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EBNEO review of the study by Oliphant EA, McKinlay CJ, McNamara D, Cavadino A, Alsweiler JM. Caffeine to prevent intermittent hypoxaemia in late preterm infants: randomised controlled dosage trial. Arch Dis Child Fetal Neonatal Ed. 2023 Mar;108(2):106-113. doi: 10.1136/archdischild-2022-324010. Epub 2022 Aug 29. PMID: 36038256 reviewed for EBNeo by Ayat Mohamed and Hassanein Moustafa from the Department of Neonatology, Newcross Hospital, Wolverhampton, United Kingdom. Read here! #neotwitter #neoEBM #EBNEOreviews #ActaPaediatrica #ADC Acta Paediatrica commentary by Ayat Mohamed and Hassanein Moustafa: Acta Paediatrica - 2024 - Mohamed - EBNEO commentary Caffeine to prevent intermittent hypoxaemia in late preterm infants .pdf COMMENTARY: Caffeine citrate is considered to be the drug of choice of apnea of prematurity. Caffeine therapy reduces the incidence of intermittent hypoxaemia, duration of mechanical ventilation and lung damage in preterm babies who are born before 28 week gestation (1). Intermittent hypoxemia is the brief and repetitive episodes of dropped haemoglobin oxygen saturation from the normal oxygenation state, which are followed by returning to normal oxygenation baseline state. Preterm babies are more likely to have more frequent episodes of Intermittent hypoxia until term-equivalent age with no clear potential clinical triggers of developing apnea (2). The frequent occurrence of these episodes of desaturations in preterm infants have been suggested to be associated with later poor neurodevelopmental outcomes (3). Late preterm infants, who are born between 34 0/7 and 36 6/7 weeks gestational age, account for an important proportion of newborn babies requiring admission to the neonatal unit because of respiratory morbidity (4). Nearly one third (28.6%) of late preterm newborns were reported to have apnea of prematurity which was attributed to both lung and respiratory centre immaturity, and hence required treatment (5) Furthermore, a prospective cohort observational study showed that there is a great risk of having intermittent hypoxemia in late preterm babies (6). Therefore, preventing or reducing intermittent hypoxemia episodes in late preterm infants could be associated with improving the neurodevelopmental outcomes. This study was published in a reputable journal and declared no conflict of interest. It started with a large sample size and clear primary and prespecified secondary outcomes. However, there was a high rate of withdrawal of significant number of eligible babies in the higher dose caffeine. This was because of poor tolerability and administration difficulty, which may be attributed to the bitter solution taste as caffeine was received orally, in addition to the difficulty to give big volume in higher doses. The optimal dosage of caffeine citrate for reducing intermittent hypoxia in late preterm infants was not clear. This study used different dosages, and it is important to determine the most effective dose without adverse effects. It might be worth conducting longer and larger trials using more palatable caffeine formulation to assess the efficacy and safety of caffeine therapy in high doses, in addition to recording concurrent use of other medication that may interact with caffeine citrate. This would be very beneficial alongside with comparing early prophylactic versus late caffeine therapy and duration of caffeine treatment in late preterm infants in order to come to a definitive conclusion regarding its routine use on this population. REFERENCES Chavez L, Bancalari E. Caffeine: Some of the Evidence behind Its Use and Abuse in the Preterm Infant. Neonatology. 2022;119(4):428-432. Rhein LM, Dobson NR, Darnall RA, Corwin MJ, Heeren TC, Poets CF, McEntire BL, Hunt CE; Caffeine Pilot Study Group. Effects of caffeine on intermittent hypoxia in infants born prematurely: a randomized clinical trial. JAMA Pediatr. 2014;168(3):250-7. Pillekamp F, Hermann C, Keller T, von Gontard A, Kribs A, Roth B. Factors influencing apnea and bradycardia of prematurity – implications for neurodevelopment. Neonatology. 2007;91(3):155-61. Consortium on Safe Labor. Hibbard JU, Wilkins I, Sun L, Gregory K, Haberman S, et al. Respiratory morbidity in late preterm births. JAMA 2010; 304:419–25. Olivier F, Nadeau S, Caouette G, Piedboeuf B. Association between Apnea of Prematurity and Respiratory Distress Syndrome in Late Preterm Infants: An Observational Study. Front Pediatr. 2016 Sep 26;4:105. Williams LZJ, McNamara D, Alsweiler JM. Intermittent Hypoxemia in Infants Born Late Preterm: A Prospective Cohort Observational Study. J Pediatr. 2019; 204:89-95.e1.

EBNEO review of the study Zhu X, et al on Nasal Oscillation Post-Extubation (NASONE) Study Group. Noninvasive High-Frequency Oscillatory Ventilation vs Nasal Continuous Positive Airway Pressure vs Nasal Intermittent Positive Pressure Ventilation as Postextubation Support for Preterm Neonates in China: A Randomized Clinical Trial. JAMA Pediatr. 2022 Jun 1;176(6):551-559. PMID: 35467744 reviewed for EBNeo by Faeq Almudares and Bheru Gandhi from College of Medicine/Division of Neonatology, Texas Children’s Hospital. Read here! #neotwitter #neoEBM #EBNEOreviews #ActaPaediatrica #JAMApediatrics Acta Paediatrica commentary by Faeq Almudares and Bheru Gandhi: Acta Paediatrica - 2024 - Almudares - EBNEO Commentary Non%E2%80%90invasive high%E2%80%90frequency oscillatory ventilation vs nasal.pdf COMMENTARY: Invasive mechanical ventilation (IMV) while life-saving in neonates with severe respiratory failure, is often associated with worsened neonatal outcomes, including bronchopulmonary dysplasia (BPD), lower neurodevelopmental scores and death.1 In order to reduce complications of IMV, various non-invasive ventilation (NIV) strategies have been studied to evaluate improvement in extubation success. Nasal high-frequency oscillatory ventilation (NHFOV) is a newer NIV mode. NHFOV generates high mean airway pressure with superimposed oscillations, thus decreasing air trapping seen with high nasal continuous positive airway pressure (NCPAP) pressures.2 It can also eliminate the need for synchronisation with nasal intermittent positive pressure ventilation (NIPPV).2 The NASONE (Nasal Oscillation Post-Extubation) study is the largest randomised control trial to assess NHFOV's superiority over NCPAP in preventing reintubation and reducing IMV duration. NHFOV's effectiveness was not significantly different than NIPPV.3 This study was unique in its direct comparison of the three NIV modes: NHFOV, NCPAP and NIPPV. It was well-designed and adequately powered to investigate the primary outcomes. Its design enhances that generalizability of the approach, although the effectiveness of the intervention may vary in certain patient populations. The analysis was conducted via an intention-to-treat basis, with no crossover between groups permitted. However, in clinical practice, different NIV modes may be attempted before intubation. Although NHFOV showed greater effectiveness than NCPAP in preventing re-intubation, it did not impact BPD incidence. Using a pragmatic approach with a range of gestational ages, the paper assumes 31–32 week infants would have the same severity of lung disease as 25–26-week infants, and that NHFOV would have a similar effect. Upon limiting the analysis to extremely premature neonates or infants with severe respiratory failure, the secondary analysis showed NHFOV was associated with a decreased incidence of moderate to severe BPD.4 Limitations include lack of diversity in ethnicity and racial backgrounds of the cohort and the absence of NIPPV synchronisation. Given the overall limited availability of NIPPV synchronisation, the study's approach was appropriate. The lower rates of antenatal steroid use in the study cohort may have influenced the measured outcomes, but those rates were similar between intervention groups. Nevertheless, caution is needed when implementing the trial results in different hospitals and regions. There were no reported adverse outcomes associated with higher pressures experienced by neonates in the NHFOV group compared to the NCPAP and NIPPV groups. This aligns with previously reported results.5 However, it is important to acknowledge that the assessment of feeding intolerance was limited and did not include the rates of feeding interruptions or abdominal distension. Nonetheless, infants in the NHFOV group had statistically significantly higher weight gain than the NCPAP group. The difference in weight gain, 13 g versus 12 g, may be clinically insignificant but does show that HFOV did not compromise growth. This trial contributes to the evidence supporting the efficacy and safety of NHFOV in preterm infants, underscoring its potential advantages over NCPAP.6, 7 Further trials are warranted to confirm the short-term benefits of NHFOV and to investigate its long-term efficacy and safety in preterm infants.

July EbNEO Article of the Month by Madhi SA, et al on the Potential for Maternally Administered Vaccine for Infant Group B Streptococcus published in the New England Journal of Medicine (doi: 10.1056/NEJMoa2116045) reviewed for EBNeo by Dustin Flannery and Karen Puopolo from Children’s Hospital of Philadelphia. Read here! EBNEO REVIEW Also hear it discussed on the Incubator Podcast #neotwitter #neoEBM #EBNEOreviews #ActaPaediatrica #NEJM Acta Paediatrica commentary by Dustin Flannery and Karen Puopolo: Acta Paediatrica - 2023 - Flannery - EBNEO Commentary Safety and immunogenicity of GBS vaccine in pregnancy and.pdf COMMENTARY: "Group B Streptococcus (GBS) causes approximately 150,000 stillbirths and infant deaths annually worldwide.1 Infants who are exposed to maternal GBS colonization are at risk of sepsis and meningitis, which when not fatal, are associated with significant life-long morbidity.2 Accordingly, the development of a maternal GBS vaccine is a public health priority.1 A vaccine could help prevent GBS-associated morbidities and mortality. The results of this phase 2, randomized, placebo-controlled trial provide not only evidence that Pfizer’s GBS hexavalent vaccine (GBS6) is safe and immunogenic; the parallel seroepidemiology data also provide an evidence-based serocorrelate of protection that can be utilized in future studies.3 In some regions, universal GBS screening and targeted intrapartum antibiotic prophylaxis (IAP) have led to a substantial decline in cases of early-onset disease, though several limitations serve as the foundation for maternal GBS vaccine development.4 First, in many regions, IAP is not standard of care. Second, early-onset disease still persists in regions utilizing IAP due to limitations in antenatal screening. Third, a substantial portion of early-onset disease occurs among preterm infants, who may not benefit from late pregnancy screening and IAP. Fourth, IAP does not impact late-onset disease. Lastly, there are evolving concerns about the impact of IAP on maternal and neonatal dysbiosis, and selection pressure leading to colonization and infection with antibiotic-resistant organisms.5 The investigators provide reassuring data that GBS6 is safe. Maternal and infant adverse events were similar between groups and no serious adverse events were attributed to the vaccine. The vaccine was immunogenic in pregnant women and placental antibody transfer, known to be less robust for GBS compared with other pathogens, was achieved at concentrations that correlate with proposed threshold concentrations for protection against invasive infant disease. Importantly, investigators used a cross-standardized immunoassay and propose a single protective threshold that could be utilized in ongoing and future GBS vaccine research. The study had several limitations. The study was conducted in a setting that does not use IAP, as the impact of IAP on infant infection could cloud the picture when assessing a serologic threshold of protection. Serologic estimates from low- and middle-income countries may overestimate thresholds for high-income countries. Demographics of the study cohort may limit generalizability: enrolled pregnant persons were generally young, multiparous, of Black-African race/ethnicity, and roughly one third had HIV infection. The estimated serocorrelate of protection should also be viewed with caution. Acknowledging the remarkable effort represented by this study, the serocorrelate modeling was based on measurements from only 77 cases: when broken out by 6 serotypes and early- and late-onset disease, only type III infection was represented by >10 cases. The authors emphasize that the reported serocorrelate must be better defined in future studies with different populations. Such studies are needed to address the effect of pre-existing, naturally-acquired serotype-specific antibody on vaccine response, as well as maternal morbidities that may affect placental antibody transfer. Finally, a larger set of case-control data encompassing all common serotypes and both early- and late-onset disease is needed to generate robust estimates for serotype-specific serocorrelates of protection."

Article of the Month by Gentle SJ, Rysavy MA, Li L, et al. on Heterogeneity of Treatment Effects of Hydrocortisone by Risk of Bronchopulmonary Dysplasia or Death Among Extremely Preterm Infants in the National Institute of Child Health and Human Development Neonatal Research Network Trial: A Secondary Analysis of a Randomized Clinical Trial published in the JAMA Network Open reviewed by Nicolas Bamat and Timothy Nelin from Children's Hospital of Philadelphia. Read here! EbNeo Review:https://buff.ly/3rvpvjw Also listen it discussed on The Incubator Podcast! Incubator:https://buff.ly/3EUq61t #neotwitter #neoEBM #EBNEOreviews #ActaPaediatrica #JAMA Acta Paediatrica commentary by Timothy Nelin and Nicolas Bamat: Acta Paediatrica - 2023 - Nelin - EBNEO Commentary Does the effect of hydrocortisone in preterm infants depend on the.pdf "BPD remains the most common chronic morbidity of preterm birth despite advances in the survival of preterm infants.1, 2 Prior studies demonstrated postnatal corticosteroid effects vary with infants' baseline BPD risk, motivating the current study to investigate if an infant's baseline predicted risk for BPD or death modifies the effect of hydrocortisone.3, 4 Unlike prior metaregression analyses comparing data between trials, Gentle et al. compared data among infants enrolled in the NICHD NRN Hydrocortisone Trial and did not identify statistically significant differences in the effects of hydrocortisone on death, BPD, or neurodevelopmental impairment when analysed by infants' baseline risk for BPD or death. The findings published by Gentle et al. must be considered within the context of a subpopulation of extremely preterm infants with high baseline illness severity and may not generalise to broader preterm populations. The current data do not examine whether the baseline risk for BPD or death modifies the effect of hydrocortisone in all extremely preterm infants as infants in the NICHD NRN Hydrocortisone Trial carried a high risk for developing BPD based on the physiologic definition5–83.4% of infants in the hydrocortisone group and 86.4% of infants in the placebo group developed the composite outcome of death or BPD.6Prior studies investigating postnatal hydrocortisone found that 49% and 71% of infants receiving placebo died or developed BPD, with lower rates of death or BPD among hydrocortisone exposed infants.7, 8 Infants in those studies were exposed to hydrocortisone within 24 h of birth and at a median of 10 days, respectively. Therefore, infants in the NICHD NRN Hydrocortisone Trial represent a subset of extremely preterm infants with higher overall risk for death or BPD and were exposed to hydrocortisone at an older age. While no significant interaction of hydrocortisone treatment and baseline risk for BPD or death with the primary efficacy outcome was noted, close investigation suggests a trend towards a lower comparative relative risk for the development of grade 2 or 3 BPD in infants in the highest quartile of BPD or death risk (RR 0.94; 95% CI 0.81, 1.09) compared to infants in the lowest quartile of risk (RR 1.13; 95% CI 0.82, 1.55). The risk difference estimates for these quartiles highlight the clinical relevance of these trends: an estimate of a 5% higherabsolute risk for BPD or death among infants exposed to hydrocortisone in the lowest risk quartile and a 5% lower absolute risk among infants exposed to hydrocortisone in the highest risk quartile. These data suggest that infants with higher risks of BPD or death may comparatively benefit from postnatal hydrocortisone as administered in this trial, but with too much uncertainty. In conclusion, among extremely preterm infants enrolled in the NICHD NRN Hydrocortisone Trial, the effect of hydrocortisone was not modified by baseline risk for developing grades 2 or 3 BPD or death. Further research in larger and more representative cohorts of extremely preterm infants would aid in understanding potential differential effects of hydrocortisone exposure among infants with baseline differences in lung disease severity."

We would like to promote one of our latest reviews, on antenatal magnesium for preterm delivery and risk of cerebral palsy. You find the full review on our web site, ebneo.org

We would like to promote one of the recent EBNEO reviews, this time about a family-centre early intervention and later outcome in VLBW infants. Read the full review on the EBNEO web site.

Welcome to the 4th international Conference for Evidence-Based Neonatology, 10-12 November 2017, in Hyderabad India! Click here to register! As the number of articles world-wide in the medical press explodes, the importance of understanding and disseminating the principles of Evidence Based Medicine becomes greater. This is a central focus of the Society of EBNEO. At this Fourth international meeting of our young society, as in prior meetings – we include talks with both neonatal contents and clinical epidemiological methodology. We hope that this meeting will facilitate an international on-going collaboration and interchange. This meeting will be in association with Indian Association of Pediatrics Neonatology Chapter. There are two organizational features that are new at this year’s meeting. Firstly, we will have two workshops: one on advanced methods for meta-analysis. Secondly a workshop on running randomized controlled trials in the less well-resourced countries. In addition we have now almost 2 years after having launched the “EBNEO Journal Club”. The intent of this was to provide a structured synopsis of studies to allow a quick methodologically based over-view. It follows the model of the American College of Physicians Journal Club – which has proven an effective leaning and dissemination tool. These are now being published with pubmed referencing at Acta Paediatrica. In all of these ventures – there is ample opportunity for all neonatologists interested in methodologically based Neonatal care – to participate – from the ground level! Register to the conference by following the instructions below. We hope to see you at this exciting venture! The conference fee is only 400 USD. Click here to register today! Dr. Srinivas Murki and Dr. Vasudeva Murli on behalf of IAP Neochap associate professor Stefan Johansson, professor Haresh Kirpalani, professor Mikael Norman and associate Professor Clyde Wright; on behalf of EBNEO Conference folder and program Click here to download the conference folder with general information. Click here to download the preliminary program.

We would like to share one of our most recent EBNEO commentaries, on the recently published HIPSTER trial on whether HFNC is noninferior to nCPAP. Please find full commentary on ebneo.org

We, EBNEO, would like to share one of our latest commentaries, this time on a study on admission temperature and risk of adverse outcomes, written by Julia Maletzki, Stephanie Adzikah, Christoph Rüegger, and Dirk Bassler, at the University Hospital of Zurich, Switzerland. Find the full EBNEO review on ebneo.org!