EBNEO

Dr Kiran Shrivastava from Mumbai and Dr Abdul Razak from Australia review Sotiropoulos JX et al's #EBNEO June Article of the month: "Sotiropoulos JX, Oei JL, Schmölzer GM, Libesman S, Hunter KE, Williams JG, Webster AC, Vento M, Kapadia V, Rabi Y, Dekker J, Vermeulen MJ, Sundaram V, Kumar P, Kaban RK, Rohsiswatmo R, Saugstad OD, Seidler AL. Initial Oxygen Concentration for the Resuscitation of Infants Born at Less Than 32 Weeks’ Gestation: A Systematic Review and Individual Participant Data Network Meta-Analysis. JAMA Pediatr. 2024 Aug 1;178(8):774-783. doi: 10.1001/jamapediatrics.2024.1848. PMID: 38913382; PMCID: PMC11197034" READ HERE! Hear it discussed on the Incubator Podcast as well! Acta Commentary: Acta Paediatrica - 2024 - Shrivastava - EBNEO Commentary Comparing delivery room oxygen for preterms An IPD NMA Review.pdf The Individual Participant Data and Network Meta-analysis (IPD-NMA) examined 11 of 13 eligible studies, including data from 1003 babies, to address a critical question in neonatal care: What is the optimal initial oxygen concentration for resuscitating preterm infants born at less than 32 weeks' gestation? The authors categorised initial oxygen concentrations into three groups: low (21%–30%), intermediate (50%–65%), and high (90%–100%). They found that high initial oxygen concentrations were associated with a reduction in death compared to low and intermediate concentrations. Furthermore, they observed no differences in secondary outcomes, except for higher oxygen saturation within 5 min in the high oxygen group compared to the low oxygen group.1 These findings stand in contrast to previously conducted meta-analyses, which showed no significant effect of initial oxygen concentration on mortality. These earlier analyses typically compared low versus high oxygen concentrations based on an arbitrary distinction classifying infants exposed to intermediate oxygen as part of the high oxygen group. This categorisation likely diluted the apparent lower effect of high oxygen on mortality, ultimately leading to conclusions of no significant difference.2-4 In contrast, the IPD-NMA categorises oxygen exposure more precisely, revealing a significant reduction in mortality with high oxygen compared to both low and intermediate exposures. The striking impact of brief differences in initial oxygen exposure on such a critical outcome might prompt immediate consideration of this approach in clinical practice. However, it is essential to carefully weigh the certainty of this evidence, which remains low to very low. This lower certainty is driven by several factors, most notably statistical heterogeneity. In NMA, prediction intervals serve as a measure of heterogeneity and are based on the posterior distribution of analysis. They tell us that, with 95% certainty, the effect of a new trial would fall within this range. The authors point out that the lower mortality seen with high oxygen levels becomes nonsignificant as the prediction intervals cross the null, suggesting significant heterogeneity and reducing our confidence in the result. This statistical heterogeneity may, at least in part, be influenced by differences in how oxygen was titrated in the included trials (clinical heterogeneity). Most trials employed slow titration, while others used fast titration, and one trial even increased oxygen concentration from 0.21 to 1.0 rapidly. Such variations in oxygen delivery methods likely contributed to the observed heterogeneity.1 Additionally, the trials enrolled infants over a span of the last two decades and involved populations from different countries, further contributing to the variability. Beyond heterogeneity, other factors, such as the lack of blinding in many trials and the relatively low numbers of participants leading to imprecise estimates, also diminish confidence in the findings and raise questions about their overall reliability. While this type of IPD-NMA provides more credible evidence compared to traditional pairwise meta-analyses, the above-mentioned concerns urge caution among neonatal care providers. Should we adopt this evidence from a meta-analysis of heterogenous trials examining 1003 infants, or should we wait for more homogenous clinical trials with larger populations, such as the TORPIDO (Targeted Oxygen saturation in Respiratory care of premature Infants at Delivery: effects on Outcome) trial (1470 participants) and the HILO (higher versus lower oxygen) trial (1200 participants)?5, 6 This is just the beginning of our journey to determine the best approach to oxygen use in preterm resuscitation. Ongoing studies like OPTISTART (Optimisation of Saturation Targets And Resuscitation) may further illuminate how to optimise oxygen therapy after birth for these vulnerable infants.7

Ashlee Smith-Patel, Daniela Dinu & Elena Itriago from Baylor College of Medicine, Houston, TX, United States review Wei et al's paper: "Wei X, Franke N, Alsweiler JM, Brown GTL, Gamble GD, McNeill A, Rogers J, Thompson B, Turuwhenua J, Wouldes TA, Harding JE, McKinlay CJD; pre-hPOD Early School-age Outcomes Study Group. Dextrose gel prophylaxis for neonatal hypoglycaemia and neurocognitive function at early school age: a randomised dosage trial. Arch Dis Child Fetal Neonatal Ed. 2024 Jun 19;109(4):421-427. doi: 10.1136/archdischild-2023-326452. PMID: 38307710; PMCID: PMC11186727" for EbNeo. READ HERE! Acta Commentary: Acta Paediatrica - 2024 - Smith%E2%80%90Patel - EBNEO commentary Dextrose gel prophylaxis for neonatal hypoglycemia and.pdf Neonatal hypoglycemia is a common condition. Symptomatic neonatal hypoglycemia has been associated with white matter injury on brain magnetic resonance imaging, and even transient or undetected hypoglycemia may be associated with impaired executive functioning in early childhood.1, 2 This has led to studies evaluating prophylactic use of dextrose gel to decrease the incidence of hypoglycemia and, potentially, the incidence of neurodevelopmental impairment (NDI) later in life.3, 4 In this study, the authors were able to follow up and assess 80% of the initial cohort from the pre-hPOD trial,4 which compared various dextrose gel dosages (200 mg/kg, 400 mg/kg, 800 mg/kg, 1000 mg/kg) administered prophylactically at one hour of life with placebo. A previous analysis of the same cohort at two years of age found no difference in the composite neurosensory impairment outcome between placebo and dextrose gel,5consistent with another trial (the hPOD trial) which also compared the neurodevelopmental outcome at two years for infants born at risk and found no significant difference between 200 mg/kg 40% dextrose gel and placebo, but was underpowered to detect small but potentially clinically relevant differences in neurosensory impairment.6 The investigators evaluated multiple domains (neurocognitive function; visual perception; reading; numeracy, body size and composition; and grip strength) and found no difference in the primary outcome of cognitive impairment at 6–7 years of age for children randomised to various doses of prophylactic dextrose gel compared with control. When sample size was increased by combining all those exposed to intervention there was a lower risk of motor impairment (3% vs. 14%) and higher mean (SD) cognitive scores (106.0 (15.3) vs. 101.1 (15.7). These findings support the hypothesis that certain higher-order cognitive functions may not be fully developed at younger ages, and longer follow-up might be needed to detect poor executive function or visual impairment.3 The improvement in the motor skills at 6–7 years of age in this study which contrasts with previous reports may be due to the poor predictive value of the neurological exam and Bayley exam performed at 2 years of age in predicting motor skills later in childhood.7 However, it should also be considered that a limitation of this study were differences in baseline characteristics, with the children who were assessed being more likely to be born to older and more educated mothers, compared to those children lost to follow-up. The placebo group had a high rate of neurocognitive impairment (56%), compared with the dextrose group (48%). These results supports the hypothesis that the prophylactic gel prevented episodes of hypoglycemia that went undetected with intermittent sampling, as shown by studies using continuous glucose monitoring.2 While there were no identified adverse effects associated with the use of prophylactic dextrose gel, the number needed to treat (NNT) to prevent one case of NDI would likely be high, considering that the initial trial showed an NNT of 21 to prevent one case of hypoglycemia and larger studies.6 More studies are needed to evaluate benefits, harms, timing and dosing of prophylactic treatment in infants at risk of developing hypoglycemia.

Danielle Barber and Jill Chang from University of Colorado/ Children’s Hospital of Colorado review EbNeo August Article of the month: Nangle AM, He Z, Bhalla S, Bullock J, Carlson A, Dutt M, Hamrick S, Jones P, Piazza A, Vale A, Sewell EK. Reducing the percentage of surviving infants with acute symptomatic seizures discharged on anti-seizure medication. J Perinatol 2024. PMID 39043995 READ HERE! Acta Commentary: Acta Paediatrica - 2024 - Barber - EBNEO commentary Reducing the percentage of surviving infants with acute symptomatic.pdf.download.zip There is strong guidance to discontinue antiseizure medications (ASMs) prior to hospital discharge for neonates with acute symptomatic seizures. In the 2023 International League Against Epilepsy (ILAE) Task Force on Neonatal Seizures published guidelines,1 one of the six main recommendations is that ‘following cessation of acute provoked seizures without evidence for neonatal-onset epilepsy, ASMs should be discontinued before discharge home, regardless of magnetic resonance imaging or electroencephalographic findings’. Additionally, a comparative effectiveness study found no difference in neurodevelopmental impairment or epilepsy rates at 24 months among children whose ASM was discontinued vs. maintained at hospital discharge.2 While these recommendations have become stronger with time, they are not new: it has been more than a decade since the 2011 WHO Guidelines on Neonatal Seizures advised considering discontinuation of ASMs in neonates who had been seizure-free for 72 h.3 Despite these strong recommendations, there remains variation in clinical practice.4-7 The intuitive bias—particularly in centres without in-person neurology to evaluate the infant during the NICU hospitalisation—is that the ‘safer’ approach is to maintain the infant on ASMs until they see a neurologist in clinic. However, unnecessary ASM may contribute to long-term cognitive impairment8 and does not diminish the risk for future seizures.2, 4, 6 Inclusion of standardised treatment pathways for management of neonatal seizures has been shown to reduce the number of infants discharged home on ASMs. In the ILAE Task Force on Neonatal Seizures, 80% of experts surveyed ‘completely agreed’ and the remaining 20% of experts ‘mostly agreed’ that ‘a standardized treatment pathway for the management of neonatal seizures should be available in each neonatal unit’.1 Across hospitals with neonatal seizure treatment pathways, there is broad agreement on much of the treatment approach, including early discontinuation of ASMs.9 In Nangle et al., the authors describe the initiation of a neonatal seizure pathway in three hospitals where it did not previously exist and found ~50% reduction in infants discharged on ASMs in the subsequent epoch. Notably, the authors even reached 0% of infants with acute symptomatic seizures discharged on ASMs in 2023 at their Delivery Hospitals. We would like to particularly highlight that the authors of this study demonstrated feasibility and meaningful improvement in hospitals without in-person neurology consult availability. In fact, although possibly confounding by disease severity and seizure burden, fewer infants were discharged on ASM in the hospitals without neurology consult compared to the NICU with neurology consultation available. Additionally, their success highlights the benefits of working in multidisciplinary teams—both across various types of clinicians and partnerships between neonatology and neurology.

Dr Chidi Anakebe, Dr Sohaib Bin Nawaz, and Dr Haji Sheeraz Khan from the UK review the article Hemmingsen D, Moster D, Engdahl BL, Klingenberg C. Sensorineural hearing impairment among preterm children: a Norwegian population-based study. Arch Dis Child Fetal Neonatal Ed 2024;0: F1–F7. doi:10.1136/archdischild-2024-326870 for EbNeo. READ HERE! Acta Commentary: Acta Paediatrica - 2024 - Anakebe - EBNEO Commentary Risk stratification of sensorineural hearing impairment in preterm.pdf The incidence of moderate to severe bilateral hearing deficit (>50 dB) is estimated to occur in 1–3 per 1000 live births in healthy infants and 2–4 per 100 infants admitted to the NICU.1SNHI can lead to developmental delays as well as psychological and mental health issues, which adds to the existing challenges of being born prematurely.2 Risk factors associated with SNHI include family history of hearing loss, craniofacial anomalies, complex congenital abnormalities, congenital infections (such as TORCH), low birth weight, prematurity, hyperbilirubinemia requiring exchange transfusion, use of ototoxic medications, bacterial meningitis, a low Apgar score (<7 at 5 min), mechanical ventilation for at least five days, and NICU care lasting >7 days.2, 3 This extensive study included over 60 000 preterm infants over a 16-year period, focusing on the risk of SNHI in preterm infants born between 22 and 36 weeks. It allowed a follow-up period of five years to capture cases of late-onset hearing impairment. The findings align with previous studies, showing a higher prevalence of SNHI (1.4%) in preterm infants compared to the reference group (0.7%), with the highest risk observed (5.2%) in extreme preterm infants (gestational age 22–27 weeks). The increased incidence of SNHI in younger gestational age is related to the development of the auditory system, as the structural auditory system develops in the first 20 weeks of life, while the neurosensory system only becomes functional around 25 weeks.4 Insults to this developmental process can result in varying degrees of hearing impairment. Routine hearing screenings for infants involve non-invasive methods such as otoacoustic emissions (OAE) and confirmatory Auditory Brainstem Response (cABR) testing.1 Infants with hearing loss due to neural conduction disorders or auditory neuropathy may require ABR testing, as OAE alone may not detect their SNHI.3 This study made use of either diagnostic methods which may not have captured all infants with hearing impairment (HI) due to neurodysfunction. It also did not grade the severity of HI nor disclosed cases of isolated conductive HI and other forms of HI were broadly classed as ‘unspecified’. Other limitations of this study include: No grade of the severity of intracranial hemorrhage or periventricular leukomalacia, despite considering them as risk factors for SNHI. No clear definition of non-invasive ventilation, making it unclear what types of respiratory support were included. Did not specify the treatment methods used for jaundice in infants. No data analysis of uni/bilateral hearing impairment. No information on infants who received hearing aids or cochlear implants. Data were collected from five mandatory health and social registries in Norway, though Norway has 17 national health registries,5 and no explanation was given on registry selection. The study did not mention other potential congenital infectious variables, such as congenital cytomegalovirus infection.6 Overall, while this study provides valuable insights into the prevalence and risk factors of SNHI in preterm infants, addressing these limitations could further enhance understanding in this area.

Mary Eileen Foster and Harsha Gowda from Neonatal Unit, Birmingham Heartlands Hospital, UK, write an EbNeo Review on: Gallup JA, Ndakor SM, Pezzano C, Pinheiro JMB. Randomized Trial of Surfactant Therapy via Laryngeal Mask Airway Versus Brief Tracheal Intubation in Neonates Born Preterm. J Pediatr. 2023 Mar;254:17-24.e2. doi: 10.1016/j.jpeds.2022.10.009. Epub 2022 Oct 12. PMID: 36241051 READ HERE! Acta Commentary: Acta Paediatrica - 2024 - Foster - EBNEO commentary Surfactant administration via laryngeal mask airway versus brief.pdf Globally, neonatal practices are intensely focused on reducing the prevalence of bronchopulmonary dysplasia (BPD) and its associated comorbidities. The administration of surfactant has been shown to reduce the risk of death and BPD in preterm infants. Since its introduction in 19801, surfactant administration has revolutionised the treatment of respiratory distress syndrome (RDS), consequently diminishing the risk of developing BPD4. Over the decades, the strategies for surfactant delivery have evolved significantly, encompassing a range of different techniques from INSURE method (Intubation-SURfactant-Extubation) to less invasive surfactant administration (LISA). INSURE was developed to reduce the amount of time neonates remained intubated and ventilated to reduce its complications while still receiving surfactant and reducing BPD, meanwhile LISA was developed after a neonates failed to come off the ventilator with the INSURE method7. However, the standard approach to administering surfactant still involves the use of laryngoscope either direct or video for endotracheal intubation with ETT or LISA catheter for surfactant administration. These approaches may need pain relief or sedation. In 2013, the laryngeal mask airway (LMA) has emerged as an effective method for surfactant delivery, showcasing a significantly reduces the need for intubation and mechanical ventilation in premature infants with moderate respiratory distress syndrome (RDS)2. The advantages of utilising LMA are significant, including the obviation of laryngoscope use, which simplifies the procedure for operators. This, in turn, reduces the necessity for sedative medications. Furthermore, LMA presents minimal contraindications, which primarily encompass maxillofacial, tracheal, or established pulmonary malformations. However, a notable limitation of LMA use is the absence of sizes appropriate for very low birth weight or extremely premature infants, with the smallest available size being 1, which is only licensed to be used in infants who are more than 2 kilograms6. Additionally, there is a noticeable gap in scientific validation for this approach. In this current study, we can see that LMA had a lower failure rate (20%) compared to ETT (29%), demonstrating its non-inferiority when it came to this paper’s primary outcome. This paper shows that administering surfactant via LMA can have advantages over the more traditional methods. Some of these advantages include that it is more user friendly, and less training required for its use. Sedative medications, such as remifentanil, can themselves increase the failure rate in more traditional methods such as InSuRe. These findings provide valuable insight into the ongoing discourse on minimally invasive surfactant administration, with a method that could potentially decrease the need for mechanical ventilation and its associated risks. However, the non-inferiority margin of 20% is notably generous, potentially obscuring clinically significant differences between the two methods. This choice, coupled with the small sample size, attenuates the study’s statistical power, rendering the conclusion of non-inferiority less compelling than it might otherwise be. Furthermore, the methodological divergence in pre-medication between groups injects an additional variable into the comparative analysis this could have been attenuated if the comparison would have been done between LMA and another less invasive surfactant administration technique such as LISA. Another limitation is failure to reach the target sample size due to slow recruitment and Covid 19 pandemic. It is worth mentioning that there was also a mid-protocol change which can affect the way we interpret the results. The changes included difference in timings to define failure of procedure (ventilation in the first 72 hours rather than 120 hours), saturations target in eligibility criteria (90-95% vs 85%), changing randomization allocation from 1:1 to 2:1 favoring LMA, which can introduce contextual bias to units were LMA is not seen as favorable, and lastly that it was intended as a multi-centric trial. While the study presents an intriguing alternative to traditional surfactant administration methods, its findings must be interpreted with caution. The pursuit of innovation in neonatal care is commendable, but it must be grounded in solid, evidence-based research to ensure that new practices offer tangible benefits without compromising patient safety. As such, this trial represents an important step in an ongoing journey rather than a definitive destination. Further large multi-centric RCT data is required before the results can be generalised and adopted for routine practice. References: 1) Halliday HL. History of surfactant from 1980. Biol Neonate. 2005;87(4):317-22. doi: 10.1159/000084879. Epub 2005 Jun 1. PMID: 15985754. 2) Pejovic, N. J., Myrnerts Höök, S., Byamugisha, J., Alfvén, T., Lubulwa, C., Cavallin, F., & Tylleskär, T. (2020). A Randomized Trial of Laryngeal Mask Airway in Neonatal Resuscitation. The New England Journal of Medicine, 383(22), 2138-2147. https://doi.org/10.1056/NEJMoa2005333 3) Glenn T, Fischer L, Markowski A, Carr CB, Malay S, Hibbs AM. Complicated Intubations are Associated with Bronchopulmonary Dysplasia in Very Low Birth Weight Infants. Am J Perinatol. 2023 Aug;40(11):1245-1252. doi: 10.1055/s-0041-1736130. Epub 2021 Sep 9. PMID: 34500482; PMCID: PMC9239052. 4) Hsiu-Lin Chen, Shu-Ting Yang, Pin-Chun Su, & Hao-Wei Chung. (2024). The outcomes of preterm infants with neonatal respiratory distress syndrome treated by minimally invasive surfactant therapy and non-invasive ventilation. Biomedicines, 12(4), 838. https://doi.org/10.3390/biomedicines12040838 5) Roberts, K. D., Brown, R., Lampland, A. L., Leone, T. A., Rudser, K. D., & Finer, N. N., et al. (2018). Laryngeal mask airway for surfactant administration in neonates: A randomized, controlled trial. Journal of Pediatrics, 193, 40-46. https://doi.org/10.1016/j.jpeds.2017.09.080 6) Aitken, J., & O’Shea, J. (2021). Could laryngeal mask airways be used to stabilise neonates at birth by those with limited intubation experience? *Archives of Disease in Childhood, 106*(2), 197-200. https://doi.org/10.1136/archdischild-2020-321441 7) Bugter, I. A. L., Janssen, L. C. E., Dieleman, J., Kramer, B. W., Andriessen, P., & Niemarkt, H. J. (2020). Introduction of less invasive surfactant administration (LISA), impact on diagnostic and therapeutic procedures in early life: A historical cohort study. BMC Pediatrics, 20, Article 421. https://doi.org/10.1186/s12887-020-02325-0

Tristan Dear and Jane Stremming from USA review EbNeo April 2024 Article of the Month: Alexander T, Asadi S, Meyer M, Harding JE, Jiang Y, Alsweiler JM, et al. Nutritional Support for Moderate-to-Late–Preterm Infants — A Randomized Trial. N Engl J Med. 2024;390:1493–1504. PMID 38657245. READ HERE! Hear it on the Journal Club of the Incubator Podcast! Acta Commentary: Acta Paediatrica - 2024 - Dear - EBNEO commentary Nutritional support for moderate%E2%80%90to%E2%80%90late%E2%80%90preterm infants A randomized.pdf This trial, Nutritional Support for Moderate-to-Late Preterm Infants – A Randomized Trial [1], aimed to assess routine nutritional interventions in moderate-to-late preterm gestation infants, as there is limited literature guiding current nutritional strategies for this population. It examines three interventions (intravenous amino acid solution versus dextrose solution until full enteral feedings were established, milk supplement when mother’s milk was insufficient versus exclusive use of mother’s milk, and taste and smell exposure before gastric tube feeding versus no exposures) and assessed body-fat percentage at 4 months corrected gestational age and time to full enteral feeding. The study found no significant differences in these outcomes. It is well established that nutrition is essential to growth rate, body composition, and neurodevelopment. Historically, preterm infants have faltering growth after delivery and are unable to match their in-utero growth rates, and undernutrition is a primary driver [2]. Interventions that may improve growth include parenteral nutrition, early enteral feeding initiation, and introduction of smell and taste with gavage feeds. There is debate about whether the addition of short-term parenteral nutrition is beneficial to newborns, as evidence in older populations suggests there may be increased morbidities with early introduction of parenteral nutrition [3]. This publication by Alexander et al. suggests that enriched nutritional support is not beneficial to an infant’s short-term growth. Further follow-up is ongoing, with planned assessment of neurodevelopment and growth at 2 years of age [4]. This study adds to the growing literature on the addition of smell and taste during tube feedings, demonstrating that while there appear to be minimal adverse effects, there is little identified benefit. A randomized control trial published in 2021 assessed effects of smell and taste during tube feeding on the growth of infants born under 29 weeks gestation and found no difference in weight at the time of discharge [5]. A recent Cochrane review also found that exposure to smell and taste of milk has little effect on time to full sucking feeds [6], consistent with findings in this study. Limitations of this study include applicability only to parents intending to breastfeed, lack of stratification for small for gestation infants, unblinded study design, and high rates of protocol deviation for infants in the exclusively mother’s milk intervention. Infants born at this gestational age often receive milk fortification; however, the authors did not explicitly describe the protocol for fortification. Findings cannot be applied to infants with complicated clinical courses, as most infants reached full enteral feeds by one week of life. The authors conclude that routine nutritional interventions while transitioning to full nutrition of mothers’ milk do not affect time to full enteral feeds or body composition at 4 months corrected age. Thus providers can collaborate with caregivers to develop a feeding plan that will best support establishment of exclusive breast milk feeds. While follow-up is still ongoing, these findings have implications for nutritional options while in the NICU, reinforce the importance of lactation support, and have the potential to reduce healthcare costs and interventions during an infant’s hospital stay. References 1. Alexander T, Asadi S, Meyer M, Harding JE, Jiang Y, Alsweiler JM, et al. Nutritional Support for Moderate-to-Late–Preterm Infants — A Randomized Trial. N Engl J Med. 2024;390: 1493–1504. 2. Hay WW Jr. Nutritional Support Strategies for the Preterm Infant in the Neonatal Intensive Care Unit. Pediatr Gastroenterol Hepatol Nutr. 2018;21: 234–247. 3. Fivez T, Kerklaan D, Mesotten D, Verbruggen S, Wouters PJ, Vanhorebeek I, et al. Early versus late parenteral nutrition in critically ill children. N Engl J Med. 2016;374: 1111–1122. 4. Bloomfield FH, Harding JE, Meyer MP, Alsweiler JM, Jiang Y, Wall CR, et al. The DIAMOND trial – DIfferent Approaches to MOderate & late preterm Nutrition: Determinants of feed tolerance, body composition and development: protocol of a randomised trial. BMC Pediatr. 2018;18: 220. 5. Beker F, Liley HG, Hughes IP, Jacobs SE, Macey J, Twitchell E, et al. Effects on growth of smell and taste of milk during tube feeding of preterm infants: A randomized clinical trial: A randomized clinical trial. JAMA Pediatr. 2021;175: 1115–1123. 6. Delgado Paramo L, Bronnert A, Lin L, Bloomfield FH, Muelbert M, Harding JE. Exposure to the smell and taste of milk to accelerate feeding in preterm infants. Cochrane Database Syst Rev. 2024;5: CD013038.

Puneet Sharma and Brian King from US review EbNeo March 2024 Article of the Month: HIP Trial Investigators; Blakely ML, Krzyzaniak A, Dassinger MS, Pedroza C, Weitkamp J, Gosain A, et al. Effect of Early vs Late Inguinal Hernia Repair on Serious Adverse Event Rates in Preterm Infants: A Randomized Clinical Trial. JAMA 2024;331(12):1035-44. PMID 38530261. READ HERE! Acta Commentary: Acta Paediatrica - 2024 - Sharma - EBNEO Commentary The impact of timing of inguinal hernia repair on outcomes in preterm.pdf Optimal timing of inguinal hernia repair is uncertain due to the competing concerns around risk of anesthesia in neonates and risk of hernia-related complications such as incarceration (1). This study is a well-designed, multicentered trial that demonstrates short term benefits to performing inguinal hernia repair after NICU discharge. Furthermore, the use of Bayesian analyses allows for more pragmatic and clinically oriented interpretation of the outcomes. Late repair led to fewer serious adverse events and fewer days in the hospital, with a greater effect in vulnerable populations like extremely preterm infants and those with BPD. Of note, there were more laparoscopic procedures in the early repair group, which are associated with shorter operation time and less complications than laparotomy (2). However, the combination of better outcomes for patients and potentially less healthcare utilization (and costs), makes late repair an appealing choice. Furthermore, this intervention is very straightforward to implement. However, the broad definition of serious adverse event that is used in the composite primary outcome highlights important limitations when interpreting the results. For example, the most common adverse event in both groups was apnea requiring intervention, which could have a very broad range of clinical significance. Furthermore, cardiac arrest, of which there were three in the late repair group compared to zero in the early, is weighted equally to apnea. Similarly, more infants in the late repair group had incarcerated hernia, but this was broadly classified and included both surgical repairs and bedside reductions. A major limitation with composite outcomes is that they can provide a false equivalency between included outcomes, making it difficult to assess an intervention’s effect on individual outcomes. This limitation is well documented, and yet many trials in neonatology continue to use them due to their benefits when powering trials (3). Alternate statistical approaches exist to address some of these limitations, one of which is the desirability of outcome ranking (DOOR). DOOR uses a patient-centric approach to rank outcomes from most to least desirable and was recently used in a post-hoc analysis of a neonatal trial (4). Interpretation of this study’s findings might change using the DOOR approach. For example, more patients in the late repair group did not undergo surgery, often due to spontaneous closure. This outcome was not emphasized by the authors but may be a desirable outcome ranked highly by families. Similarly, the outcomes of apnea and incarceration would likely not be ranked equivalently using the DOOR approach. Another important factor to consider with late repair is the additional burden it can place on families. Families that were deemed unable to follow up were excluded, but this is an important cohort. Families may prefer repair during admission as both a financial decision and convenience. While the late repair group had fewer hospital days, a readmission was required. Greater financial burden may be placed on families with readmission, both due to increased cost-sharing and out-of-pocket costs (5). If many of the adverse events in the early repair group are short term and mild, some families may still elect for early repair depending on their values and preferences. Differences in long term outcomes, which are being studied, may also alter the potential tradeoffs. Studies have been conducted to clarify what outcomes are most important to parents of children with bronchopulmonary dysplasia (6). A similar study in this patient population would undoubtedly provide important context on the timing of repair. REFERENCES Wang KS; Committee on Fetus and Newborn, American Academy of Pediatrics; Section on Surgery, American Academy of Pediatrics. Assessment and management of inguinal hernia in infants. Pediatrics. 2012;130(4):768-773. PMID: 23008462. Davies DA, Rideout DA, Clarke SA. The International Pediatric Endosurgery Group Evidence-Based Guideline on Minimal Access Approaches to the Operative Management of Inguinal Hernia in Children. J Laparoendosc Adv Surg Tech A. 2020;30(2):221-227. PMID: 28140751. Cordoba G, Schwartz L, Woloshin S, Bae H, Gøtzsche PC. Definition, reporting, and interpretation of composite outcomes in clinical trials: systematic review. BMJ. 2010;341:c3920. PMID: 20719825. Katheria AC, El Ghormli L, Rice MM, Dorner RA, Grobman WA, Evans SR. Application of desirability of outcome ranking to the milking in non-vigorous infants trial. Early Hum Dev. 2024;189:105928. PMID: 38211436. King BC, Mowitz ME, Zupancic JAF. The financial burden on families of infants requiring neonatal intensive care. Semin Perinatol. 2021;45(3):151394. PMID: 33581862. Callahan KP, Kielt MJ, Feudtner C et al. Ranking future outcomes most important to parents of children with bronchopulmonary dysplasia. J Pediatr. 2023;259:113455. PMID: 37172804. Acta Paediatrica - 2024 - Sharma - EBNEO Commentary The impact of timing of inguinal hernia repair on outcomes in preterm.pdf

Rashida Javed and Harsha Gowda from UK review EbNeo January 2024 Article of the Month: Gupta S, Subhedar NV, Bell JL, et al. Trial of Selective Early Treatment of Patent Ductus Arteriosus with Ibuprofen. N Engl J Med. 2024;390(4):314-325. doi:10.1056/NEJMoa2305582. PMID: 38265644 READ HERE! Hear it on the Journal Club of the Incubator Podcast! Acta Commentary: Acta Paediatrica - 2024 - Javed - EBNEO commentary Patent ductus arteriosus PDA To treat early or not with ibuprofen.pdf Patent ductus arteriosus (PDA) is common in extreme preterm infants1, and its management is a subject of debate2. A large PDA of more than 1.5mm in diameter which is persistent beyond 3 days of age is associated with a higher mortality and morbidity as well as a greater risk of bronchopulmonary dysplasia3. Systematic reviews of randomized, controlled trials showed that pharmacological treatment with ibuprofen induced PDA closure had no beneficial effects on clinical outcomes4,5. Therefore, the pharmacological treatment of PDA in extreme preterm infants has decreased6. However, the evidence to support this strategy is limited and contradictory7. In the Baby-OSCAR trial, preterm infants between 23+0 weeks to 28+6 weeks, death or moderate or severe bronchopulmonary dysplasia assessed at 36 weeks of postmenstrual age occurred in 69.2% (220/318) infants in the ibuprofen group and 63.5% (202/318) in the placebo group (adjusted risk ratio 1.09, 95% CI 0.98-1.20). This was statistically not significant. Subgroup analysis of primary outcome for each gestational age favors placebo group but none were statistically significant as numbers were small. Secondary outcomes like intraventricular hemorrhage, cystic periventricular leukomalacia, clinically significant pulmonary hemorrhage, and discharge on home oxygen were higher in ibuprofen group but none of them were statistically significant. PDA closed or less than 1.5mm in diameter at 3 weeks of age confirmed by echocardiography was 55.5% (176/317) in the ibuprofen group compared to 37% (117/316) in the placebo group (adjusted risk ratio, 1.50; 95% CI, 1.30 to 1.74). Open-label treatment including surgical ligation was 14.2% in the ibuprofen group and 29.8% in the placebo group. Even though in the ibuprofen group, more PDA closed or less than 1.5mm in diameter at 3 weeks of age, no improvement in the primary outcome was observed. The limitations of the trial were, not meeting the enrolment goal of 730 infants because of non-availability of drugs, changes in the clinical practice and effect of COVID-19 pandemic. Although early assessment for randomization was encouraged, first dose of ibuprofen or a placebo was administered at a median of 61 hours after birth. This trial did not target hemodynamically significant PDA identified by clinical findings, rather than those screened by echocardiography. Other important limitation was, in spite of strict criteria, open-label therapy was received in 29.8% in the placebo group which made it more difficult to identify between-group differences in clinical outcomes. Despite above limitations, the baby OSCAR trial is the largest study on early pharmacological treatment of PDA using strict echocardiography screening criteria to diagnose hemodynamically significant PDA. Recently published Beneductus trial in similar gestational age group and comparable primary and secondary outcomes as the baby OSCAR trial showed expected management of PDA noninferior to early management with ibuprofen8. Cochrane reviews published in 2020 on ibuprofen as a prevention of PDA and treatment of PDA concluded that ibuprofen closes PDA but did not benefit short term or long-term outcomes9. To conclude, in extreme preterm infants with large PDA, there is no evidence that early treatment with ibuprofen would reduce the risk of death or moderate or severe BPD at 36 weeks postmenstrual age. It is plausible that an attempt to close the PDA with ibuprofen may be more harmful than the condition itself. Ibuprofen has potential adverse effects and there are no proven clinical benefits. So, clinicians should avoid using it for early treatment of PDA. References: Lee JA, Kim M-J, Oh S, Choi BM. Current status of therapeutic strategies for patent ductus arteriosus in very-low-birthweight infants in Korea. J Korean Med Sci 2015; 30: Suppl 1: S59-S66. Benitz WE. Treatment of persistent patent ductus arteriosus in preterm infants: time to accept the null hypothesis? J Perinatol 2010; 30: 241-52. Sellmer A, Bjerre JV, Schmidt MR, et al. Morbidity and mortality in preterm neonates with patent ductus arteriosus on day 3. Arch Dis Child Fetal Neonatal Ed 2013; 98: F505-F510. Jansen EJS, Hundscheid T, Onland W, Kooi EMW, Andriessen P, de Boode WP. Factors associated with benefit of treatment of patent ductus arteriosus in preterm infants: a systematic review and meta-analysis. Front Pediatr 2021; 9: 626262. Mitra S, Florez ID, Tamayo ME, et al. Association of placebo, indomethacin, ibuprofen, and acetaminophen with closure of hemodynamically significant patent ductus arteriosus in preterm infants: a systematic review and meta-analysis. JAMA 2018; 319: 1221-38. Ngo S, Profit J, Gould JB, Lee HC. Trends in patent ductus arteriosus diagnosis and management for very low birth weight infants. Pediatrics 2017; 139(4): e20162390. Hundscheid T, Jansen EJS, Onland W, Kooi EMW, Andriessen P, de Boode WP. Conservative management of patent ductus arteriosus in preterm infants — a systematic review and meta-analyses assessing differences in outcome measures between randomized controlled trials and cohort studies. Front Pediatr 2021; 9: 626261. Hundscheid T, Onland W, Kooi EMW, et al. Expectant Management or Early Ibuprofen for Patent Ductus Arteriosus. N Engl J Med. 2023;388(11):980-990. doi:10.1056/NEJMoa2207418 Ohlsson A, Walia R, Shah SS. Ibuprofen for the treatment of patent ductus arteriosus in preterm or low birth weight (or both) infants. Cochrane Database Syst Rev. 2020;2(2):CD003481. Published 2020 Feb 11.

Rashida Javed and Harsha Gowda from University Hospitals, Birmingham, UK review EbNeo October Article of the Month "Kidman AM, Manley BJ, Boland RA, et al. Higher versus lower nasal continuous positive airway pressure for extubation of extremely preterm infants in Australia (ÉCLAT): a multicentre, randomised, superiority trial. Lancet Child Adolesc Health. 2023 Dec;7(12):844-851. https://doi.org/10.1016/S2352-4642(23)00235-3. Epub 2023 Oct 27. PMID: 38240784." READ HERE! Hear it discussed on the Incubator Podcast! Acta Commentary: Acta Paediatrica - 2024 - Javed - EBNEO Commentary Reducing extubation failure in extreme preterm infants higher vs.pdf Despite advances in non-invasive respiratory support, extremely preterm infants experience extubation failure frequently which can be associated with morbidity and mortality1. The increased risk of extubation failure is due to lung immaturity, poor chest compliance and immature respiratory drive2. Nasal continuous positive airway pressure (nCPAP) or high flow have been the mainstay of post extubation respiratory support3. Following extubation, nCPAP settings vary between centers. Higher set nCPAP levels post extubation may help to maintain end expiratory lung volume and reduce atelectasis. But, a small pilot RCT by Kitsommart et al in 2013 comparing high vs low nCPAP pressures showed no difference in extubation failure rates4. In the ECLAT study, extubating infants less than 28-week gestation to a higher nCPAP of 10cmH2O reduced extubation failure (35% – 24/69 infants) compared to standard nCPAP group (57% – 39/69 infants) with risk difference of -21.7%, 95% CI -38.5% to -3.7%. The number needed to treat was 5 infants meaning five infants needed to receive higher nCPAP to standard nCPAP to prevent one additional extubation failure. Stratification for gestational age subgroups (22-25 and 26-27 completed weeks) also showed a lower extubation failure rate in the nCPAP group receiving higher pressures, especially in the more mature subgroup. However, the study was underpowered for subgroup analysis. The secondary outcomes showed no significant differences between groups which was also underpowered. The most common adverse events, such as pneumothorax, pulmonary interstitial emphysema, spontaneous intestinal perforation, and death were similar in both groups. All infants had exogenous surfactant prior to recruitment which might had contributed to minimal incidence of pneumothorax in higher nCPAP group. 13(19%) infants in standard nCPAP group and 2(3%) in higher nCPAP deviated from protocol to increased nCPAP level above the prescribed level. All these infants were eventually re-intubated within the primary outcome period. Recruitment ceased at 74% of planned sample size due to recurrent pauses during COVID-19 pandemic. Other limitations are clinicians were not blinded and actual distending pressure in alveoli was not measured. Also, there were no standardized criteria for readiness for extubation. Inspite of above limitations, it is a well-designed randomized control trial showing benefits of higher nCPAP reducing extubation failure. Buzzella et al did randomized control trial in 93 infants of less than 30 weeks gestational age to a higher nCPAP of 7-9 cmH2O or a lower nCPAP of 4-6 cmH2O and found a significant reduction in extubation failure in higher nCPAP group5. But in the ECLAT trial, a much higher nCPAP was used and more immature infants were included. All the extubation failure in higher nCPAP group occurred in first 72hours and nil between 73-168 hours compared to 12 in standard nCPAP group. Probably this suggests the importance of high alveoli end expiratory pressure after extubation to prevent later atelectasis and extubation failure. To conclude, the ECLAT study provides evidence for the use of higher nCPAP in infants less than 28 weeks’ gestation to reduce extubation failure compared to standard nCPAP. There was no difference in BPD rates observed, so the benefit of higher nCPAP (9-11 cmH2O) is questionable. Further large RCT adequately powered to compare BPD rates is required to better evaluate the safety and efficacy of higher post-extubation nCPAP levels on outcomes of greater importance to clinicians and families.' References: Razak A, Shah PS, Ye XY, Mukerji A. Post‐extubation use of non‐invasive respiratory support in preterm infants: a network meta‐analysis. Cochrane Database Syst Rev. 2021;2021(10):CD014509. Published 2021 Oct 25. Kidman AM, Manley BJ, Boland RA, Davis PG, Bhatia R. Predictors and outcomes of extubation failure in extremely preterm infants. J Paediatr Child Health. 2021;57(6):913–9. Awanti, Srinivas & Pol, Ramesh & Katti, Arun. (2023). A randomized controlled trial to compare the success rates and efficacy of high flow nasal cannulae versus nasal continuous positive airway pressure in post extubation period in neonates. International Journal of Contemporary Pediatrics. 10. 510-513. 10.18203/2349-3291.ijcp20230728. Kitsommart R, MHSc AK, Al-Saleem N. Levels of nasal CPAP applied during the immediate post- extubation phase. A Randomized Controlled Pilot Trial2013;3:9. Buzzella B, Claure N, D’Ugard C, Bancalari E. A randomized controlled trial of two nasal continuous positive airway pressure levels after extubation in preterm infants. J Pediatr 2014; 164: 46–51.

Vonita Chawla from University of Arkansas for Medical Sciences / Arkansas Children’s Hospital reviews the paper "Motojima Y, Nishimura E, Kabe K, Namba F. Management and outcomes of periviable neonates born at 22 weeks of gestation: a single-center experience in Japan. J Perinatol 2023; 43(11):1385-1391. PMID: 37393397" for EbNeo. READ HERE! Acta Commentary: Acta Paediatrica - 2024 - Chawla - EBNEO Commentary Management and outcomes of periviable neonates born at 22 weeks of.pdf 'In 1991, an amendment to the Eugenic Protection Act lowered the limit of viability to 22 weeks of gestation, in Japan (1). Backed by a robust prenatal care program (2), the Japanese longitudinal experience in caring for neonates born at the cusp of viability has led to improved outcomes (3). Subsequently, active resuscitation is offered to most neonates born at 22 weeks GA, i.e.>80% of these neonates are intubated at birth, according to the year 2020 report of the Neonatal Research Network (NRN) Database, Japan (4) despite a lower rate of antenatal steroid use (~50%). In this study, Motojima et al describe the experience of a single Japanese tertiary center, in caring for periviable neonates born as early as 2013. In this cohort of 29 neonates, overall favorable outcomes are noted with more than 80% survival. Strikingly, only one neonate (5%) in this group developed CP long-term, and only 2 infants (11%) had severe NDI, with the overall greatest impairment seen in the language-social domain. Key maternal/infant characteristics include universal prenatal care, a considerably higher median birth weight of 512 g (compared to median birth weight of 480 g reported by the National Institute of Child Health and Human Development NRN, 2013-2018) (5), use of C-section as the predominant mode of delivery and comparable rates (5) of antenatal steroid administration (34%), both of which are associated with increased survival in this population (6). Maternal illnesses and other prenatal exposures such as smoking and recreational drugs are not listed. Cord milking is practiced commonly, which is currently not standard of care for infants <28 weeks GA, due to an increased risk of IVH (7). Interestingly, in this study, the incidence of severe IVH remained low. Other noteworthy management strategies include early enteral feeding (100% of infants fed by day of life (DOL) 1, despite 90% of these infants requiring some inotropic support), frequent use of neonatologist-performed echocardiograms to inform decisions regarding fluid management, PDA, selection/titration of inotropes/vasopressors, etc., and lung-protective approach to ventilation. All infants are on non-invasive respiratory support by 40 weeks PMA. Postnatal steroid use is not mentioned and a distinction between early vs. late onset sepsis is not made. Probiotics are used as early as DOL 0 in some neonates and phenobarbital is the primary sedative used in the first week of life. Worldwide, several centers have well-established neonatal hemodynamics programs, however, this highly specialized area of neonatology is still evolving and many neonatal intensive care units rely on traditional clinical parameters. This may be one of many reasons for such wide variation in clinical practice and outcomes related to periviable neonates (8). Given the overall improved survival, the American College of Obstetricians and Gynecologists has provided updated recommendations to consider antenatal steroids for GA 22w 0d – 22w 6d (9). Careful consideration should be given to individual patient factors including maternal comorbidities, presence of fetal/neonatal anomalies, inborn versus outborn neonates, resource availability, and most importantly, expectations of the families when choosing active resuscitation for these infants.' References Nishida H, Ishizuka Y. Survival rate of extremely low birth weight infants and its effect on the amendment of the Eugenic Protection Act in Japan. Acta Paediatr Jpn 1992; 34(6):612-6. PMID: 1285508. Kusuda S, Hirano S, Nakamura T. Creating experiences from active treatment towards extremely preterm infants born at less than 25 weeks in Japan. Semin Perinatol 2022; 46(1):151537. PMID: 34862068. Miyazawa T, Arahori H, Ohnishi S, Shoji H, Matsumoto A, Wada YS, et al. Mortality and morbidity of extremely low birth weight infants in Japan, 2015. Pediatr Int 2023; 65(1):e15493. PMID: 36740921. Website for the Neonatal Research Network Database Japan: https://plaza.umin.ac.jp/nrndata/indexe.htm Bell EF, Hintz SR, Hansen NI, Bann CM, Wyckoff MH, DeMauro SB et al; Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network. Mortality, In-Hospital Morbidity, Care Practices, and 2-Year Outcomes for Extremely Preterm Infants in the US, 2013-2018. JAMA 2022; 327(3):248-263. PMID: 35040888. Vidavalur R, Hussain Z, Hussain N. Association of Survival at 22 Weeks’ Gestation With Use of Antenatal Corticosteroids and Mode of Delivery in the United States. JAMA Pediatr 2023; 177(1):90-93. PMID: 36315137. Katheria A, Reister F, Essers J, Mendler M, Hummler H, Subramaniam A et al. Association of Umbilical Cord Milking vs Delayed Umbilical Cord Clamping With Death or Severe Intraventricular Hemorrhage Among Preterm Infants. JAMA. 2019; 322(19):1877-1886. PMID: 31742630. Silva ER, Shukla VV, Tindal R, Carlo WA, Travers CP. Association of Active Postnatal Care With Infant Survival Among Periviable Infants in the US. JAMA Netw Open 2023; 6(1):e2250593. PMID: 36656583 Website for the American College of Obstetricians and Gynecologists: https://www.acog.org/clinical/clinical-guidance/practice-advisory/articles/2021/09/use-of-antenatal-corticosteroids-at-22-weeks-of-gestation

Lucy Loft, Kristin N Ferguson, and David G Tingay from Australia review the EbNeo September 2023 Article of the Month: "Dargaville PA, Kamlin COF, Orsini F, Wang X, De Paoli AG, Kanmaz Kutman HG, et al. Two-Year Outcomes After Minimally Invasive Surfactant Therapy in Preterm Infants. Follow-Up of the OPTIMIST-A Randomized Clinical Trial. JAMA 2023; 330:1054-63. PMID 37695601." Read here! Hear it discussed on the Incubator podcast! Acta Commentary: Acta Paediatrica - 2024 - Loft - EBNEO Commentary De%E2%80%90MIST%E2%80%90ifying the 2%E2%80%90year outcomes of non%E2%80%90invasive surfactant therapy.pdf "Minimally invasive surfactant therapy (MIST), whereby surfactant is administered intra-tracheally during the continuation of non-invasive respiratory support, has been advocated as a method of addressing the dual respiratory challenges defining preterm birth; surfactant-deficiency and avoiding invasive respiratory support. The OPTIMIST-A trial, an international, blinded, randomised controlled trial, comparing MIST to a sham treatment in extremely preterm infants (25-28 weeks gestational age) receiving non-invasive support, found that although there was no difference in the primary composite outcome of death or bronchopulmonary dysplasia (BPD), rates of BPD and early intubation were lower in the MIST group.(1) The authors of the OPTIMIST-A trial now report their secondary 2-year outcome data. There was no difference in the composite primary outcome of neurodevelopmental disability or death at 2-years corrected age, providing reassurance on the safety of the intervention. This is an important finding as both the parents and clinicians were blinded to their baby’s treatment, and sedation was not used during laryngoscopy. There was, however, a statistically significant decrease in the measures of respiratory morbidity at 2-years corrected age in the MIST group. There is a biological plausibility to these findings, and they should be treated as important. Early surfactant likely blunts the early injury and inflammation events in the lung that lead to the cascade of escalating respiratory needs, BPD diagnosis and increased post-discharge risks (such as lower respiratory tract infection).(2) Interestingly, the authors found the rates of 2-year respiratory health were higher than BPD rates. The authors speculated that many infants without a diagnosis of BPD still had lung injury that manifested in early life with respiratory symptoms and vulnerability to respiratory infection. This highlights the limitations of BPD definitions in representing later functional respiratory status, which parents often rate as more important than a diagnosis of BPD.(3) Respiratory function was predominantly defined via parental reporting of hospital admissions and wheezing. Whilst pragmatic, the OPTIMIST-A study demonstrates the need for reproducible, objective and validated functional methods of defining early life respiratory health. This would benefit babies, their families, clinicians, and researchers, not only in understanding the expected respiratory trajectory, but also to guide the development of interventions both in the NICU and beyond to optimise long-term respiratory health. Follow-up rates were high. The strength of this follow-up population size is however marred by the use of increasingly subjective follow-up techniques. Despite initially aiming for in-person health reviews and Bayley Scales of Infant and Toddler Development (Third Edition) assessment, this was impractical in some regions (in part due to the COVID-19 pandemic). Subsequently, an online parent-completed survey was developed utilising the validated Parent Report of Children’s Abilities (Revised) questionnaire for neurodevelopmental disability assessment.(4) This highlights a dilemma common to many international NICU trials involving multiple languages and health services; high follow-up rates with pragmatic follow-up measures versus standardised high-quality follow-up with high attrition rates and the risk of minimal meaningful outcome data. In the case of OPTIMIST-A, where no neurological risks were identified during the NICU admission, the balance of pragmatism appears appropriate. REFERENCES Dargaville PA, Kamlin COF, Orsini F, Wang X, De Paoli AG, Kanmaz Kutman HG, et al. Effect of Minimally Invasive Surfactant Therapy Vs Sham Treatment on Death or Bronchopulmonary Dysplasia in Preterm Infants with Respiratory Distress Syndrome: The OPTIMIST-A Randomized Clinical Trial. JAMA2021; 326; 2478-87. Tingay DG, Wallace MJ, Bhatia R, Schmolzer GM, Zahra VA, Dolan MJ, et al. Surfactant before the first inflation at birth Improves spatial distribution of ventilation and reduces lung injury in preterm lambs. J Appl Physiol 2014; 116, 251-8. Thivierge E, Luu TM, Bourque CJ, Barrington KJ, Pearce R, Jaworski M, et al. Pulmonary important outcomes after extremely preterm birth: Parental perspectives. Acta Paediatr 2023; 112, 970-6. Johnson S, Bountziouka V, Brocklehurst P, Linsell L, Marlow N, et al. Standardisation of the Parent Report of Children’s Abilities-Revised (PARCA-R): a norm-referenced assessment of cognitive and language development at age 2 years. Lancet Child Adolesc Health 2019; 3: 705-712."

Read Sara Stucker and Ellen Diego's EbNeo review of the paper "Abiramalatha T, Ramaswamy VV, Bandyopadhyay T, Somanath SH, Shaik NB, Pullattayil AK, Weiner GM. Interventions to Prevent Bronchopulmonary Dysplasia in Preterm Neonates: An Umbrella Review of Systematic Reviews and Meta-analyses. JAMA Pediatrics 2022; 176:502-516. PMID 35226067." Read full review here! ACTA COMMENTARY: Acta Paediatrica - 2024 - Stucker - EBNEO commentary Umbrella review evaluating interventions to decrease risk of.pdf "Bronchopulmonary Dysplasia (BPD) continues to affect preterm infants despite medical advances. Identifying effective prevention strategies is difficult due to the multifactorial nature of the disease. This umbrella review evaluated 154 systematic reviews with meta-analyses of randomized control trials (RCTs) to identify interventions effective at preventing BPD or mortality at 36 weeks’ postmenstrual age (PMA) in preterm infants. One hundred and ten of those systematic reviews are rated as high quality with 12 comparisons showing significant benefits from the intervention in reducing the risk of BPD or mortality at 36 weeks’ PMA with high certainty of evidence (COE). Essential components of assessing umbrella reviews include evaluating for a focused question, appropriate study inclusion, and quality assessment of included studies (1). The authors of this paper selected a focused question and conducted a comprehensive literature review from multiple databases, likely capturing the majority of relevant studies. Established quality scoring tools (GRADE and AMSTAR2) assessed meta-analyses and systematic reviews with independent evaluation by 2 authors and detailed descriptions of grading criteria provided in the supplemental materials (2, 3). Umbrella reviews only evaluate interventions previously studied in systematic reviews with meta-analyses of RCTs, limiting available studies for inclusion and the ability to perform in-depth adverse outcome analysis. Correctly interpreting consolidated statistical data is essential for accurate analysis and evaluation. For example, iNO, oxygen saturations of 85-89%, and vitamin A were associated with decreased risk of BPD, but not the combined outcome of BPD or mortality. The authors concluded this may suggest an increased risk of mortality, however, an editorial reply from Dr. Romero Lopez provided an alternative analysis using the example of Vitamin A (4). The editorial reply importantly emphasizes that observing the effect of an intervention on some but not all elements of a composite outcome does not imply the intervention has the opposite effect on the remaining elements. In this case, the study reported mortality data and did not see an increased risk (5). Facilitating an open dialogue discussing statistical analysis and conclusions is essential for deepening provider understanding of literature analysis and appropriate application to clinical practice to improve care. This study provides the clinician with valuable scaffolding to guide further literature evaluation focusing on adverse outcome analysis and applying as appropriate to clinical decision-making. Adherence to high COE strategies for BPD reduction can be assessed at the facility-level by performing a best practice gap analysis for clinical protocol development and targeted quality improvement. Quality improvement studies have successfully decreased BPD rates by combining multiple interventions supported in this umbrella review into respiratory care bundles, including the use of delivery room CPAP and avoiding endotracheal intubation. At least one center has successfully maintained BPD rates of 5-7% for decades, supporting the feasibility and sustainability of utilizing a bubble CPAP care bundle to optimize care (6). Other studies have successfully decreased rates of intubation and BPD via respiratory care bundle implementation that includes initiation of CPAP in the delivery room, strict intubation and extubation criteria, and standardization of respiratory care provided (7,8,9).. REFERENCES Critical Appraisal Skills Programme. CASP Systematic Review Checklist. Available at: casp-uk.net/casp-tools-checklists/ 2022. Accessed: August 3rd, 2023. Shea BJ, Reeves BC, Wells G, Thuku M, Hamel C, Moran J, et al. AMSTAR 2: A critical appraisal tool for systematic reviews that include randomised or non-randomised studies of healthcare interventions, or both. BMJ 2017; 358: j4008. Balshem H, Helfand M, Schünemann HJ, Oxman AD, Kunz R, Brozek J, et al. GRADE guidelines: 3. Rating the quality of evidence. Journal of Clinical Epidemiology 2011; 64: 401–406. Mar Romero Lopez M. Comment on “Interventions to Prevent Bronchopulmonary Dysplasia in Preterm Neonates.” JAMA Network, 2022. Available at: jamanetwork.com/journals/jamapediatrics/article-abstract/2789460 Darlow BA, Graham PJ, Rojas-Reyes MX. Vitamin A supplementation to prevent mortality and short- and long-term morbidity in very low birth weight infants. Cochrane Database Syst Rev. 2016; 8:CD000501. Aly H, Mohamed MA. An experience with a bubble CPAP bundle: is chronic lung disease preventable? Pediatric Research 2020; 88: 444–450. Levesque BM, Kalish LA, LaPierre J, Welch M, Porter V. Impact of implementing 5 potentially better respiratory practices on neonatal outcomes and costs. Pediatrics 2011; 128. Kakkilaya VB, Weydig HM, Smithhart WE, Renfro SD, Garcia KM, Brown CM, et al. Decreasing continuous positive airway pressure failure in preterm infants. Pediatrics 2021; 148. Kubicka Z, Zahr E, Rousseau T, Feldman HA, Fiascone J. Quality improvement to reduce chronic lung disease rates in very-low birth weight infants: High compliance with a respiratory care bundle in a small NICU. Journal of Perinatology 2018; 38: 285–292."

September EBNeo Article of the Month on the RCT by Salas AA, Gunawan E, Nguyen K, Reeves A, Argent V, Finck A, Carlo WA. Early Human Milk Fortification in Infants Born Extremely Preterm: A Randomized Trial. Pediatrics. 2023 Sep 1;152(3):e2023061603. doi: 10.1542/peds.2023-061603. PMID: 37551512; PMCID: PMC10471508 reviewed by See Siong How and Atul Malhotra from Monash University and Camilia Martin from Cornell University. Read here! Hear it discussed on the Incubator Podcast! #neotwitter #neoEBM #EBNEOreviews #ActaPaediatrica Acta Paediatrica commentary: Acta Paediatrica - 2024 - How - EBNEO commentary Early human milk fortification in infants born extremely preterm A.pdf " The aim of this trial (IMPACT—Increased Milk Protein to Accrue Critical Tissue) was to evaluate whether early human milk fortification with a human-derived human milk fortifier resulted in increased fat-free mass (FFM) compared to non-fortified human milk in extremely preterm infants.1 Authors report on a randomized trial investigating the approach of starting human milk fortification early on enteral feeding day 2, compared to their practice of feeding unfortified milk until the infant reached full-volume feeding. Though many centers have begun fortifying feedings as early as 40-60 mL/k/day, the intervention in this study, starting with fortified feedings as early as day 2, is less common and has not been formally studied. The authors found no statistically significant difference in the primary outcome (FFM z-score at term) between the 2 groups. Secondary outcome results indicated better linear growth (0.9 vs 0.8 cm per week) with early milk fortification compared with fortification at or above 120 mL/kg per day. There were less weight and head circumference z-score declines in the intervention group in comparison to the control group (-0.8 vs -1.1 from birth to day 14; -0.9 vs -1.3 through 36 weeks’ postmenstrual age, respectively). Adverse events (NEC and spontaneous intestinal perforation) were rare and similar between groups. However, it is important to note that the study was not powered to detect differences in these adverse events. A notable strength of this study is that more than 20% of infants included were born at 23 weeks of gestation or less (these infants are often excluded from studies but are an important group to study). An accompanying editorial by Belfort comprehensively summarises the salient points of this study, citing single-center and small study population as limitations; blinding and randomization as strengths; and evaluating body composition as a novel and clinically relevant approach.2 Accrual of data reinforces the importance of fat-free mass for infant outcomes, but specific guidance on promoting and driving body composition early in the postnatal period is lacking. To answer this question, it will be important to evaluate other real-time measures of body composition that link the intervention more closely with the desired outcome. Novel bedside measures will also help overcome the limitations currently present with ADP, specifically the inability to obtain measures in the more ill infants.3 The lack of comparison to bovine HMF in this study was a missed opportunity and will be an important aspect to consider for future studies. Convincing data to support the use of one fortifier over another does not exist. This can be deducted from a Cochrane review in 2019, looking into human milk-derived fortifiers versus bovine milk-derived fortifiers for the prevention of mortality and morbidity in preterm neonates.4 If the type of fortification is part of the nutritional question (as it may have been in this case), then both should be used while controlling for the other aspects of the diet (base diet and diet used for supplemental volume). The study did not provide details about other comorbidities (such as bronchopulmonary dysplasia), rates of sepsis or oxygen support in the two study groups. This would be important for assessing the characteristics between the infants in control and intervention groups. The number of infants who received breast milk (BM) vs donor breast milk (DBM) was not provided. This may be a factor that can affect the primary and secondary outcomes as the protein content may be different between these two forms of breast milk.5,6Even though the rate of NEC was rare, it is important for the study to outline the clinical profile/severity of the infants who developed NEC, including the number of medical vs surgical NEC. In addition to the exclusion criteria defined in this study, it may be important to consider that some infants may not be the best candidates for early fortification, as this can affect the overall dropout rates of the study population and the study outcomes. A selection or exclusion criteria for these infants may be an aspect to consider. Some examples of this population include infants with clinically significant congenital heart disease, enrollment in another clinical study affecting nutritional management, failure to start minimum enteral feeds before 21 days of life, or intestinal perforation or necrotizing enterocolitis before tolerating fortified feeds. In summary, the IMPACT study did not show a statistically significant difference in FFM with early human-derived, human milk fortification. The authors did observe differences in length gain and head circumference, showing a positive contribution to anthropometrics with fortification prior to the attainment of full enteral feedings. Notably, despite this, there was still a reduction in anthropometric z-scores (as observed in the negative z scores for declines in weight-for-age, head circumference-for-age and length-for-age in both control and interventions groups), indicating that as a neonatal community there remains room for improvement in understanding and optimizing growth for premature infants. Long-term neurodevelopmental studies will be critical to make a determination of how specific growth patterns relate to ourcomes." REFERENCES Salas AA, Gunawan E, Nguyen K, Reeves A, Argent V, Finck A, Carlo WA. Early human milk fortification in infants born extremely preterm: a randomized trial. Pediatrics. 2023 Aug 8. Belfort MB. Sooner Is Better: Early Human Milk Fortification for Hospitalized Preterm Infants <29 Weeks. Pediatrics. 2023 Sep 1;152(3):e2023062391. doi: 10.1542/peds.2023-062391. PMID: 37551455. van Gils RHJ, Wauben LSGL, Helder OK. Body size measuring techniques enabling stress-free growth monitoring of extreme preterm infants inside incubators: A systematic review. PLoS One. 2022 Apr 22;17(4):e0267285. doi: 10.1371/journal.pone.0267285. PMID: 35452486; PMCID: PMC9033282. Premkumar MH, Pammi M, Suresh G. Human milk‐derived fortifier versus bovine milk‐derived fortifier for prevention of mortality and morbidity in preterm neonates. Cochrane Database of Systematic Reviews 2019, Issue 11. Art. No.: CD013145. DOI: 10.1002/14651858.CD013145.pub2. Accessed 05 December 2023. Ballard O, Morrow AL. Human milk composition: nutrients and bioactive factors. Pediatr Clin North Am. 2013 Feb;60(1):49-74. doi: 10.1016/j.pcl.2012.10.002. PMID: 23178060; PMCID: PMC3586783. Narasimhan SR, Kinchen J, Kifle A, Jegatheesan P, Song D.Metabolomic differences between mothers’ own breast milk and donor breast milk. Pediatrics. 2018; 141(1_MeetingAbstract):272. doi:10.1542/PEDS.141.1MA3.272

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.