Neonatal Trials Research Articles

Nurses' Knowledge, Communication Needs, and Future Directions in Neonatal Research: Results of an International Survey.

Preterm birth is a significant contributor to neonatal morbidity and mortality. Despite legislative efforts to increase pediatric drug development, neonatal clinical trials continue to be infrequent. The International Neonatal Consortium (INC) includes nurses as key stakeholders in their mission to accelerate safe and effective therapies for neonates. INC developed a survey for nurses, physicians, and parents to explore communication practices and stakeholders' perceptions and knowledge regarding clinical trials in neonatal intensive care units (NICUs). A stepwise consensus approach was used to solicit responses to an online survey. The convenience sample was drawn from INC organizations representing the stakeholder groups. Representatives from the National Association of Neonatal Nurses and the Council of International Neonatal Nurses, Inc, participated in all stages of the survey development process, results analysis, and publication of results. Participants included 188 nurses or nurse practitioners, mainly from the United States, Canada, the European Union, and Japan; 68% indicated some level of research involvement. Nurses expressed a lack of effective education to prepare them for participation in research. Results indicated a lack of a central information source for staff and systematic approaches to inform families of studies. The majority of nurses indicated they were not asked to provide input into clinical trials. Nurses were uncertain about research consent and result disclosure processes. This study indicates the need to educate nurses in research, improve NICU research communication through standardized, systematic pathways, and leverage nurse involvement to enhance research communication.

Antiseizure medication at discharge in infants with hypoxic-ischaemic encephalopathy: an observational study

ObjectivesTo assess variability in continuation of antiseizure medication (ASM) at discharge and to evaluate if continuation of ASM at discharge is associated with death or disability among infants with hypoxic-ischaemic...

Different Approaches to requesting Consent for Routine data linkage in Neonatal follow-up (ACORN): protocol for a 2×2 factorial randomised trial

IntroductionRoutinely collected data can be linked to research data to create a rich dataset and inform practice. However, consent is normally required to link identifiable data. Reported rates of consent...

Next-Generation Probiotic Therapy to Protect the Intestines From Injury.

Probiotics are live microorganisms that, when administered in adequate amounts, provide health benefits to the host. Some strains of the probiotic Lactobacillus reuteri (L. reuteri) have both antimicrobial and anti-inflammatory properties that may be exploited for the treatment and prevention of different gastrointestinal diseases, including necrotizing enterocolitis (NEC) and Clostridioides difficile (C. difficile) infection. Our laboratory has developed a new delivery system for L. reuteri in which the probiotic is incubated with biocompatible, semipermeable, porous dextranomer microspheres (DM) that can be loaded with beneficial and diffusible cargo. L. reuteri can be induced to form a biofilm by incubating the bacteria on the surface of these microspheres, which enhances the efficacy of the probiotic. Loading the DM with sucrose or maltose induces L. reuteri to produce more biofilm, further increasing the efficacy of the probiotic. Using a rat model of NEC, L. reuteri administered in its biofilm state significantly increases animal survival, reduces the incidence of NEC, preserves gut barrier function, and decreases intestinal inflammation. In a murine model of Clostridiodes difficile infection, L. reuteri administered in its biofilm state decreases colitis when administered either before or after C. difficile induction, demonstrating both prophylactic and therapeutic efficacy. There are currently no FDA-approved probiotic preparations for human use. An FDA-approved phase I clinical trial of L. reuteri in its biofilm state in healthy adults is currently underway. The results of this trial will be used to support a phase 1 clinical trial in neonates, with the goal of utilizing L. reuteri in its biofilm state to prevent NEC in premature neonates in the future.

Can the history of empiric antibiotic treatment for neonatal sepsis inform future global trials?

Antimicrobial resistance is a major threat to the Sustainable Development Goal to reduce neonatal mortality to 12 per 1000 live births [1]. Current global rates are at 17 per 1000 live births with variation between <1 and 50 per 1000 live births [2]. There are many contributing factors limiting the success of reaching this target including preterm birth, intrapartum-related complications, and birth defects. However, one of the other leading causes of mortality is neonatal sepsis. Current World Health Organization (WHO) guidelines recommend using a combination of ampicillin (or penicillin) and gentamicin for the empiric treatment of neonatal sepsis [3].

Comparison of BARD®LIFESTREAM™ covered balloon-expandable stent versus GORE® VIABAHN™ covered self-expandable stent in treatment of aortoiliac obstructive disease: study protocol for a prospective randomized controlled trial (NEONATAL trial)

BackgroundCovered stent has become one of the mainstream therapies for aortoiliac obstructive disease (AIOD), with a higher patency rate than bare metal stent. Covered balloon-expandable (CBE) stent can be placed more accurately with higher a radial support force, while covered self-expanding (CSE) stent has greater elasticity and higher trackability. However, there is no level I evidence regarding the comparison safety and efficacy between the CSE stent and CBE stent in AIOD to date. Therefore, this study aims to compare the efficacy and safety of CBE stent (BARD®LIFESTREAM™) and CSE stent (GORE® VIABAHN™) in AIOD.MethodsThis trial is a prospective, single-center, parallel, noninferiority, randomized controlled trial. A total of 106 patients will be enrolled and these patients will be randomized to either the CBE stent group or the CSE stent group. The primary end point of the study is the occurrence of target lesion revascularization (TLR) at 12 months after the intervention.DiscussionTo our knowledge, the ballooN sElf cOver steNt AorToiliAc occuLusive (NEONATAL) trial is the first RCT to compare CBE and CSE stent in AIOD patients. The main aim is to compare the TLR of the target lesion between CBE stent and CSE stent at 12 months post-procedure. The results of clinical trials may contribute to establishing a strategic guideline for choosing the optimal type of covered stent in the treatment of AIOD patients.Trial registrationChinese Clinical Trials Registry ChiCTR2100046734. Registered on 27 May 2021

Analgesic effect of inhaled lavender essential oil for frenotomy in healthy neonates: a randomized clinical trial.

BackgroundNeonatal pain may affect long-term neurodevelopment and must be treated. Frenotomy is a painful procedure wherein a common strategy to relieve pain (sucking) cannot be used because the technique is performed on the tongue. Lavender essential oil (LEO) has sedative and antispasmodic properties and has been successfully used to treat pain during heel puncture and vaccination. Our aim was to demonstrate if the use of inhaled LEO is effective in reducing pain during frenotomy in healthy, full-term neonates.MethodsWe conducted a randomized clinical trial in neonates who underwent a frenotomy between August 2020 and April 2021. We assessed pain using pre and post-procedure heart rate and oxygen saturation, crying time and Neonatal Infant Pain Scale (NIPS) score. Patients with type 3 tongue tie were randomized into the “experimental group” and “control group”. In both groups, we performed swaddling, administered oral sucrose, and let the newborn suck for two minutes. In the experimental group, we also placed a gauze pad with one drop of LEO under the neonate’s nose for two minutes prior to and during the frenotomy.ResultsWe enrolled 142 patients (71 per group). The experimental group showed significantly lower NIPS scores (1.88 vs 2.92) and cried almost half the amount of time (14.8 vs. 24.6 seconds, P = 0.006). Comparing with the control group, we observed no side effects in either of the groups.ConclusionsWe observed a significant decrease in crying time and lower NIPS scores in the neonates who received inhaled LEO and underwent a frenotomy for type 3 tongue-ties. Thus, we recommend using inhaled LEO during neonatal frenotomies.Supplementary InformationThe online version contains supplementary material available at 10.1007/s12519-022-00531-7.

Evaluation of the Safety of a Plant-Based Infant Formula Containing Almonds and Buckwheat in a Neonatal Piglet Model.

A randomized neonatal piglet trial was conducted to evaluate the safety and the effects of a plant-based formula containing almonds and buckwheat as the main ingredients on growth and plasma parameters. From postnatal day (PND) 2 to 21, the piglets were fed a dairy-based milk formula (Similac Advance) or a plant-based formula (Else Nutrition) and all piglets were euthanized at day 21. No diarrhea was observed after PND 8 and all the piglets completed the trial. Body growth, kcal intake, the complete plasma count parameters and hematological parameters were within the reference range in both groups. Organ growth and development was similar between the two groups. Plasma glucose was higher in the dairy-based-fed piglets relative to the plant-based at 2 weeks of age. Liver function biomarkers levels were greater in the plasma of the plant-based compared to the dairy-based fed group. In addition, calcium levels were higher in the plant-based fed piglets at 1 week of age. Thus, the plant-based formula tested in this study was well tolerated by the piglets and supported similar growth compared to dairy-based milk formula. Therefore, the results support the safety of the tested plant-based infant formula during the neonatal period in comparison to the dairy-based formula fed group.

Ursodeoxycholic acid prevention on cholestasis associated with total parenteral nutrition in preterm infants: a randomized trial

Preterm infants with long-term parenteral nutrition (PN) therapy are at risk for cholestasis associated with total parenteral nutrition (PNAC). This study examined the safety and efficacy of ursodeoxycholic acid (UDCA) in preventing PNAC in preterm infants. Our research aimed to investigate the prophylactic effect of preventive oral UDCA on PNAC in preterm infants. We compared oral administration of UDCA prophylaxis with no prophylaxis in a randomized, open-label, proof-of-concept trial in preterm neonates with PN therapy. The low-birth-weight preterm infants (< 1800g) who were registered to the neonatal intensive care unit (NICU) within 24hours after birth were randomized. The main endpoint was the weekly values of direct bilirubin (DB) of neonates during the NICU stay. Eventually, a total of 102 preterm neonates from January 2021 to July 2021 were enrolled in this prospective study (42 in the UDCA group and 60 in the control group). Notably, the peak serum level of DB [13.0 (12-16) vs. 15.2 (12.5-19.6) μmol/L, P < 0.05)] was significantly lower in the UDCA group than that in the control group without prevention. The peak serum level of total bilirubin (101.1 ± 34 vs. 116.5 ± 28.7μmol/L, P < 0.05) was also significantly lower in the UDCA group than in the control group. Furthermore, the proportion of patients who suffered from neonatal cholestasis (0.0% vs. 11.7%, P < 0.05) in the UDCA group was significantly lower. UDCA prophylaxis is beneficial in preventing PNAC in NICU infants receiving prolonged PN.

EBNEO Commentary: Effect of systemic hydrocortisone initiated 7-14days after birth in ventilated preterm infants on mortality and neurodevelopment at 2years' corrected age.

Halbmeijer NM, Onland W, Cools F, Swarte R, van der Heide-Jalving M, Merkus MP, van Kaam AH. Effect of Systemic Hydrocortisone Initiated 7–14 Days after Birth in Ventilated Preterm Infants on Mortality and Neurodevelopment at 2 years' Corrected Age. JAMA 2021; 324 (6):355–357. PMID 34313697. The safety and effectiveness of postnatal corticosteroids (PCS) to prevent or treat BPD remain an active area of research. After fluctuations in their popularity over the past 40 years, PCS remain widely used as treatments for extremely preterm infants with evolving BPD in neonatal intensive care units worldwide. The Cochrane Library has two reviews of PCS, based on the timing of drug commencement: ‘early’ use (<8 days of age)1 and ‘late’ use (>7 days of age).2 Dexamethasone and hydrocortisone have been the primary systemic PCS of interest. Dexamethasone has been studied more extensively than hydrocortisone as ‘early’ therapy (21/32 randomised trials on the Cochrane review were on Dexamethasone) and despite an important reduction in rates of death or BPD rate at 36 weeks' PMA, the incidence of cerebral palsy is higher (RR 1.42, 95% CI 1.06–1.91)2 in these infants who received Dexamethasone. The PREMILOC3 trial in 2016 attempted to assess the effect of ‘early’ systemic hydrocortisone use in premature neonates treated within the first 10 days of life and despite the early cessation of the trial, demonstrated improved survival without BPD at 36 weeks' PMA (OR 1.48, 95% CI 1.02–2.16, p = 0.04) with no increased risk for long-term neurodevelopmental impairment at 22 months' corrected age.4 From this study, it was postulated that hydrocortisone may be the early PCS of choice for the prevention of BPD. The STOP-BPD trial is the first to address the ‘late’ use of hydrocortisone in infants at high risk of BPD. It reported no important difference in the primary composite outcome of death or BPD at 36 weeks' PMA (70.7% hydrocortisone vs 73.7% in placebo, p = 0.54), although there was a reduction in mortality at 36 weeks' PMA (15.5% vs 23.7%, OR 0.59; 95% CI 0.35–0.995 p = 0.048). The authors acknowledged that the study was not powered to detect smaller differences in the primary outcome, also limiting the ability to detect important differences at 2 years. At the 2-year follow-up assessment, the composite outcome of death and NDI was not statistically significantly different (OR 0.79 95% CI 0.51–1.22 p = 0.28). However, the reduced risk of death in the hydrocortisone group persisted. The risk of death was lower in the hydrocortisone group (39/181 vs 56/190) by 8%, a clinically important effect size, even if the result did not reach accepted levels of statistical significance. These results demonstrate that dichotomous composite endpoints in neonatal trials, where the components that are not equal in importance, can be fraught.5 We note the high rate of open-label hydrocortisone use within this trial. Table 26 in the primary study shows that 108/190 (57%) infants in the placebo group eventually received ‘rescue’ hydrocortisone for their clinical status. This may have reduced the power of the trial to demonstrate beneficial or harmful effects of hydrocortisone, both in the short (36 weeks' PMA) and longer term (2 years). This study further fuels the discussion regarding the interaction between baseline BPD risk and the treatment effect of PCS on longer term outcomes in extremely preterm infants.7 Patient selection, timing and choice of systemic PCS remain topics of research. Current trials are underway of alternative methods of administering PCS to prevent BPD in the sickest preterm infants.8 https://ebneo.org/stop-bpd-2-years Prof Peter Davis is co-author for the cited reference 6 and was a co-investigator for the DART study. A/Prof Brett Manley and Prof Peter Davis are current co-investigators on the PLUSS trial of intratracheal budesonide. A/Prof Brett Manley is a co-author on the updated Cochrane Reviews of early and late postnatal corticosteroids which are in press at time of writing.

Strategies in Neonatal Care to Promote Growth and Neurodevelopment of the Preterm Infant.

Recommendations for nutrition of very preterm and very low birth weight infants have developed over time with our understanding of the requirements of preterm babies and the awareness of widespread poor postnatal growth. In general, the trend has been towards enhancing nutrition, but more recent recommendations have begun to raise questions with respect to the potential for high and early nutritional intakes, particularly of protein, to carry risks such as refeeding syndrome. However, large gaps in our knowledge remain for both macro- and micronutrient requirements to support optimal growth and how nutrition and growth relate to important long-term outcomes. Closing these knowledge gaps has been hampered by inconsistent reporting of nutrition intakes and growth parameters, small trials with short-term outcomes and the use of a variety of different methods of monitoring growth. The challenge now is for future research to address these issues through consensus building around the important questions that need to be answered, how to report data from neonatal nutritional trials and whether large trials answering important questions can take place through development of consortia that undertake similar trials in multiple jurisdictions with agreements to share data.

Optimised versus standard dosing of vancomycin in infants with Gram-positive sepsis (NeoVanc): a multicentre, randomised, open-label, phase 2b, non-inferiority trial

Vancomycin is the most widely used antibiotic for neonatal Gram-positive sepsis, but clinical outcome data of dosing strategies are scarce. The NeoVanc programme comprised extensive preclinical studies to inform a randomised controlled trial to assess optimised vancomycin dosing. We compared the efficacy of an optimised regimen to a standard regimen in infants with late onset sepsis that was known or suspected to be caused by Gram-positive microorganisms. NeoVanc was an open-label, multicentre, phase 2b, parallel-group, randomised, non-inferiority trial comparing the efficacy and toxicity of an optimised regimen of vancomycin to a standard regimen in infants aged 90 days or younger. Infants with at least three clinical or laboratory sepsis criteria or confirmed Gram-positive sepsis with at least one clinical or laboratory criterion were enrolled from 22 neonatal intensive care units in Greece, Italy, Estonia, Spain, and the UK. Infants were randomly assigned (1:1) to either the optimised regimen (25 mg/kg loading dose, followed by 15 mg/kg every 12 h or 8 h dependent on postmenstrual age, for 5 ± 1 days) or the standard regimen (no loading dose; 15 mg/kg every 24 h, 12 h, or 8 h dependent on postmenstrual age for 10 ± 2 days). Vancomycin was administered intravenously via 60 min infusion. Group allocation was not masked to local investigators or parents. The primary endpoint was success at the test of cure visit (10 ± 1 days after the end of actual vancomycin therapy) in the per-protocol population, where success was defined as the participant being alive at the test of cure visit, having a successful outcome at the end of actual vancomycin therapy, and not having a clinically or microbiologically significant relapse or new infection requiring antistaphylococcal antibiotics for more than 24 h within 10 days of the end of actual vancomycin therapy. The non-inferiority margin was -10%. Safety was assessed in the intention-to-treat population. This trial is registered at ClinicalTrials.gov (NCT02790996). Between March 3, 2017, and July 29, 2019, 242 infants were randomly assigned to the standard regimen group (n=122) or the optimised regimen group (n=120). Primary outcome data in the per-protocol population were available for 90 infants in the optimised group and 92 in the standard group. 64 (71%) of 90 infants in the optimised group and 73 (79%) of 92 in the standard group had success at test of cure visit; non-inferiority was not confirmed (adjusted risk difference -7% [95% CI -15 to 2]). Incomplete resolution of clinical or laboratory signs after 5 ± 1 days of vancomycin therapy was the main factor contributing to clinical failure in the optimised group. Abnormal hearing test results were recorded in 25 (30%) of 84 infants in the optimised group and 12 (15%) of 79 in the standard group (adjusted risk ratio 1·96 [95% CI 1·07 to 3·59], p=0·030). There were six vancomycin-related adverse events in the optimised group (one serious adverse event) and four in the standard group (two serious adverse events). 11 infants in the intention-to-treat population died (six [6%] of 102 infants in the optimised group and five [5%] of 98 in the standard group). In the largest neonatal vancomycin efficacy trial yet conducted, no clear clinical impact of a shorter duration of treatment with a loading dose was demonstrated. The use of the optimised regimen cannot be recommended because a potential hearing safety signal was identified; long-term follow-up is being done. These results emphasise the importance of robust clinical safety assessments of novel antibiotic dosing regimens in infants. EU Seventh Framework Programme for research, technological development and demonstration.

Protocol: Pentoxifylline optimal dose finding trial in preterm neonates with suspected late onset sepsis (PTX-trial)

BackgroundLate onset sepsis is a leading cause of death and morbidity in preterm infants. Despite optimal antibiotic treatment, sepsis related mortality and morbidity is still high. Pentoxifylline (PTX) is a methylxanthine with promising immunomodulatory properties, which can be used as an additional therapy next to antibiotics in preterm infants. PTX is increasingly used off-label in neonatal intensive care units, however up till now no dose finding study has been done for PTX in this specific population. The aim of this study (PTX-trial) is to determine the optimal dose of PTX in preterm infants (gestational age < 30 weeks) with (suspected) late onset sepsis. Dose finding in this particular population is unique, since for most drugs used in neonates the optimal dosage has not been investigated in phase II dose-seeking studies.MethodsThe PTX-trial is a prospective open label sequential dose-optimization study with an adapted continual reassessment method. An up-and-down dose-response design will be used, with dose step-up and step-down titration after every 3 patients. The PTX starting dosage will be 30 mg/kg/day in 6 hours as described in most previous neonatal studies. Efficacy is defined by means of biochemical and clinical parameters. Toxicity in these vulnerable patients is unwarranted. The optimal dose is defined as the ED75 (i.e., clinically and chemically effective dose for 75% of patients) in preterm neonates with late onset sepsis. We plan to include 30 neonates to determine the optimal dose using this study design. Subsequently, the optimal dose will be validated in 10 additional preterm neonates. In parallel, pharmacokinetics of PTX and its metabolites will be described as well as longitudinal evaluation of metabolomics and proteomics.DiscussionThe study has been approved by the Regional Medical Ethics Board of Erasmus Medical Center University Rotterdam (MEC 2019-0477) and registered at Clinicaltrials.gov (NCT04152980). Results of the main trial and each of the secondary endpoints will be submitted for publications in peer-reviewed journals.Trial registrationClinicaltrials.gov, NCT04152980, Registered November 6th, 2019

Laryngeal mask ventilation with chest compression during neonatal resuscitation: randomized, non-inferiority trial in lambs.

Background:Effective positive pressure ventilation is a critical factor in newborn resuscitation. Neonatal endotracheal intubation (ETT) needs considerable training and experience, which poses a human factor challenge. Laryngeal mask airway (LMA) ventilation can be a secure and viable alternative during the initial stages of newborn resuscitation. However, there is limited evidence for its use during chest compression (CC).Methods:Seventeen lambs were randomized into LMA or ETT ventilation post cord occlusion induced cardiac arrest. After 5 minutes of cardiac arrest, resuscitation was initiated as per NRP recommendations. Ventilation, oxygenation, systemic and pulmonary hemodynamic parameters were recorded till return of spontaneous circulation (ROSC) or 20 minutes.Results:Baseline characteristics were similar between the groups. The incidence of ROSC was 75% (6/8) in the LMA group and 56% (5/9) in the ETT group (p = 0.74). The median (IQR) time to achieve ROSC was 6.85 min (6 min – 9.1 min) in the LMA group and 7.50 min (5.33 min – 18 min) in the ETT group (p = 0.65).Conclusion:LMA ventilation during CC is feasible and non-inferior to ETT in this model.

Cost impact of procalcitonin-guided decision making on duration of antibiotic therapy for suspected early-onset sepsis in neonates

BackgroundsThe large, international, randomized controlled NeoPInS trial showed that procalcitonin (PCT)-guided decision making was superior to standard care in reducing the duration of antibiotic therapy and hospitalization in neonates suspected of early-onset sepsis (EOS), without increased adverse events. This study aimed to perform a cost-minimization study of the NeoPInS trial, comparing health care costs of standard care and PCT-guided decision making based on the NeoPInS algorithm, and to analyze subgroups based on country, risk category and gestational age.MethodsData from the NeoPInS trial in neonates born after 34 weeks of gestational age with suspected EOS in the first 72 h of life requiring antibiotic therapy were used. We performed a cost-minimization study of health care costs, comparing standard care to PCT-guided decision making.ResultsIn total, 1489 neonates were included in the study, of which 754 were treated according to PCT-guided decision making and 735 received standard care. Mean health care costs of PCT-guided decision making were not significantly different from costs of standard care (€3649 vs. €3616). Considering subgroups, we found a significant reduction in health care costs of PCT-guided decision making for risk category ‘infection unlikely’ and for gestational age ≥ 37 weeks in the Netherlands, Switzerland and the Czech Republic, and for gestational age < 37 weeks in the Czech Republic.ConclusionsHealth care costs of PCT-guided decision making of term and late-preterm neonates with suspected EOS are not significantly different from costs of standard care. Significant cost reduction was found for risk category ‘infection unlikely,’ and is affected by both the price of PCT-testing and (prolonged) hospitalization due to SAEs.

Association Between Increased Seizures During Rewarming After Hypothermia for Neonatal Hypoxic Ischemic Encephalopathy and Abnormal Neurodevelopmental Outcomes at 2-Year Follow-up

Compared with normothermia, hypothermia has been shown to reduce death or disability in neonatal hypoxic ischemic encephalopathy but data on seizures during rewarming and associated outcomes are scarce. To determine whether electrographic seizures are more likely to occur during rewarming compared with the preceding period and whether they are associated with abnormal outcomes in asphyxiated neonates receiving hypothermia therapy. This prespecified nested cohort study of infants enrolled in the Optimizing Cooling (OC) multicenter Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) Neonatal Research Network trial from December 2011 to December 2013 with 2 years' follow-up randomized infants to either 72 hours of cooling (group A) or 120 hours (group B). The main trial included 364 infants. Of these, 194 were screened, 10 declined consent, and 120 met all predefined inclusion criteria. A total of 112 (90%) had complete data for death or disability. Data were analyzed from January 2018 to January 2020. Serial amplitude electroencephalography recordings were compared in the 12 hours prior and 12 hours during rewarming for evidence of electrographic seizure activity by 2 central amplitude-integrated electroencephalography readers blinded to treatment arm and rewarming epoch. Odds ratios and 95% CIs were evaluated following adjustment for center, prior seizures, depth of cooling, and encephalopathy severity. The primary outcome was the occurrence of electrographic seizures during rewarming initiated at 72 or 120 hours compared with the preceding 12-hour epoch. Secondary outcomes included death or moderate or severe disability at age 18 to 22 months. The hypothesis was that seizures during rewarming were associated with higher odds of abnormal neurodevelopmental outcomes. A total of 120 newborns (70 male [58%]) were enrolled (66 in group A and 54 in group B). The mean (SD) gestational age was 39 (1) weeks. There was excellent interrater agreement (κ, 0.99) in detection of seizures. More infants had electrographic seizures during the rewarming epoch compared with the preceding epoch (group A, 27% vs 14%; P = .001; group B, 21% vs 10%; P = .03). Adjusted odd ratios (95% CIs) for seizure frequency during rewarming were 2.7 (1.0-7.5) for group A and 3.2 (0.9-11.6) for group B. The composite death or moderate to severe disability outcome at 2 years was significantly higher in infants with electrographic seizures during rewarming (relative risk [95% CI], 1.7 [1.25-2.37]) after adjusting for baseline clinical encephalopathy and seizures as well as center. Findings that higher odds of electrographic seizures during rewarming are associated with death or disability at 2 years highlight the necessity of electroencephalography monitoring during rewarming in infants at risk. ClinicalTrials.gov Identifier: NCT01192776.

Expecting equity: reimagining the delivery of racial/ethnic representation in neonatal clinical trials.

Expecting equity: reimagining the delivery of racial/ethnic representation in neonatal clinical trials.

Does tuberculosis screening improve individual outcomes? A systematic review.

BackgroundTo determine if tuberculosis (TB) screening improves patient outcomes, we conducted two systematic reviews to investigate the effect of TB screening on diagnosis, treatment outcomes, deaths (clinical review assessing 23 outcome indicators); and patient costs (economic review).MethodsPubmed, EMBASE, Scopus and the Cochrane Library were searched between 1/1/1980-13/4/2020 (clinical review) and 1/1/2010-14/8/2020 (economic review). As studies were heterogeneous, data synthesis was narrative.FindingsClinical review: of 27,270 articles, 18 (n=3 trials) were eligible. Nine involved general populations. Compared to passive case finding (PCF), studies showed lower smear grade (n=2/3) and time to diagnosis (n=2/3); higher pre-treatment losses to follow-up (screened 23% and 29% vs PCF 15% and 14%; n=2/2); and similar treatment success (range 68-81%; n=4) and case fatality (range 3-11%; n=5) in the screened group. Nine reported on risk groups. Compared to PCF, studies showed lower smear positivity among those culture-confirmed (n=3/4) and time to diagnosis (n=2/2); and similar (range 80-90%; n=2/2) treatment success in the screened group. Case fatality was lower in n=2/3 observational studies; both reported on established screening programmes. A neonatal trial and post-hoc analysis of a household contacts trial found screening was associated with lower all-cause mortality. Economic review: From 2841 articles, six observational studies were eligible. Total costs (n=6) and catastrophic cost prevalence (n=4; range screened 9-45% vs PCF 12-61%) was lower among those screened.InterpretationWe found very limited patient outcome data. Collecting and reporting this data must be prioritised to inform policy and practice.FundingWHO and EDCTP.

Inter-rater reliability of the neonatal adverse event severity scale using real-world Neonatal clinical trial data

ObjectiveThe Neonatal Adverse Event Severity Scale (NAESS) was developed to improve scoring of neonatal adverse events (AEs) and accelerate neonatal drug development. This is the first validation study of the novel tool.Study designRetrospective validation study assessing the inter-rater reliability (IRR) of the NAESS. Reviewers used real-world AE data from a neonatal trial. Intra-class correlation (ICC) statistical analysis was performed.ResultSixty AEs were randomly assigned to twelve reviewers for a total of 240 severity scores. Generic and AE-specific NAESS tables were assessed. The ICC was 0.63 (95% confidence interval 0.51 to 0.73). Percent variation due to reviewer and residual error was 0.03 and 0.34, respectively.ConclusionIn this first study of the NAESS tool, an ICC of 0.63 indicates moderate reliability. Results highlight the need for improved data collection on neonatal AE forms, augmented training on the NAESS tool, and will inform the prospective validation studies.

Are we enrolling representative cohorts of premature infants in our clinical trials?

To compare the difference in outcomes in a subset population of infants "eligible but not enrolled; ENE" vs those who were "eligible and enrolled, EE" in The Australian Placental Transfusion Study (APTS). Population-based multicentre retrospective cohort study. A total of 535 (17.7%) infants were categorized as EE and 2489 (82.3%) ENE. ENE infants were significantly more premature (mean gestation 27.0 vs 28.0 weeks) but otherwise of similar anthropometric measures compared to EE infants. ENE infants had significantly higher incidences of low Apgar scores <7 at 5 min, CLD, IVH and PDA requiring treatment. Using a multivariate adjusted-analysis, ENE were at a greater risk for mortality (OR 1.86; 95% CI, 1.30-2.67, p < 0.001). Antenatal consenting may lead to biased population representation, which may affect trial results' generalizability. Retrospective consent or waiver of consent may improve the generalizability of neonatal and emergency clinical trials.