing enterocolitis, bronchopulmonary dysplasia, or death at 36 weeks' postmenstrual age. (Funded by the Netherlands Organization for Health Research and Development and the Belgian Health Care Knowledge Center; BeNeDuctus ClinicalTrials.gov number, NCT02884219; EudraCT number, 2017-001376-28.).

Effect of Systemic Hydrocortisone on Brain Abnormalities and Regional Brain Volumes in Ventilator-dependent Infants Born Preterm: Substudy of the SToP-BPD Study.

OBJECTIVE: To evaluate whether a high cumulative dose of systemic hydrocortisone affects brain development compared with placebo when initiated between 7 and 14 days after birth in ventilated infants born preterm. STUDY DESIGN: A double-blind, placebo-controlled, randomized trial was conducted in 16 neonatal intensive care units among infants born at <30 weeks of gestation or with a birth weight of <1250 g who were ventilator-dependent in the second week after birth. Three centers performed MRI at term-equivalent age. Brain injury was assessed on MRI using the Kidokoro scoring system and compared between the 2 treatment groups. Both total and regional brain volumes were calculated using an automatic segmentation method and compared using multivariable regression analysis adjusted for baseline variables. RESULTS: From the 3 centers, 78 infants participated in the study and 59 had acceptable MRI scans (hydrocortisone group, n = 31; placebo group, n = 28). Analyses of the median global brain abnormality score of the Kidokoro score showed no difference between the hydrocortisone and placebo groups (median, 7; IQR, 5-9 vs median, 8, IQR, 4-10, respectively; P = .92). In 39 infants, brain tissue volumes were measured, showing no differences in the adjusted mean total brain tissue volumes, at 352 ± 32 mL in the hydrocortisone group and 364 ± 51 mL in the placebo group (P = .80). CONCLUSIONS: Systemic hydrocortisone started in the second week after birth in ventilator-dependent infants born very preterm was not found to be associated with significant differences in brain development compared with placebo treatment. TRIAL REGISTRATION: The SToP-BPD study was registered with the Netherlands Trial Register (NTR2768; registered on 17 February 2011; https://www.trialregister.nl/trial/2640) and the European Union Clinical Trials Register (EudraCT, 2010-023777-19; registered on 2 November 2010; https://www.clinicaltrialsregister.eu/ctr-search/trial/2010-023777-19/NL).

Effects of postnatal corticosteroids on lung development in newborn animals. A systematic review.

BACKGROUND: Postnatal systemic corticosteroids reduce the risk of bronchopulmonary dysplasia but the effect depends on timing, dosing, and type of corticosteroids. Animal studies may provide valuable information on these variable effects. This systematic review summarizes the effects of postnatal systemic corticosteroids on lung development in newborn animals. METHODS: A systematic search was performed in PubMed and Embase in December 2022. The protocol was published on PROSPERO (CRD42021177701). RESULTS: Of the 202 eligible studies, 51 were included. Only newborn rodent studies met the inclusion criteria. Most studies used dexamethasone (98%). There was huge heterogeneity in study outcome measures and corticosteroid treatment regimens. Reporting of study quality indicators was mediocre and risk of bias was unclear due to poor reporting of study methodology. Meta-analysis showed that postnatal corticosteroids caused a decrease in body weight as well as persistent alveolar simplification. Subgroup analyses revealed that healthy animals were most affected. CONCLUSION: In newborn rodents, postnatal systemic corticosteroids have a persistent negative effect on body weight and lung development. There was huge heterogeneity in experimental models, mediocre study quality, unclear risk of bias, and very small subgroups for meta-analysis which limited firm conclusions. IMPACT: Postnatal corticosteroids reduce the risk of bronchopulmonary dysplasia but the effect depends on timing, dosing, and type of corticosteroids while the underlying mechanism of this variable effect is unknown. This is the first systematic review and meta-analysis of preclinical newborn animal studies reviewing the effect of postnatal systemic corticosteroids on lung development. In newborn rodent models, postnatal corticosteroids have a persistent negative effect on body weight and lung alveolarization, especially in healthy animals.

Corticosteroids for the prevention and treatment of bronchopulmonary dysplasia: an overview of systematic reviews.

BACKGROUND: Bronchopulmonary dysplasia (BPD) remains an important complication of prematurity. Pulmonary inflammation plays a central role in the pathogenesis of BPD, explaining the rationale for investigating postnatal corticosteroids. Multiple systematic reviews (SRs) have summarised the evidence from numerous randomised controlled trials (RCTs) investigating different aspects of administrating postnatal corticosteroids. Besides beneficial effects on the outcome of death or BPD, potential short- and long-term harms have been reported. OBJECTIVES: The primary objective of this overview was to summarise and appraise the evidence from SRs regarding the efficacy and safety of postnatal corticosteroids in preterm infants at risk of developing BPD. METHODS: We searched the Cochrane Database of Systematic Reviews, MEDLINE, Embase, CINAHL, and Epistemonikos for SRs in April 2023. We included all SRs assessing any form of postnatal corticosteroid administration in preterm populations with the objective of ameliorating pulmonary disease. All regimens and comparisons were included. Two review authors independently checked the eligibility of the SRs comparing corticosteroids with placebo, and corticosteroids with different routes of administration and regimens. The included outcomes, considered key drivers in the decision to administer postnatal corticosteroids, were the composite outcome of death or BPD at 36 weeks' postmenstrual age (PMA), its individual components, long-term neurodevelopmental sequelae, sepsis, and gastrointestinal tract perforation. We independently assessed the methodological quality of the included SRs by using AMSTAR 2 (A Measurement Tool to Assess Systematic Reviews) and ROBIS (Risk Of Bias In Systematic reviews) tools. We assessed the certainty of the evidence using GRADE. We provided a narrative description of the characteristics, methodological quality, and results of the included SRs. MAIN RESULTS: We included nine SRs (seven Cochrane, two non-Cochrane) containing 87 RCTs, 1 follow-up study, and 9419 preterm infants, investigating the effects of postnatal corticosteroids to prevent or treat BPD. The quality of the included SRs according to AMSTAR 2 varied from high to critically low. Risk of bias according to ROBIS was low. The certainty of the evidence according to GRADE ranged from very low to moderate. Early initiated systemic dexamethasone (< seven days after birth) likely has a beneficial effect on death or BPD at 36 weeks' PMA (risk ratio (RR) 0.88, 95% confidence interval (CI) 0.81 to 0.95; number needed to treat for an additional beneficial outcome (NNTB) 16, 95% CI 10 to 41; I2 = 39%; 17 studies; 2791 infants; moderate-certainty evidence) and on BPD at 36 weeks' PMA (RR 0.72, 95% CI 0.63 to 0.82; NNTB 13, 95% CI 9 to 21; I2 = 39%; 17 studies; 2791 infants; moderate-certainty evidence). Early initiated systemic hydrocortisone may also have a beneficial effect on death or BPD at 36 weeks' PMA (RR 0.90, 95% CI 0.82 to 0.99; NNTB 18, 95% CI 9 to 594; I2 = 43%; 9 studies; 1376 infants; low-certainty evidence). However, these benefits are likely accompanied by harmful effects like cerebral palsy or neurosensory disability (dexamethasone) or gastrointestinal perforation (both dexamethasone and hydrocortisone). Late initiated systemic dexamethasone (≥ seven days after birth) may have a beneficial effect on death or BPD at 36 weeks' PMA (RR 0.75, 95% CI 0.67 to 0.84; NNTB 5, 95% CI 4 to 9; I2 = 61%; 12 studies; 553 infants; low-certainty evidence), mostly contributed to by a beneficial effect on BPD at 36 weeks' PMA (RR 0.76, 95% CI 0.66 to 0.87; NNTB 6, 95% CI 4 to 13; I2 = 14%; 12 studies; 553 infants; low-certainty evidence). No harmful side effects were shown in the outcomes chosen as key drivers to the decision to start or withhold late systemic dexamethasone. No effects, either beneficial or harmful, were found in the subgroup meta-analyses of late hydrocortisone studies. Early initiated inhaled corticosteroids probably have a beneficial effect on death and BPD at 36 weeks' PMA (RR 0.86, 95% CI 0.75 to 0.99; NNTB 19, 95% CI not applicable; I2 = 0%; 6 studies; 1285 infants; moderate-certainty evidence), with no apparent adverse effects shown in the SRs. In contrast, late initiated inhaled corticosteroids do not appear to have any benefits or harms. Endotracheal instillation of corticosteroids (budesonide) with surfactant as a carrier likely has a beneficial effect on death or BPD at 36 weeks' PMA (RR 0.60, 95% CI 0.49 to 0.74; NNTB 4, 95% CI 3 to 6; I2 = 0%; 2 studies; 381 infants; moderate-certainty evidence) and on BPD at 36 weeks' PMA. No evidence of harmful effects was found. There was little evidence for effects of different starting doses or timing of systemic corticosteroids on death or BPD at 36 weeks' PMA, but potential adverse effects were observed for some comparisons. Lowering the dose might result in a more unfavourable balance of benefits and harms. Moderately early initiated systemic corticosteroids, compared with early systemic corticosteroids, may result in a higher incidence of BPD at 36 weeks' PMA. Pulse dosing instead of continuous dosing may have a negative effect on death and BPD at 36 weeks' PMA. We found no differences for the comparisons of inhaled versus systemic corticosteroids. AUTHORS' CONCLUSIONS: This overview summarises the evidence of nine SRs investigating the effect of postnatal corticosteroids in preterm infants at risk for BPD. Late initiated (≥ seven days after birth) systemic administration of dexamethasone is considered an effective intervention to reduce the risk of BPD in infants with a high risk profile for BPD, based on a favourable balance between benefits and harms. Endotracheal instillation of corticosteroids (budesonide) with surfactant as a carrier is a promising intervention, based on the beneficial effect on desirable outcomes without (so far) negative side effects. Pending results of ongoing large, multicentre RCTs investigating both short- and long-term effects, endotracheal instillation of corticosteroids (budesonide) with surfactant as a carrier is not appropriate for clinical practice at present. Early initiated (< seven days after birth) systemic dexamethasone and hydrocortisone and late initiated (≥ seven days after birth) hydrocortisone are considered ineffective interventions, because of an unfavourable balance between benefits and harms. No conclusions are possible regarding early and late inhaled corticosteroids, as more research is needed.

Neurodevelopmental Outcomes at Two Years' Corrected Age of Very Preterm Infants after Implementation of a Post-Discharge Responsive Parenting Intervention Program (TOP Program).

OBJECTIVE: To compare neurodevelopmental outcomes at 2 years corrected age (CA) between infants born very preterm (VP) who did or did not receive a postdischarge responsive parenting intervention (Transmural developmental support for very preterm infants and their parents [TOP program]) between discharge home and 12 months' CA. STUDY DESIGN: The Systemic Hydrocortisone to Prevent Bronchopulmonary Dysplasia (SToP-BPD) study showed no differences between treatment groups in motor and cognitive development using the Dutch Bayley Scales of Infant Development and behavior using the Child Behavior Checklist at 2 years' CA. During its study period, the TOP program was gradually scaled up nationwide in the same population, providing an opportunity to evaluate the effect of this program on neurodevelopmental outcome, after adjusting for baseline differences. RESULTS: Among 262 surviving VP infants in the SToP-BPD study, 35% received the TOP program. Infants in the TOP group had a significantly lower incidence of a cognitive score <85 (20.3% vs 35.2%; adjusted absolute risk reduction: -14.1% [95% CI: -27.2 to -1.1]; P = .03), and a significantly higher mean cognitive score (96.7 ± 13.8), compared with the non-TOP group (92.0 ± 17.5; crude mean difference: 4.7 [95% CI: 0.3 to 9.2]; P = .03). No significant differences were found on motor scores. For behavior problems, a small but statistically significant effect for anxious/depressive problems was found in the TOP group (50.5 vs 51.2; P = .02). CONCLUSIONS: VP infants supported by the TOP program from discharge until 12 months' CA had better cognitive function at 2 years' CA. This study demonstrates a sustained positive effect of the TOP program in VP infants.

Exhaled Volatile Organic Compounds for Early Prediction of Bronchopulmonary Dysplasia in Infants Born Preterm.

OBJECTIVE(S): To investigate the predictive performances of exhaled breath volatile organic compounds (VOCs) for development of bronchopulmonary dysplasia (BPD) in infants born preterm. METHODS: Exhaled breath was collected from infants born <30 weeks' gestation at days 3 and 7 of life. Ion fragments detected by gas chromatography-mass spectrometry analysis were used to derive and internally validate a VOC prediction model for moderate or severe BPD at 36 weeks of postmenstrual age. We tested the predictive performance of the National Institute of Child Health and Human Development (NICHD) clinical BPD prediction model with and without VOCs. RESULTS: Breath samples were collected from 117 infants (mean gestation 26.8 ± 1.5 weeks). Thirty-three percent of the infants developed moderate or severe BPD. The VOC model showed a c-statistic of 0.89 (95% CI 0.80-0.97) and 0.92 (95% CI 0.84-0.99) for the prediction of BPD at days 3 and 7, respectively. Adding the VOCs to the clinical prediction model in noninvasively supported infants resulted in significant improvement in discriminative power on both days (day 3: c-statistic 0.83 vs 0.92, P value .04; day 7: c-statistic 0.82 vs 0.94, P value .03). CONCLUSIONS: This study showed that VOC profiles in exhaled breath of preterm infants on noninvasive support in the first week of life differ between those developing and not developing BPD. Adding VOCs to a clinical prediction model significantly improved its discriminative performance.

Prediction Models for Bronchopulmonary Dysplasia in Preterm Infants: A Systematic Review and Meta-Analysis.

OBJECTIVE: To review systematically and assess the accuracy of prediction models for bronchopulmonary dysplasia (BPD) at 36 weeks of postmenstrual age. STUDY DESIGN: Searches were conducted in MEDLINE and EMBASE. Studies published between 1990 and 2022 were included if they developed or validated a prediction model for BPD or the combined outcome death/BPD at 36 weeks in the first 14 days of life in infants born preterm. Data were extracted independently by 2 authors following the Critical Appraisal and Data Extraction for Systematic Reviews of Prediction Modelling Studies (ie, CHARMS) and PRISMA guidelines. Risk of bias was assessed using the Prediction model Risk Of Bias ASsessment Tool (ie, PROBAST). RESULTS: Sixty-five studies were reviewed, including 158 development and 108 externally validated models. Median c-statistic of 0.84 (range 0.43-1.00) was reported at model development, and 0.77 (range 0.41-0.97) at external validation. All models were rated at high risk of bias, due to limitations in the analysis part. Meta-analysis of the validated models revealed increased c-statistics after the first week of life for both the BPD and death/BPD outcome. CONCLUSIONS: Although BPD prediction models perform satisfactorily, they were all at high risk of bias. Methodologic improvement and complete reporting are needed before they can be considered for use in clinical practice. Future research should aim to validate and update existing models.

Comparison of New Bronchopulmonary Dysplasia Definitions on Long-Term Outcomes in Preterm Infants.

OBJECTIVE: To compare the discriminative performances of the 2018 National Institutes of Health (NIH) and the 2019 Jensen definitions of bronchopulmonary dysplasia (BPD) with the 2001 NIH definition on adverse neurodevelopmental and respiratory outcomes at 2 years and 5 years corrected age. STUDY DESIGN: In this single-center retrospective cohort study, outcomes of infants born at <30 weeks of gestational age were collected. The 3 definitions of BPD were compared by adding the different definitions to the National Institute of Child Health and Human Development's outcome prediction model for neurodevelopmental impairment (NDI) or death. Discriminative performance was compared for both outcomes at 2 years and 5 years corrected age by calculating the areas under the receiver operating characteristic curve and z-statistics. RESULTS: The presence of BPD and its severity were determined in 584 infants. There were considerable shifts in BPD grading among the different definitions. At both time points, all BPD definition models had comparable discriminating power for NDI and respiratory morbidity, with one exception. Compared with the 2001 NIH definition, the 2018 NIH definition had less predictive power for the neurologic outcome at 2 years corrected age. CONCLUSIONS: Our comparison of the 3 BPD definitions shows similar discriminative performance on long term neurodevelopmental and respiratory outcomes at 2 years and 5 years corrected age.

Glucocorticoid signature of preterm infants developing bronchopulmonary dysplasia.

BACKGROUND: Systemic inflammation plays a key role in the development of bronchopulmonary dysplasia (BPD). Cortisol is known to dampen inflammation. However, adrenal function following preterm birth is characterized by insufficient cortisol levels for the degree of inflammation, and a relative abundancy of cortisol precursors. We investigated whether this pattern could contribute to the development of BPD in preterm infants born <30 weeks of gestation. METHODS: Cortisol, cortisone, 17-OH progesterone (17-OHP) and 11-deoxycortisol were measured in serum obtained at postnatal days 1, 3, 7, 14 and 28, using liquid-chromatography-tandem-mass-spectrometry. The presence of BPD was ascertained at 36 weeks postmenstrual age. RESULTS: Sixty-five infants were included for analysis, of whom 32 (49%) developed BPD. Preterm infants developing BPD, as compared to those without BPD, had higher levels of 17-OHP, 11-deoxycortisol and cortisone relative to cortisol in their first week of life, but not at birth or beyond day 7. CONCLUSION: Preterm infants developing BPD had higher levels of cortisol precursors and cortisone relative to cortisol in their first week of life than infants without BPD. These findings suggest that BPD is preceded by an activated hypothalamus-pituitary-adrenal axis that could not meet the high cortisol demands, which may predispose to inflammation and BPD. IMPACT: Relative adrenal insufficiency is common in the first weeks after preterm birth, resulting in insufficient cortisol production for the degree of inflammation and a relative abundance of cortisol precursors; Whether this pattern contributes to the development of bronchopulmonary dysplasia (BPD) is not fully elucidated, since most studies focused on cortisol levels; Preterm infants developing BPD had higher levels of cortisol precursors and cortisone relative to cortisol in the first week of life, suggestive of a hypothalamus-pituitary-adrenal-axis activation during BPD development which cannot meet the high cortisol demands in tissues; This glucocorticoid pattern is likely to dispose to inflammation and BPD.

Bronchopulmonary dysplasia is not related to neurofilament light for neuroaxonal damage in preterm infants.

BACKGROUND: Neurofilament light (NfL) has been identified as a biomarker for neuroaxonal damage in preterm infants, but its relation with bronchopulmonary dysplasia (BPD) has not been established. We hypothesized that BPD is associated with increased NfL levels at an early stage, indicative of early neuroaxonal damage. METHODS: We included preterm infants born <30 weeks of gestation for assessment of NfL levels from cord blood and blood obtained at postnatal days 3, 7, 14, and 28. We used linear regression analysis to compare NfL levels between infants with moderate/severe BPD and infants with no/mild BPD, and linear mixed model analysis to compare the effect of time on NfL levels between groups. RESULTS: Sixty-seven infants with a gestational age (GA) of 27 ± 1.3 weeks were included for analysis, of whom 19 (28%) developed moderate/severe BPD. Although NfL levels were higher at every time point in infants with BPD, statistical significance was lost after adjustment for GA, small for gestational age (SGA) and intraventricular hemorrhage (IVH). Groups did not differ in NfL change over time. CONCLUSIONS: The positive association between BPD and NfL in the first weeks of life could be explained by GA, SGA and IVH rather than by development of BPD. IMPACT: Neurofilament light chain (NfL) is a known biomarker for neuroaxonal damage. Biomarkers for brain damage during the first weeks of life in preterm infants developing BPD are lacking. NfL levels obtained during the first weeks of life did not differ between infants with and without BPD in analyses adjusted for GA, SGA, and IVH.

Caffeine dosing regimens in preterm infants with or at risk for apnea of prematurity.

BACKGROUND: Very preterm infants often require respiratory support and are therefore exposed to an increased risk of bronchopulmonary dysplasia (chronic lung disease) and later neurodevelopmental disability. Caffeine is widely used to prevent and treat apnea (temporal cessation of breathing) associated with prematurity and facilitate extubation. Though widely recognized dosage regimes have been used for decades, higher doses have been suggested to further improve neonatal outcomes. However, observational studies suggest that higher doses may be associated with harm. OBJECTIVES: To determine the effects of higher versus standard doses of caffeine on mortality and major neurodevelopmental disability in preterm infants with (or at risk of) apnea, or peri-extubation. SEARCH METHODS: We searched CENTRAL, MEDLINE, Embase, CINAHL, the World Health Organization (WHO) International Clinical Trials Registry Platform (ICTRP), and clinicaltrials.gov in May 2022. The reference lists of relevant articles were also checked to identify additional studies. SELECTION CRITERIA: We included randomized (RCTs), quasi-RCTs and cluster-RCTs, comparing high-dose to standard-dose strategies in preterm infants. High-dose strategies were defined as a high-loading dose (more than 20 mg of caffeine citrate/kg) or a high-maintenance dose (more than 10 mg of caffeine citrate/kg/day). Standard-dose strategies were defined as a standard-loading dose (20 mg or less of caffeine citrate/kg) or a standard-maintenance dose (10 mg or less of caffeine citrate/kg/day). We specified three additional comparisons according to the indication for commencing caffeine: 1) prevention trials, i.e. preterm infants born at less than 34 weeks' gestation, who are at risk for apnea; 2) treatment trials, i.e. preterm infants born at less than 37 weeks' gestation, with signs of apnea; 3) extubation trials: preterm infants born at less than 34 weeks' gestation, prior to planned extubation. DATA COLLECTION AND ANALYSIS: We used standard methodological procedures expected by Cochrane. We evaluated treatment effects using a fixed-effect model with risk ratio (RR) for categorical data and mean, standard deviation (SD), and mean difference (MD) for continuous data.  MAIN RESULTS: We included seven trials enrolling 894 very preterm infants (reported in Comparison 1, i.e. any indication). Two studies included infants for apnea prevention (Comparison 2), four studies for apnea treatment (Comparison 3) and two for extubation management (Comparison 4); in one study, indication for caffeine administration was both apnea treatment and extubation management (reported in Comparison 1, Comparison 3 and Comparison 4). In the high-dose groups, loading and maintenance caffeine doses ranged from 30 mg/kg to 80 mg/kg, and 12 mg/kg to 30 mg/kg, respectively; in the standard-dose groups, loading and maintenance caffeine doses ranged from 6 mg/kg to 25 mg/kg, and 3 mg/kg to 10 mg/kg, respectively. Two studies had three study groups: infants were randomized in three different doses (two of them matched our definition of high dose and one matched our definition of standard dose); high-dose caffeine and standard-dose caffeine were compared to theophylline administration (the latter is included in a separate review). Six of the seven included studies compared high-loading and high-maintenance dose to standard-loading and standard-maintenance dose, whereas in one study standard-loading dose and high-maintenance dose was compared to standard-loading dose and standard-maintenance dose. High-dose caffeine strategies (administration for any indication) may have little or no effect on mortality prior to hospital discharge (risk ratio (RR) 0.86, 95% confidence of interval (CI) 0.53 to 1.38; risk difference (RD) -0.01, 95% CI -0.05 to 0.03; I² for RR and RD = 0%; 5 studies, 723 participants; low-certainty evidence). Only one study enrolling 74 infants reported major neurodevelopmental disability in children aged three to five years (RR 0.79, 95% CI 0.51 to 1.24; RD -0.15, 95% CI -0.42 to 0.13; 46 participants; very low-certainty evidence). No studies reported the outcome mortality or major neurodevelopmental disability in children aged 18 to 24 months and 3 to 5 years. Five studies reported bronchopulmonary dysplasia at 36 weeks' postmenstrual age (RR 0.75, 95% CI 0.60 to 0.94; RD -0.08, 95% CI -0.15 to -0.02; number needed to benefit (NNTB) = 13; I² for RR and RD = 0%; 723 participants; moderate-certainty evidence). High-dose caffeine strategies may have little or no effect on side effects (RR 1.66, 95% CI 0.86 to 3.23; RD 0.03, 95% CI -0.01 to 0.07; I² for RR and RD = 0%; 5 studies, 593 participants; low-certainty evidence). The evidence is very uncertain for duration of hospital stay (data reported in three studies could not be pooled in meta-analysis because outcomes were expressed as medians and interquartile ranges) and seizures (RR 1.42, 95% CI 0.79 to 2.53; RD 0.14, 95% CI -0.09 to 0.36; 1 study, 74 participants; very low-certainty evidence). We identified three ongoing trials conducted in China, Egypt, and New Zealand. AUTHORS' CONCLUSIONS: High-dose caffeine strategies in preterm infants may have little or no effect on reducing mortality prior to hospital discharge or side effects. We are very uncertain whether high-dose caffeine strategies improves major neurodevelopmental disability, duration of hospital stay or seizures. No studies reported the outcome mortality or major neurodevelopmental disability in children aged 18 to 24 months and 3 to 5 years. High-dose caffeine strategies probably reduce the rate of bronchopulmonary dysplasia. Recently completed and future trials should report long-term neurodevelopmental outcome of children exposed to different caffeine dosing strategies in the neonatal period. Data from extremely preterm infants are needed, as this population is exposed to the highest risk for mortality and morbidity. However, caution is required when administering high doses in the first hours of life, when the risk for intracranial bleeding is highest. Observational studies might provide useful information regarding potential harms of the highest doses.

Systemic corticosteroid regimens for prevention of bronchopulmonary dysplasia in preterm infants.

BACKGROUND: Systematic reviews showed that systemic postnatal corticosteroids reduce the risk of bronchopulmonary dysplasia (BPD) in preterm infants. However, corticosteroids have also been associated with an increased risk of neurodevelopmental impairment. It is unknown whether these beneficial and adverse effects are modulated by differences in corticosteroid treatment regimens related to type of steroid, timing of treatment initiation, duration, pulse versus continuous delivery, and cumulative dose. OBJECTIVES: To assess the effects of different corticosteroid treatment regimens on mortality, pulmonary morbidity, and neurodevelopmental outcome in very low birth weight infants. SEARCH METHODS: We conducted searches in September 2022 of MEDLINE, the Cochrane Library, Embase, and two trial registries, without date, language or publication- type limits. Other search methods included checking the reference lists of included studies for randomized controlled trials (RCTs) and quasi-randomized trials. SELECTION CRITERIA: We included RCTs comparing two or more different treatment regimens of systemic postnatal corticosteroids in preterm infants at risk for BPD, as defined by the original trialists. The following comparisons of intervention were eligible: alternative corticosteroid (e.g. hydrocortisone) versus another corticosteroid (e.g. dexamethasone); lower (experimental arm) versus higher dosage (control arm); later (experimental arm) versus earlier (control arm) initiation of therapy; a pulse-dosage (experimental arm) versus continuous-dosage regimen (control arm); and individually-tailored regimens (experimental arm) based on the pulmonary response versus a standardized (predetermined administered to every infant) regimen (control arm). We excluded placebo-controlled and inhalation corticosteroid studies. DATA COLLECTION AND ANALYSIS: Two authors independently assessed eligibility and risk of bias of trials, and extracted data on study design, participant characteristics and the relevant outcomes. We asked the original investigators to verify if data extraction was correct and, if possible, to provide any missing data. We assessed the following primary outcome: the composite outcome mortality or BPD at 36 weeks' postmenstrual age (PMA). Secondary outcomes were: the components of the composite outcome; in-hospital morbidities and pulmonary outcomes, and long-term neurodevelopmental sequelae. We analyzed data using Review Manager 5 and used the GRADE approach to assess the certainty of the evidence. MAIN RESULTS: We included 16 studies in this review; of these, 15 were included in the quantitative synthesis. Two trials investigated multiple regimens, and were therefore included in more than one comparison. Only RCTs investigating dexamethasone were identified. Eight studies enrolling a total of 306 participants investigated the cumulative dosage administered; these trials were categorized according to the cumulative dosage investigated, 'low' being < 2 mg/kg, 'moderate' being between 2 and 4 mg/kg, and 'high' > 4 mg/kg; three studies contrasted a high versus a moderate cumulative dose, and five studies a moderate versus a low cumulative dexamethasone dose. We graded the certainty of the evidence low to very low because of the small number of events, and the risk of selection, attrition and reporting bias. Overall analysis of the studies investigating a higher dose versus a lower dosage regimen showed no differences in the outcomes BPD, the composite outcome death or BPD at 36 weeks' PMA, or abnormal neurodevelopmental outcome in survivors assessed. Although there was no evidence of a subgroup difference for the higher versus lower dosage regimens comparisons (Chi2 = 2.91, df = 1 (P = 0.09), I2 = 65.7%), a larger effect was seen in the subgroup analysis of moderate-dosage regimens versus high-dosage regimens for the outcome cerebral palsy in survivors. In this subgroup analysis, there was an increased risk of cerebral palsy (RR 6.85, 95% CI 1.29 to 36.36; RD 0.23, 95% CI 0.08 to 0.37; P = 0.02; I² = 0%; NNTH 5, 95% CI 2.6 to 12.7; 2 studies, 74 infants). There was evidence of subgroup differences for higher versus lower dosage regimens comparisons for the combined outcomes death or cerebral palsy, and death and abnormal neurodevelopmental outcomes (Chi2 = 4.25, df = 1 (P = 0.04), I2 = 76.5%; and Chi2 = 7.11, df = 1 (P = 0.008), I2 = 85.9%, respectively). In the subgroup analysis comparing a high dosage regimen of dexamethasone versus a moderate cumulative-dosage regimen, there was an increased risk of death or cerebral palsy (RR 3.20, 95% CI 1.35 to 7.58; RD 0.25, 95% CI 0.09 to 0.41; P = 0.002; I² = 0%; NNTH 5, 95% CI 2.4 to 13.6; 2 studies, 84 infants; moderate-certainty evidence), and death or abnormal neurodevelopmental outcome (RR 3.41, 95% CI 1.44 to 8.07; RD 0.28, 95% CI 0.11 to 0.44; P = 0.0009; I² = 0%; NNTH 4, 95% CI 2.2 to 10.4; 2 studies, 84 infants; moderate-certainty evidence). There were no differences in outcomes between a moderate- and a low-dosage regimen. Five studies enrolling 797 infants investigated early initiation of dexamethasone therapy versus a moderately early or delayed initiation, and showed no significant differences in the overall analyses for the primary outcomes. The two RCTs investigating a continuous versus a pulse dexamethasone regimen showed an increased risk of the combined outcome death or BPD when using the pulse therapy. Finally, three trials investigating a standard regimen versus a participant-individualized course of dexamethasone showed no difference in the primary outcome and long-term neurodevelopmental outcomes. We assessed the GRADE certainty of evidence for all comparisons discussed above as moderate to very low, because the validity of all comparisons is hampered by unclear or high risk of bias, small samples of randomized infants, heterogeneity in study population and design, non-protocolized use of 'rescue' corticosteroids and lack of long-term neurodevelopmental data in most studies. AUTHORS' CONCLUSIONS: The evidence is very uncertain about the effects of different corticosteroid regimens on the outcomes mortality, pulmonary morbidity, and long term neurodevelopmental impairment. Despite the fact that the studies investigating higher versus lower dosage regimens showed that higher-dosage regimens may reduce the incidence of death or neurodevelopmental impairment, we cannot conclude what the optimal type, dosage, or timing of initiation is for the prevention of BPD in preterm infants, based on current level of evidence. Further high quality trials would be needed to establish the optimal systemic postnatal corticosteroid dosage regimen.

Systemic corticosteroids for the prevention of bronchopulmonary dysplasia, a network meta-analysis.

BACKGROUND: Despite considerable improvement in outcomes for preterm infants, rates of bronchopulmonary dysplasia (BPD) remain high, affecting an estimated 33% of very low birthweight infants, with corresponding long-term respiratory and neurosensory issues. Systemic corticosteroids can address the inflammation underlying BPD, but the optimal regimen for prevention of this disease, balancing of the benefits with the potentially meaningful risks of systemic corticosteroids, continues to be a medical quandary. Numerous studies have shown that systemic corticosteroids, particularly dexamethasone and hydrocortisone, effectively treat or prevent BPD. However, concerning short and long-term side effects have been reported and the optimal approach to corticosteroid treatment remains unclear. OBJECTIVES: To determine whether differences in efficacy and safety exist between high-dose dexamethasone, moderate-dose dexamethasone, low-dose dexamethasone, hydrocortisone, and placebo in the prevention of BPD, death, the composite outcome of death or BPD, and other relevant morbidities, in preterm infants through a network meta-analysis, generating both pairwise comparisons between all treatments and rankings of the treatments. SEARCH METHODS: We searched the Cochrane Library for all systematic reviews of systemic corticosteroids for the prevention of BPD and searched for completed and ongoing studies in the following databases in January 2023: Cochrane Central Register of Controlled Trials, MEDLINE, Embase, and clinical trial databases. SELECTION CRITERIA: We included randomized controlled trials (RCTs) in preterm infants (< 37 weeks' gestation) at risk for BPD that evaluated systemic corticosteroids (high-dose [≥ 4 mg/kg cumulative dose] dexamethasone, moderate-dose [≥ 2 to < 4 mg/kg] dexamethasone, low-dose [< 2 mg/kg] dexamethasone, or hydrocortisone) versus control or another systemic corticosteroid. DATA COLLECTION AND ANALYSIS: Our main information sources were the systematic reviews, with reference to the original manuscript only for data not included in these reviews. Teams of two paired review authors independently performed data extraction, with disagreements resolved by discussion. Data were entered into Review Manager 5 and exported to R software for network meta-analysis (NMA). NMA was performed using a frequentist model with random-effects. Two separate networks were constructed, one for early (< seven days) initiation of treatment and one for late (≥ seven days) treatment initiation, to reflect the different patient populations evaluated. We assessed the certainty of evidence derived from the NMA for our primary outcomes using principles of the GRADE framework modified for application to NMA. MAIN RESULTS: We included 59 studies, involving 6441 infants, in our analyses. Only six of the included studies provided direct comparisons between any of the treatment (dexamethasone or hydrocortisone) groups, forcing network comparisons between treatments to rely heavily on indirect evidence through comparisons with placebo/no treatment groups. Thirty-one studies evaluated early corticosteroid treatment, 27 evaluated late corticosteroid treatment, and one study evaluated both early and late corticosteroid treatments. Early treatment (prior to seven days after birth): Benefits:NMA for early treatment showed only moderate-dose dexamethasone to decrease the risk of BPD at 36 weeks' postmenstrual age (PMA) compared with control (RR 0.56, 95% CI 0.39 to 0.80; moderate-certainty evidence), although the other dexamethasone dosing regimens may have similar effects compared with control (high-dose dexamethasone, RR 0.71, 95% CI 0.50 to 1.01; low-certainty evidence; low-dose dexamethasone, RR 0.83, 95% CI 0.67 to 1.03; low-certainty evidence). Other early treatment regimens may have little or no effect on the risk of death at 36 weeks' PMA. Only moderate-dose dexamethasone decreased the composite outcome of death or BPD at 36 weeks' PMA compared with control (RR 0.77, 95% CI 0.60 to 0.98; moderate-certainty evidence). HARMS: Low-dose dexamethasone increased the risk for cerebral palsy (RR 1.92, 95% CI 1.12 to 3.28; moderate-certainty evidence) compared with control. Hydrocortisone may decrease the risk of major neurosensory disability versus low-dose dexamethasone (RR 0.65, 95% CI 0.41 to 1.01; low-certainty evidence). Late treatment (at seven days or later after birth): Benefits: NMA for late treatment showed high-dose dexamethasone to decrease the risk of BPD both versus hydrocortisone (RR 0.66, 95% CI 0.51 to 0.85; low-certainty evidence) and versus control (RR 0.72, CI 0.59 to 0.87; moderate-certainty evidence). The late treatment regimens evaluated may have little or no effect on the risk of death at 36 weeks' PMA. High-dose dexamethasone decreased risk for the composite outcome of death or BPD compared with all other treatments (control, RR 0.69, 95% CI 0.59 to 0.80, high-certainty evidence; hydrocortisone, RR 0.69, 95% CI 0.58 to 0.84, low-certainty evidence; low-dose dexamethasone, RR 0.73, 95% CI 0.60 to 0.88, low-certainty evidence; moderate-dose dexamethasone, RR 0.76, 95% CI 0.62 to 0.93, low-certainty evidence). HARMS: No effect was observed for the outcomes of major neurosensory disability or cerebral palsy. The evidence for the primary outcomes was of overall low certainty, with notable deductions for imprecision and heterogeneity across the networks. AUTHORS' CONCLUSIONS: While early treatment with moderate-dose dexamethasone or late treatment with high-dose dexamethasone may lead to the best effects for survival without BPD, the certainty of the evidence is low. There is insufficient evidence to guide this therapy with regard to plausible adverse long-term outcomes. Further RCTs with direct comparisons between systemic corticosteroid treatments are needed to determine the optimal treatment approach, and these studies should be adequately powered to evaluate survival without major neurosensory disability.

Randomized Trial of Platelet-Transfusion Thresholds in Neonates.

BACKGROUND: Platelet transfusions are commonly used to prevent bleeding in preterm infants with thrombocytopenia. Data are lacking to provide guidance regarding thresholds for prophylactic platelet transfusions in preterm neonates with severe thrombocytopenia. METHODS: In this multicenter trial, we randomly assigned infants born at less than 34 weeks of gestation in whom severe thrombocytopenia developed to receive a platelet transfusion at platelet-count thresholds of 50,000 per cubic millimeter (high-threshold group) or 25,000 per cubic millimeter (low-threshold group). Bleeding was documented prospectively with the use of a validated bleeding-assessment tool. The primary outcome was death or new major bleeding within 28 days after randomization. RESULTS: A total of 660 infants (median birth weight, 740 g; and median gestational age, 26.6 weeks) underwent randomization. In the high-threshold group, 90% of the infants (296 of 328 infants) received at least one platelet transfusion, as compared with 53% (177 of 331 infants) in the low-threshold group. A new major bleeding episode or death occurred in 26% of the infants (85 of 324) in the high-threshold group and in 19% (61 of 329) in the low-threshold group (odds ratio, 1.57; 95% confidence interval [CI], 1.06 to 2.32; P=0.02). There was no significant difference between the groups with respect to rates of serious adverse events (25% in the high-threshold group and 22% in the low-threshold group; odds ratio, 1.14; 95% CI, 0.78 to 1.67). CONCLUSIONS: Among preterm infants with severe thrombocytopenia, those randomly assigned to receive platelet transfusions at a platelet-count threshold of 50,000 per cubic millimeter had a significantly higher rate of death or major bleeding within 28 days after randomization than those who received platelet transfusions at a platelet-count threshold of 25,000 per cubic millimeter. (Funded by the National Health Service Blood and Transplant Research and Development Committee and others; Current Controlled Trials number, ISRCTN87736839 .).

Severity of Bronchopulmonary Dysplasia and Neurodevelopmental Outcome at 2 and 5 Years Corrected Age.

OBJECTIVE: To evaluate the association between bronchopulmonary dysplasia (BPD) severity and risk of neurodevelopmental impairment (NDI) at 2 years and 5 years corrected age and to examine whether this association changes over time. STUDY DESIGN: This single-center retrospective cohort study included patients with a gestational age <30 weeks surviving to 36 weeks postmenstrual age, divided into groups according to BPD severity. NDI was defined as having cognitive or motor abilities below -1 SD, cerebral palsy, or a hearing or a visual impairment. The association was assessed using a multivariate logistic regression model analysis, adjusting for known confounders for NDI, and mixed-model analysis. RESULTS: Of the 790 surviving infants (15% diagnosed with mild BPD, 9% with moderate BPD, and 10% with severe BPD), 88% and 82% were longitudinally assessed at 2 years and 5 years corrected age, respectively. The mixed-model analysis showed a statistically significant increase in NDI at all levels of BPD severity compared with infants with no BPD, and a 5-fold increased risk in NDI was seen from 2 years to 5 years corrected age in all degrees of BPD severity. The strength of this association between NDI and BPD severity did not change over time. CONCLUSIONS: Increased BPD severity is associated with increased risk of NDI at both 2 years and 5 years corrected age. The absolute incidence of NDI increased significantly from 2 years to 5 years corrected age for all BPD severity categories, but this increased risk was similar at both time points in each category.

Umbilical cord blood culture in neonatal early-onset sepsis: a systematic review and meta-analysis.

BACKGROUND: Peripheral blood culture (PBC) is considered the gold standard for diagnosis of neonatal early-onset sepsis (EOS), but its diagnostic value can be questioned. We aimed to systematically asses the diagnostic test accuracy (DTA) of umbilical cord blood culture (UCBC) for EOS. METHODS: A systematic literature search was performed in PubMed, Embase, Web of Science, and the Cochrane Library. Studies performing UCBC for the diagnosis of EOS were included. RESULTS: A total of 1908 articles were screened of which 17 were included. Incidences of positive PBC and UCBC were low in all studies. There was a large heterogeneity in the consistency between positive PBC and UCBC outcomes. PBC had a pooled sensitivity of 20.4% (95% CI 0.0-40.9) and specificity of 100.0% (95% CI 100.0-100.0) compared to 42.6% (95% CI 12.7-72.4%) and 97.8% (95% CI 93.1-100.0) of UCBC for clinical EOS, defined as clinical sepsis regardless of PBC outcomes. CONCLUSIONS: This systematic review shows that, compared to PBC, UCBC has higher sensitivity and comparable specificity for clinical EOS and might be considered as diagnostic test for EOS. Due to the limited number of studies, low incidences of EOS cases, and the imperfect reference standards for EOS, results should be interpreted cautiously. IMPACT: This is the first systematic review and meta-analysis investigating the diagnostic test accuracy of umbilical cord blood culture for neonatal early-onset sepsis. Peripheral blood culture is considered the gold standard for diagnosis of neonatal early-onset sepsis, but its value for this specific diagnosis can be questioned. Umbilical cord blood culture has higher sensitivity and comparable specificity for diagnosis of neonatal early-onset sepsis compared to peripheral blood culture, circumventing the risk for iatrogenic anemia and consequently might be used as a diagnostic tool for early-onset sepsis. Quality of evidence was regarded as low due to imperfect diagnostic methods of neonatal early-onset sepsis.

Neonatal pulmonary hypertension after severe early-onset fetal growth restriction: post hoc reflections on the Dutch STRIDER study.

The aim was to reflect on the unexpected finding of persistent pulmonary hypertension of the neonate (PPHN) and pulmonary hypertension in infants born within the Dutch STRIDER trial, its definition and possible pathophysiological mechanisms. The trial randomly assigned pregnant women with severe early-onset fetal growth restriction to sildenafil 25 mg three times a day versus placebo. Sildenafil use did not reduce perinatal mortality and morbidity, but did result in a higher rate of neonatal pulmonary hypertension (PH). The current paper reflects on the used definition, prevalence, and possible pathophysiology of the data on pulmonary hypertension. Twenty infants were diagnosed with pulmonary hypertension (12% of 163 live born infants). Of these, 16 infants had PPHN shortly after birth, and four had pulmonary hypertension associated with sepsis or bronchopulmonary dysplasia. Four infants with PPHN in the early neonatal period subsequently developed pulmonary hypertension associated with bronchopulmonary dysplasia in later life. Infants with pulmonary hypertension were at lower gestational age at delivery, had a lower birth weight and a higher rate of neonatal co-morbidity. The infants in the sildenafil group showed a significant increase in pulmonary hypertension compared to the placebo group (relative risk 3.67; 95% confidence interval 1.28 to 10.51, P = 0.02). CONCLUSION: Pulmonary hypertension occurred more frequent among infants of mothers allocated to antenatal sildenafil compared with placebo. A possible pathophysiological mechanism could be a "rebound" vasoconstriction after cessation of sildenafil. Additional studies and data are necessary to understand the mechanism of action. WHAT IS KNOWN: • In the Dutch STRIDER trial, persistent pulmonary hypertension in the neonate (PPHN) was more frequent among infants after antenatal sildenafil exposure versus placebo. WHAT IS NEW: • The current analysis focuses on the distinction between PPHN and pulmonary hypertension associated with sepsis or bronchopulmonary dysplasia and on timing of diagnosis and aims to identify the infants at risk for developing pulmonary hypertension. • The diagnosis pulmonary hypertension is complex, especially in infants born after severe early-onset fetal growth restriction. The research field could benefit from an unambiguous consensus definition and standardized screening in infants at risk is proposed.

Late (≥ 7 days) inhaled corticosteroids to reduce bronchopulmonary dysplasia in preterm infants.

BACKGROUND: Bronchopulmonary dysplasia (BPD), defined as oxygen dependence at 36 weeks' postmenstrual age (PMA), remains an important complication of prematurity. Pulmonary inflammation plays a central role in the pathogenesis of BPD. Attenuating pulmonary inflammation with postnatal systemic corticosteroids reduces the incidence of BPD in preterm infants but may be associated with an increased risk of adverse neurodevelopmental outcomes. Local administration of corticosteroids via inhalation may be an effective and safe alternative. OBJECTIVES: To assess the benefits and harms of inhaled corticosteroids versus placebo, initiated between seven days of postnatal life and 36 weeks' postmenstrual age, to preterm infants at risk of developing bronchopulmonary dysplasia. SEARCH METHODS: We searched CENTRAL, MEDLINE, Embase, CINAHL, and three trials registries to August 2022. We searched conference proceedings and the reference lists of retrieved articles for additional studies. SELECTION CRITERIA: We included randomised controlled trials (RCTs) comparing inhaled corticosteroids to placebo, started between seven days' postnatal age (PNA) and 36 weeks' PMA, in infants at risk of BPD. We excluded trials investigating systemic corticosteroids versus inhaled corticosteroids. DATA COLLECTION AND ANALYSIS: We collected data on participant characteristics, trial methodology, and inhalation regimens. The primary outcomes were mortality, BPD, or both at 36 weeks' PMA. Secondary outcomes included short-term respiratory outcomes (mortality or BPD at 28 days' PNA, failure to extubate, total days of mechanical ventilation and oxygen use, and need for systemic corticosteroids) and adverse effects. We contacted the trial authors to verify the validity of extracted data and to request missing data. We analysed all data using Review Manager 5. Where possible, we reported the results of meta-analyses using risk ratios (RRs) and risk differences (RDs) for dichotomous outcomes and mean differences (MDs) for continuous outcomes, along with their 95% confidence intervals (CIs). We analysed ventilated and non-ventilated participants separately. We used the GRADE approach to assess the certainty of the evidence. MAIN RESULTS: We included seven trials involving 218 preterm infants in this review. We identified no new eligible studies in this update. The evidence is very uncertain regarding whether inhaled corticosteroids affects the combined outcome of mortality or BPD at 36 weeks' PMA (RR 1.10, 95% CI 0.74 to 1.63; RD 0.07, 95% CI -0.21 to 0.34; 1 study, 30 infants; very low-certainty) or its separate components: mortality (RR 3.00, 95% CI 0.35 to 25.78; RD 0.07, 95% CI -0.08 to 0.21; 3 studies, 61 infants; very low-certainty) and BPD (RR 1.00, 95% CI 0.59 to 1.70; RD 0.00, 95% CI -0.31 to 0.31; 1 study, 30 infants; very low-certainty) at 36 weeks' PMA. Inhaled corticosteroids may reduce the need for systemic corticosteroids, but the evidence is very uncertain (RR 0.51, 95% CI 0.26 to 1.00; RD -0.22, 95% CI -0.42 to -0.02; number needed to treat for an additional beneficial outcome 5, 95% CI 2 to 115; 4 studies, 74 infants; very low-certainty). There was a paucity of data on short-term and long-term adverse effects. Despite a low risk of bias in the individual studies, we considered the certainty of the evidence for all comparisons discussed above to be very low, because the studies had few participants, there was substantial clinical heterogeneity between studies, and only three studies reported the primary outcome of this review. AUTHORS' CONCLUSIONS: Based on the available evidence, we do not know if inhaled corticosteroids initiated from seven days of life in preterm infants at risk of developing BPD reduces mortality or BPD at 36 weeks' PMA. There is a need for larger randomised placebo-controlled trials to establish the benefits and harms of inhaled corticosteroids.

Frequency and duration of extreme hypoxemic and hyperoxemic episodes during manual and automatic oxygen control in preterm infants: a retrospective cohort analysis from randomized studies.

OBJECTIVE: Neonatal exposure to episodic hypoxemia and hyperoxemia is highly relevant to outcomes. Our goal was to investigate the differences in the frequency and duration of extreme low and high SpO2 episodes between automated and manual inspired oxygen control. DESIGN: Post-hoc analysis of a cohort from prospective randomized cross-over studies. SETTING: Seven tertiary care neonatal intensive care units. PATIENTS: Fifty-eight very preterm neonates (32 or less weeks PMA) receiving respiratory support and supplemental oxygen participating in an automated versus manual oxygen control cross-over trial. MAIN MEASURES: Extreme hypoxemia was defined as a SpO2 < 80%, extreme hyperoxemia as a SpO2 > 98%. Episode duration was categorized as < 5 seconds, between 5 to < 30 seconds, 30 to < 60 seconds, 60 to < 120 seconds, and 120 seconds or longer. RESULTS: The infants were of a median postmenstrual age of 29 (28-31) weeks, receiving a median FiO2 of 0.28 (0.25-0.32) with mostly receiving non-invasive respiratory support (83%). While most of the episodes were less than 30 seconds, longer episodes had a marked effect on total time exposure to extremes. The time differences in each of the three longest durations episodes (30, 60, and 120 seconds) were significantly less during automated than during manual control (p < 0.001). Nearly two-third of the reduction of total time spent at the extremes between automated and manual control (3.8 to 2.1% for < 80% SpO2 and 3.0 to 1.6% for > 98% SpO2) was seen in the episodes of at least 60 seconds. CONCLUSIONS: This study shows that the majority of episodes preterm infants spent in SpO2 extremes are of short duration regardless of manual or automated control. However, the infrequent longer episodes not only contribute the most to the total exposure, but also their reduction in frequency to the improvement associated with automated control.

Preterm neonates benefit from low prophylactic platelet transfusion threshold despite varying risk of bleeding or death.

The Platelets for Neonatal Thrombocytopenia (PlaNeT-2) trial reported an unexpected overall benefit of a prophylactic platelet transfusion threshold of 25 × 109/L compared with 50 × 109/L for major bleeding and/or mortality in preterm neonates (7% absolute-risk reduction). However, some neonates in the trial may have experienced little benefit or even harm from the 25 × 109/L threshold. We wanted to assess this heterogeneity of treatment effect in the PlaNet-2 trial, to investigate whether all preterm neonates benefit from the low threshold. We developed a multivariate logistic regression model in the PlaNet-2 data to predict baseline risk of major bleeding and/or mortality for all 653 neonates. We then ranked the neonates based on their predicted baseline risk and categorized them into 4 risk quartiles. Within these quartiles, we assessed absolute-risk difference between the 50 × 109/L- and 25 × 109/L-threshold groups. A total of 146 neonates died or developed major bleeding. The internally validated C-statistic of the model was 0.63 (95% confidence interval, 0.58-0.68). The 25 × 109/L threshold was associated with absolute-risk reduction in all risk groups, varying from 4.9% in the lowest risk group to 12.3% in the highest risk group. These results suggest that a 25 × 109/L prophylactic platelet count threshold can be adopted in all preterm neonates, irrespective of predicted baseline outcome risk. Future studies are needed to improve the predictive accuracy of the baseline risk model. This trial was registered at www.isrctn.com as #ISRCTN87736839.