Neonatal Trials Research Articles

Application of desirability of outcome ranking to the milking in non-vigorous infants trial

ObjectivesNeonatal trials have traditionally used binary composite short-term (such as death or bronchopulmonary dysplasia) or longer-term (such as death or severe neurodevelopmental impairment) outcomes. We applied the Desirability Of Outcome Ranking (DOOR) method to rank the overall patient outcome by best (no morbidities) to worst (death). Study designUsing a completed large multicenter trial (Milking In Non-Vigorous Infants [MINVI]) of umbilical cord milking (UCM) vs. early cord clamping (ECC), we applied the DOOR methodology to neonatal outcomes. Six outcomes were chosen and ranked: no interventions or NICU admission (most desirable); received initial cardiorespiratory support at birth; neonatal intensive care unit (NICU) admission for predefined criteria; mild hypoxic-ischemic encephalopathy (HIE); moderate to severe HIE; and death (least desirable). Results1524 non-vigorous newborns born between 35 and 42 weeks' gestation had data for analysis. The DOOR distribution was different between the UCM and ECC arms, with a significantly greater probability (55.8 % [95 % CI 53.1–58.5 %; p < 0.0001]) of a randomly selected neonate having a more desirable outcome if they were in the UCM arm. DOOR probabilities of averting individual adverse outcomes such as NICU admission for predefined criteria (52.8 %; 95%CI 50.5–55.1 %) and cardiorespiratory support (54.0 %; 95%CI 51.6–56.4 %) were significantly higher among those in the UCM group. ConclusionDOOR provides an overall assessment of the benefits and harms with greater insight than typical binary composite measures to clinicians and parents when evaluating an intervention. Future neonatal trials should consider the a priori use of the DOOR methodology to evaluate trial outcomes.

Development and application of neonatal physiology-based pharmacokinetic models of amikacin and fosfomycin to assess pharmacodynamic target attainment.

Antimicrobial resistance increasingly complicates neonatal sepsis in a global context. Fosfomycin and amikacin are two agents being tested in an ongoing multicenter neonatal sepsis trial. Although neonatal pharmacokinetics (PKs) have been described for these drugs, the physiological variability within neonatal populations makes population PKs in this group uncertain. Physiologically-based pharmacokinetic (PBPK) models were developed in Simcyp for fosfomycin and amikacin sequentially for adult, pediatric, and neonatal populations, with visual and quantitative validation compared to observed data at each stage. Simulations were performed using the final validated neonatal models to determine drug exposures for each drug across a demographic range, with probability of target attainment (PTA) assessments. Successfully validated neonatal PBPK models were developed for both fosfomycin and amikacin. PTA analysis demonstrated high probability of target attainment for amikacin 15 mg/kg i.v. q24h and fosfomycin 100 mg/kg (in neonates aged 0-7 days) or 150 mg/kg (in neonates aged 7-28 days) i.v. q12h for Enterobacterales with fosfomycin and amikacin minimum inhibitory concentrations at the adult breakpoints. Repeat analysis in premature populations demonstrated the same result. PTA analysis for a proposed combination fosfomycin-amikacin target was also performed. The simulated regimens, tested in a neonatal sepsis trial, are likely to be adequate for neonates across different postnatal ages and gestational age. This work demonstrates a template for determining target attainment for antimicrobials (alone or in combination) in special populations without sufficient available PK data to otherwise assess with traditional pharmacometric methods.

Race and Ethnicity of Infants Enrolled in Neonatal Clinical Trials

Representativeness of populations within neonatal clinical trials is crucial to moving the field forward. Although racial and ethnic disparities in research inclusion are well documented in other fields, they are poorly described within neonatology. To describe the race and ethnicity of infants included in a sample of recent US neonatal clinical trials and the variability in this reporting. A systematic search of US neonatal clinical trials entered into Cochrane CENTRAL 2017 to 2021 was conducted. Two individuals performed inclusion determination, data extraction, and quality assessment independently with discrepancies adjudicated by consensus. Of 120 studies with 14 479 participants that met the inclusion criteria, 75 (62.5%) included any participant race or ethnicity data. In the studies that reported race and ethnicity, the median (IQR) percentage of participants of each background were 0% (0%-1%) Asian, 26% (9%-42%) Black, 3% (0%-12%) Hispanic, 0% (0%-0%) Indigenous (eg, Alaska Native, American Indian, and Native Hawaiian), 0% (0%-0%) multiple races, 57% (30%-68%) White, and 7% (1%-21%) other race or ethnicity. Asian, Black, Hispanic, and Indigenous participants were underrepresented, while White participants were overrepresented compared with a reference sample of the US clinical neonatal intensive care unit (NICU) population from the Vermont Oxford Network. Many participants were labeled as other race or ethnicity without adequate description. There was substantial variability in terms and methods of reporting race and ethnicity data. Geographic representation was heavily skewed toward the Northeast, with nearly one-quarter of states unrepresented. These findings suggest that neonatal research may perpetuate inequities by underrepresenting Asian, Black, Hispanic, and Indigenous neonates in clinical trials. Studies varied in documentation of race and ethnicity, and there was regional variation in the sites included. Based on these findings, funders and clinical trialists are advised to consider a 3-point targeted approach to address these issues: prioritize identifying ways to increase diversity in neonatal clinical trial participation, agree on a standardized method to report race and ethnicity among neonatal clinical trial participants, and prioritize the inclusion of participants from all regions of the US in neonatal clinical trials.

Antibiotic safety among neonates and paediatrics in a public hospital: KwaZulu-Natal.

The World Health Organization (WHO) guidelines recommend the empiric treatment of infections before definitive treatment begins. However, ethical concerns limit the availability of clinical trials in neonates and paediatrics to fully ascertain the safety profile of antibiotics in these populations. This study aimed to quantify the use of antibiotics among neonates and paediatrics and commented on the use, rationale and appropriateness of antibiotics prescribed. A secondary level public sector hospital located in Durban, KwaZulu-Natal. Demographic and treatment information of neonates and paediatrics were collected retrospectively from January 2022 to June 2022. Data were obtained from patient files and extracted for analysis using Microsoft Excel®. Analytical and descriptive statistics were used to analyse patient demographics and treatment variables. A total of 568 antibiotics, issued to 389 patients, were reviewed. Penicillins (40.1%), aminoglycosides (24.3%) and combination penicillin-beta-lactam inhibitors (23.3%) were identified as the most frequently prescribed antibiotics for inpatients. Most antibiotics prescribed to inpatients were for complications associated with pre-term birth (66.9%). Combination penicillin-beta-lactam inhibitors (34.7%), penicillins (29.5%) and cephalosporins (29.5%) were the most frequently prescribed antibiotics to outpatients. A correlation was found between the route of administration and the duration of therapy; the intravenous route (63.6%) was preferred over the oral route (36.4%) for administration. Many broad-spectrum antibiotics were prescribed, thus increasing the risk of resistance. Antibiotics were being prescribed according to the guidelines; however, there is still a need for therapeutic drug monitoring to ensure the continuation of rational drug use. There was evidence of rational use of antibiotics in the public hospital (KwaZulu-Natal), in keeping with economic and availability factors.

Physiologically Based Pharmacokinetic Modeling in Neonates: Current Status and Future Perspectives.

Rational drug use in special populations is a clinical problem that doctors and pharma-cists must consider seriously. Neonates are the most physiologically immature and vulnerable to drug dosing. There is a pronounced difference in the anatomical and physiological profiles be-tween neonates and older people, affecting the absorption, distribution, metabolism, and excretion of drugs in vivo, ultimately leading to changes in drug concentration. Thus, dose adjustments in neonates are necessary to achieve adequate therapeutic concentrations and avoid drug toxicity. Over the past few decades, modeling and simulation techniques, especially physiologically based pharmacokinetic (PBPK) modeling, have been increasingly used in pediatric drug development and clinical therapy. This rigorously designed and verified model can effectively compensate for the deficiencies of clinical trials in neonates, provide a valuable reference for clinical research design, and even replace some clinical trials to predict drug plasma concentrations in newborns. This review introduces previous findings regarding age-dependent physiological changes and pathological factors affecting neonatal pharmacokinetics, along with their research means. The application of PBPK modeling in neonatal pharmacokinetic studies of various medications is also reviewed. Based on this, we propose future perspectives on neonatal PBPK modeling and hope for its broader application.

The development and acceptability of an educational and training intervention for recruiters to neonatal trials: the TRAIN project

BackgroundSuboptimal or slow recruitment affects 30–50% of trials. Education and training of trial recruiters has been identified as one strategy for potentially boosting recruitment to randomised controlled trials (hereafter referred to as trials). The Training tRial recruiters, An educational INtervention (TRAIN) project was established to develop and assess the acceptability of an education and training intervention for recruiters to neonatal trials. In this paper, we report the development and acceptability of TRAIN.MethodsTRAIN involved three sequential phases, with each phase contributing information to the subsequent phase(s). These phases were 1) evidence synthesis (systematic review of the effectiveness of training interventions and a content analysis of the format, content, and delivery of identified interventions), 2) intervention development using a Partnership (co-design/co-creation) approach, and 3) intervention acceptability assessments with recruiters to neonatal trials.ResultsTRAIN, accompanied by a comprehensive intervention manual, has been designed for online or in-person delivery. TRAIN can be offered to recruiters before trial recruitment begins or as refresher sessions during a trial. The intervention consists of five core learning outcomes which are addressed across three core training units. These units are the trial protocol (Unit 1, 50 min, trial-specific), understanding randomisation (Unit 2, 5 min, trial-generic) and approaching and engaging with parents (Unit 3, 70 min, trial-generic). Eleven recruiters to neonatal trials registered to attend the acceptability assessment training workshops, although only four took part. All four positively valued the training Units and resources for increasing recruiter preparedness, knowledge, and confidence. More flexibility in how the training is facilitated, however, was noted (e.g., training divided across two workshops of shorter duration). Units 2 and 3 were considered beneficial to incorporate into Good Clinical Practice Training or as part of induction training for new staff joining neonatal units.ConclusionTRAIN offers a comprehensive co-produced training and education intervention for recruiters to neonatal trials. TRAIN was deemed acceptable, with minor modification, to neonatal trial recruiters. The small number of recruiters taking part in the acceptability assessment is a limitation. Scale-up of TRAIN with formal piloting and testing for effectiveness in a large cluster randomised trial is required.

Comparison of various vasopressin doses to epinephrine during cardiopulmonary resuscitation in asphyxiated neonatal piglets

BackgroundCurrent neonatal resuscitation guidelines recommend epinephrine for cardiac arrest. Vasopressin might be an alternative during asphyxial cardiac arrest. We aimed to compare vasopressin and epinephrine on incidence and time to return of spontaneous circulation (ROSC) in asphyxiated newborn piglets.Design/methodsNewborn piglets (n = 8/group) were anesthetized, intubated, instrumented, and exposed to 30 min of normocapnic hypoxia, followed by asphyxia and asystolic cardiac arrest. Piglets were randomized to 0.2, 0.4, or 0.8IU/kg vasopressin, or 0.02 mg/kg epinephrine. Hemodynamic parameters were continuously measured.ResultsMedian (IQR) time to ROSC was 172(103–418)s, 157(100–413)s, 122(93–289)s, and 276(117–480)s for 0.2, 0.4, 0.8IU/kg vasopressin, and 0.02 mg/kg epinephrine groups, respectively (p = 0.59). The number of piglets that achieved ROSC was 6(75%), 6(75%), 7(88%), and 5(63%) for 0.2, 0.4, 0.8IU/kg vasopressin, and 0.02 mg/kg epinephrine, respectively (p = 0.94). The epinephrine group had a 60% (3/5) rate of post-ROSC survival compared to 83% (5/6), 83% (5/6), and 57% (4/7) in the 0.2, 0.4, and 0.8IU/kg vasopressin groups, respectively (p = 0.61).ConclusionTime to and incidence of ROSC were not different between all vasopressin dosages and epinephrine. However, non-significantly lower time to ROSC and higher post-ROSC survival in vasopressin groups warrant further investigation.ImpactTime to and incidence of ROSC were not statistically different between all vasopressin dosages and epinephrine.Non-significantly lower time to ROSC and higher post-ROSC survival in vasopressin-treated piglets.Overall poorer hemodynamic recovery following ROSC in epinephrine piglets compared to vasopressin groups.Human neonatal clinical trials examining the efficacy of vasopressin during asphyxial cardiac arrest will begin recruitment soon.

59 Important Pulmonary Outcomes in Extremely Preterm Infants: Parental Perspectives

Abstract Background Lung Injury is frequent in extremely preterm infants. The definition of bronchopulmonary dysplasia (BPD) has changed since it was first described in 1967. Oxygen need at 36 weeks, the current definition, is not closely associated with long-term pulmonary outcomes. This outcome, used in neonatal research, has been chosen by clinicians and researchers, not by parents. Other outcomes related to chronic respiratory disease (such as hospital readmissions, work of breathing, and/or exercise limitation) are rarely measured or reported in outcome research. What pulmonary outcomes are of importance to parents is unknown. Objectives The primary objective of this part of the “parent voices project” was to create a list of respiratory outcomes that are important to parents, both during the NICU hospitalization and after discharge, to be considered in future respiratory outcome studies. Design/Methods Over one year (2020-2021), parents of infants born &amp;lt;29 weeks’ gestational age (GA) who came for follow-up visits when their children were between 18 months and 7 years old, in a large academic centre, were invited to participate. They were asked both closed and open-ended questions about the following topics: • The child’s health and what they would want to improve. • The impacts (negative and positive) of prematurity on the life of their family. • Their decisional regrets. • What they wish they had known both before birth and in the NICU, and their recommendations for clinicians. We examined all the parental answers with a view to discovering how many invoked pulmonary outcomes and which themes parents described when speaking about respiratory health. The goal was to make a list of all the respiratory outcomes that were important to families, both during the NICU hospitalization and longer term. Results were analyzed using mixed methods. Results Among parents (n=285, 98% participation rate), 44% spoke about important pulmonary outcomes. Parents invoked 25 themes when they described respiratory health, some pertaining to NICU hospitalization and others to long-term outcomes (see Table below). Some themes impacted the child (child-centred), such as exercise limitation. Many other pulmonary outcomes having an impact on parents or the whole family were described by parents (parent or family-centred themes). For example, a child who had difficulty breathing would struggle and could have disturbed sleep, but parents often described their own fear, lack of sleep (or disturbed sleep in other children). When children were hospitalized because of a respiratory illness, many of the outcomes described would be both child- and parent-centred: e.g., parental loss of work or income, and loss of equilibrium for the whole family. None of the 285 parents spoke about oxygen at 36 weeks or BPD. The prevalence of parents who describe pulmonary outcomes as impacting the child and/or family was statistically similar in parents of children with and without BPD, born before or after 25 weeks, with a BW of less or more than 750 g. Parents of male infants and those who were readmitted for respiratory issues were more likely to report important pulmonary outcomes. Conclusion Many parents of children born extremely preterm describe important pulmonary outcomes, independent of BPD. None of the parents mentioned oxygen at 36 weeks or BPD. More parents report such outcomes when their child has been readmitted for pulmonary reasons. These adverse outcomes often impact the whole family. Future research will indicate which outcomes need to be included in neonatal trials (or neonatal follow-up).

Statistical analysis plan for the Petal trial: the effects of parental touch on relieving acute procedural pain in neonates

Background: Infants undergo multiple clinically-required painful procedures during their time in hospital, and there is an increasing desire from both parents and clinical staff to have parents directly involved in their newborn’s pain relief. The Petal trial is a multicentre randomised controlled trial to investigate the effect of parental touch prior to a clinically-required heel lance on neonatal pain responses and parental anxiety. To avoid biases due to selective analysis and reporting, a clinical trial’s statistical analysis plan (SAP) should be finalised and registered prior to dataset lock and unblinding. Here, we outline the SAP for the Petal trial, which was registered on the ISRCTN registry prior to dataset lock and unblinding. The SAP is written in line with best practice guidelines to provide sufficient detail for reproducibility. Methods: The primary outcome is the neonate’s brain activity recorded using electroencephalography (EEG) in response to a heel lance blood sampling procedure. In this superiority trial, the primary objective is to investigate the potential efficacy of a parent-led non-pharmacological analgesic intervention on reducing the magnitude of neonates’ noxious stimulus-evoked brain activity. Secondary outcomes include neonatal clinical pain scores and tachycardia, and parental anxiety. Conclusions: Paediatric pain trials have been highlighted by regulatory bodies as an important and challenging topic, with interest increasing in brain imaging outcomes. The Petal trial, to which this SAP relates, is part of a larger effort of establishing a brain-based EEG outcome measure of infant pain for use in clinical trials. This SAP is thus likely to be of interest to those in academia, pharmaceutical companies, and regulatory bodies. We hope this SAP will help establish a foundation for the use of brain imaging outcomes in neonatal pain clinical trials, on which best practices can be built. Trial registration: ClinicalTrials.gov: NCT04901611, 25/05/2021; ISRCTN: ISRCTN14135962, 23/08/2021).

Stakeholders'perspectives and experiences of patient and public involvement (PPI) in clinical trials in maternal and neonatal healthcare: protocol for a qualitative evidence synthesis.

Patient and public involvement (PPI) has the potential to improve the relevance of trial outcomes and improve participant recruitment within clinical trials. However, the literature on PPI approaches, outcomes, and attitudes towards PPI in specific clinical research areas is limited. We are interested to know the current approaches to and views of PPI within maternal and neonatal clinical trials, from the perspective and experience of involved stakeholders. A qualitative evidence synthesis (QES) of stakeholders' perspectives and experiences of PPI will be conducted. Stakeholders will include any individual involved in maternal or neonatal clinical trials with experience of PPI in the area or who expresses their views on PPI. The electronic bibliographic databases CINAHL, MEDLINE, PsycINFO, EMBASE, Web of Science and the Maternity and Infant Care (OVID) will be searched from inception. Qualitative studies, mixed-methods studies where the qualitative data can be extracted independently, and surveys with open-ended qualitative questions, will be included. The QES seeks to explore stakeholders', including PPI contributors, trial participants and guardians, and trial researchers, perspectives and experiences of PPI in maternal and neonatal clinical trials. THE QES will provide an understanding of how PPI is understood, operationalised and experienced by stakeholders in maternal and neonatal clinical trials, with the aim of identifying good practice and areas for improvement. PROSPERO registration: CRD42023383878 (2 nd March 2023).

Caffeine and kidney function at two years in former extremely low gestational age neonates.

Extremely low gestational age neonates (ELGANs) are at risk for chronic kidney disease. The long-term kidney effects of neonatal caffeine are unknown. We hypothesize that prolonged caffeine exposure will improve kidney function at 22-26 months. Secondary analysis of the Preterm Erythropoietin Neuroprotection Trial of neonates <28 weeks' gestation. Participants included if any kidney outcomes were collected at 22-26 months corrected age. Exposure was post-menstrual age of caffeine discontinuation. 'reduced eGFR' <90 ml/min/1.73 m2, 'albuminuria' (>30 mg albumin/g creatinine), or 'elevated blood pressure' (BP) >95th %tile. A general estimating equation logistic regression model stratified by bronchopulmonary dysplasia (BPD) status was used. 598 participants had at least one kidney metricat follow up. Within the whole cohort, postmenstrual age of caffeine discontinuation was not associated with any abnormal measures of kidney function at 2 years. In the stratified analysis, for each additional week of caffeine, the no BPD group had a 21% decreased adjusted odds of eGFR <90ml/min/1.73m2 (aOR 0.78; CI 0.62-0.99) and the BPD group had a 15% increased adjusted odds of elevated BP (aOR 1.15; CI: 1.05-1.25). Longer caffeine exposure during the neonatal period is associated with differential kidney outcomes at 22-26 months dependent on BPD status. In participants born <28 weeks' gestation, discontinuation of caffeine at a later post menstrual age was not associated with abnormal kidney outcomes at 22-26 months corrected age. When assessed at 2 years of age, later discontinuation of caffeine in children born <28 weeks' gestation was associated with a greater risk of reduced eGFR in those without a history of BPD and an increased odds of hypertension in those with a history of BPD. More work is necessary to understand the long-term impact of caffeine on the developing kidney.

Heterogeneity and Gaps in Reporting Primary Outcomes From Neonatal Trials.

Clear outcome reporting in clinical trials facilitates accurate interpretation and application of findings and improves evidence-informed decision-making. Standardized core outcomes for reporting neonatal trials have been developed, but little is known about how primary outcomes are reported in neonatal trials. Our aim was to identify strengths and weaknesses of primary outcome reporting in recent neonatal trials. Neonatal trials including ≥100 participants/arm published between 2015 and 2020 with at least 1 primary outcome from a neonatal core outcome set were eligible. Raters recruited from Cochrane Neonatal were trained to evaluate the trials' primary outcome reporting completeness using relevant items from Consolidated Standards of Reporting Trials 2010 and Consolidated Standards of Reporting Trials-Outcomes 2022 pertaining to the reporting of the definition, selection, measurement, analysis, and interpretation of primary trial outcomes. All trial reports were assessed by 3 raters. Assessments and discrepancies between raters were analyzed. Outcome-reporting evaluations were completed for 36 included neonatal trials by 39 raters. Levels of outcome reporting completeness were highly variable. All trials fully reported the primary outcome measurement domain, statistical methods used to compare treatment groups, and participant flow. Yet, only 28% of trials fully reported on minimal important difference, 24% on outcome data missingness, 66% on blinding of the outcome assessor, and 42% on handling of outcome multiplicity. Primary outcome reporting in neonatal trials often lacks key information needed for interpretability of results, knowledge synthesis, and evidence-informed decision-making in neonatology. Use of existing outcome-reporting guidelines by trialists, journals, and peer reviewers will enhance transparent reporting of neonatal trials.

Survival benefits associated with neonatal clinical trial participation in a resource-limited setting: Quantifying the “healthy trial effect”

Survival benefits associated with neonatal clinical trial participation in a resource-limited setting: Quantifying the “healthy trial effect”

Heterogeneity of Treatment Effects of Hydrocortisone by Risk of Bronchopulmonary Dysplasia or Death Among Extremely Preterm Infants in the National Institute of Child Health and Human Development Neonatal Research Network Trial

Extremely preterm infants who develop bronchopulmonary dysplasia (BPD) are at a higher risk for adverse pulmonary and neurodevelopmental outcomes. In the National Institute of Child Health and Human Development Neonatal Research Network (NICHD NRN) Hydrocortisone Trial, hydrocortisone neither reduced rates of BPD or death nor increased rates of neurodevelopmental impairment (NDI) or death. To determine whether estimated risk for grades 2 to 3 BPD or death is associated with the effect of hydrocortisone on the composite outcomes of (1) grades 2 to 3 BPD or death and (2) moderate or severe NDI or death. This secondary post hoc analysis used data from the NICHD NRN Hydrocortisone Trial, which was a double-masked, placebo-controlled, randomized clinical trial conducted in 19 US academic centers. The NICHD HRN Hydrocortisone Trial enrolled infants born at a gestational age of less than 30 weeks who received mechanical ventilation for at least 7 days, including at the time of enrollment, and who were aged 14 to 28 postnatal days. Infants were enrolled between August 22, 2011, and February 4, 2018, with follow-up between 22 and 26 months of corrected age completed on March 29, 2020. Data were analyzed from September 13, 2021, to March 25, 2023. Infants were randomized to 10 days of hydrocortisone or placebo treatment. Infants' baseline risk of grades 2 to 3 BPD or death was estimated using the NICHD Neonatal BPD Outcome Estimator. Differences in absolute and relative treatment effects by baseline risk were evaluated using interaction terms in models fitted to the efficacy outcome of grades 2 to 3 BPD or death and the safety outcome of moderate or severe NDI or death by follow-up. Among the 799 infants included in the analysis (421 boys [52.7%]), the mean (SD) gestational age was 24.9 (1.5) weeks, and the mean (SD) birth weight was 715 (167) g. The mean estimated baseline risk for grades 2 to 3 BPD or death was 54% (range, 18%-84%) in the study population. The interaction between treatment group and baseline risk was not statistically significant on a relative or absolute scale for grades 2 to 3 BPD or death; the size of the effect ranged from a relative risk of 1.13 (95% CI, 0.82-1.55) in quartile 1 to 0.94 (95% CI, 0.81-1.09) in quartile 4. Similarly, the interaction between treatment group and baseline risk was not significant on a relative or absolute scale for moderate or severe NDI or death; the size of the effect ranged from a relative risk of 1.04 (95% CI, 0.80-1.36) in quartile 1 to 0.99 (95% CI, 0.80-1.22) in quartile 4. In this secondary analysis of a randomized clinical trial, the effect of hydrocortisone vs placebo was not appreciably modified by baseline risk for grades 2 to 3 BPD or death. ClinicalTrials.gov Identifier: NCT01353313.

Stakeholder’s perspectives and experiences of patient and public involvement (PPI) in clinical trials in maternal and neonatal healthcare: protocol for a qualitative evidence synthesis

Background: Patient and public involvement (PPI) has the potential to improve the relevance of trial outcomes and improve participant recruitment within clinical trials. However, the literature on PPI approaches, outcomes, and attitudes towards PPI in specific clinical research areas is limited. We are interested to know the current approaches to and views of PPI within maternal and neonatal clinical trials, from the perspective and experience of involved stakeholders. Methods: A qualitative evidence synthesis (QES) of stakeholders’ perspectives and experiences of PPI will be conducted. Stakeholders will include any individual involved in maternal or neonatal clinical trials with experience of PPI in the area or who expresses their views on PPI. The electronic bibliographic databases CINAHL, MEDLINE, PsycINFO, EMBASE, Web of Science and the Maternity and Infant Care (OVID) will be searched from inception. Qualitative studies, mixed-methods studies where the qualitative data can be extracted independently, and surveys with open-ended qualitative questions, will be included. Aims: The QES seeks to explore stakeholders’, including PPI contributors, trial participants and guardians, and trial researchers, perspectives and experiences of PPI in maternal and neonatal clinical trials. Discussion: THE QES will provide an understanding of how PPI is understood, operationalised and experienced by stakeholders in maternal and neonatal clinical trials, with the aim of identifying good practice and areas for improvement. PROSPERO registration: CRD42023383878 (2nd March 2023)

Generalizability of the Necrotizing Enterocolitis Surgery Trial to the Target Population of Eligible Infants

The objective of this study was to evaluate whether infants randomized in the Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network Necrotizing Enterocolitis Surgery Trial differed from eligible infants and whether differences affected the generalizability of trial results. Secondary analysis of infants enrolled in Necrotizing Enterocolitis Surgery Trial (born 2010-2017, with follow-up through 2019) at 20 US academic medical centers and an observational data set of eligible infants through 2013. Infants born ≤1000g and diagnosed with necrotizing enterocolitis or spontaneous intestinal perforation requiring surgical intervention at ≤8weeks were eligible. The target population included trial-eligible infants (randomized and nonrandomized) born during the first half of the study with available detailed preoperative data. Using model-based weighting methods, we estimated the effect of initial laparotomy vs peritoneal drain had the target population been randomized. The trial included 308 randomized infants. The target population included 382 (156 randomized and 226 eligible, non-randomized) infants. Compared with the target population, fewer randomized infants had necrotizing enterocolitis (31% vs 47%) or died before discharge (27% vs 41%). However, incidence of the primary composite outcome, death or neurodevelopmental impairment, was similar (69% vs 72%). Effect estimates for initial laparotomy vs drain weighted to the target population were largely unchanged from the original trial after accounting for preoperative diagnosis of necrotizing enterocolitis (adjusted relative risk [95% CI]: 0.85 [0.71-1.03] in target population vs 0.81 [0.64-1.04] in trial) or spontaneous intestinal perforation (1.02 [0.79-1.30] vs 1.11 [0.95-1.31]). Despite differences between randomized and eligible infants, estimated treatment effects in the trial and target population were similar, supporting the generalizability of trial results. ClinicalTrials.gov ID: NCT01029353.

National priority setting partnership using a Delphi consensus process to develop neonatal research questions suitable for practice-changing randomised trials in the UK

BackgroundThe provision of neonatal care is variable and commonly lacks adequate evidence base; strategic development of methodologically robust clinical trials is needed to improve outcomes and maximise research resources. Historically,...

Macroperiodic Oscillations: A Potential Novel Biomarker of Outcome in Neonatal Encephalopathy.

Neonatal encephalopathy (NE) is a common cause of neurodevelopmental morbidity. Tools to accurately predict outcomes after therapeutic hypothermia remain limited. We evaluated a novel EEG biomarker, macroperiodic oscillations (MOs), to predict neurodevelopmental outcomes. We conducted a secondary analysis of a randomized controlled trial of neonates with moderate-to-severe NE who underwent standardized clinical examination, magnetic resonance (MR) scoring, video EEG, and neurodevelopmental assessment with Bayley III evaluation at 18 to 24 months. A non-NE cohort of neonates was also assessed for the presence of MOs. The relationship between clinical examination, MR score, MOs, and neurodevelopmental assessment was analyzed. The study included 37 neonates with 24 of whom survived and underwent neurodevelopmental assessment (70%). The strength of MOs correlated with severity of clinical encephalopathy. MO strength and spread significantly correlated with Bayley III cognitive percentile ( P = 0.017 and 0.046). MO strength outperformed MR score in predicting a combined adverse outcome of death or disability ( P = 0.019, sensitivity 100%, specificity 77% vs. P = 0.079, sensitivity 100%, specificity 59%). MOs are an EEG-derived, quantitative biomarker of neurodevelopmental outcome that outperformed a comprehensive validated MRI injury score and a detailed systematic discharge examination in this small cohort. Future work is needed to validate MOs in a larger cohort and elucidate the underlying pathophysiology of MOs.

Evaluation of heterogeneity in effect of therapeutic hypothermia by sex among infants with neonatal encephalopathy.

Our objective was to examine heterogeneity in the effect of therapeutic hypothermia by sex in infants with moderate or severe neonatal encephalopathy. We conducted a post hoc analysis of the Induced Hypothermia trial, which included infants born at gestational ages ≥36 weeks, admitted at ≤6 postnatal hours with evidence of severe acidosis or perinatal complications and moderate or severe neonatal encephalopathy. Multivariate modified Poisson regression models were used to compare the treatment effect of whole-body hypothermia versus control, with an evaluation of interaction by sex, on the primary outcome of death or moderate or severe disability at 18-22 months of corrected age. A total of 101 infants (51 male, 50 female) were randomly assigned to hypothermia treatment and 104 infants (64 male, 40 female) to control. The primary outcome occurred in 45% of the hypothermia group and 63% of the control group (RR 0.73; 95% CI 0.56, 0.94). There was no significant difference (interaction P = 0.50) in the treatment effect of hypothermia on the primary outcome between females (RR 0.79; 95% CI 0.54, 1.17) compared to males (RR 0.63; 95% CI 0.44, 0.91). We found no evidence that sex influences the treatment effect of hypothermia in infants with moderate or severe neonatal encephalopathy. Preclinical evidence suggests a differential effect in response to cooling treatment of hypoxic-ischemic injury between males and females. We found no evidence of heterogeneity in the treatment effect of whole-body hypothermia by sex in this post hoc subgroup analysis of infants with moderate or severe neonatal encephalopathy from the National Institute of Child Health and Human Development Neonatal Research NetworkInduced Hypothermia trial.

Pulmonary important outcomes after extremely preterm birth: Parental perspectives.

To describe pulmonary important outcomes (PIO) reported by parents of children born extremely preterm. Over 1-year, all parents of children aged 18 months-7-years born <29 weeks' GA were asked regarding their perspectives. The proportion of parents who described PIO and the themes they invoked were examined. Results were analysed using mixed methods. Among parental responses (n= 285, 98% participation rate), 44% spoke about PIO, invoking 24 themes pertaining to NICU hospitalisation and/or long-term respiratory health. Some themes had an impact primarily on the child (e.g. exercise limitation), while the majority had an impact on the whole family (e.g. hospital readmissions). None mentioned oxygen at 36 weeks nor bronchopulmonary dysplasia (BPD). The proportion of responses invoking PIO were statistically similar between parents of children with and without BPD, born before or after 25 weeks or with birthweight < or ≥750 g. PIO were more likely to be mentioned in males and among those readmitted for respiratory problems. Parents describe many PIO, most related to the functional impact of lung disease on their child (and family), rather than the diagnosis of BPD itself. Most of these PIO are not primary outcomes in large neonatal trials nor collected in neonatal databases.