Childhood outcomes after low-grade intraventricular haemorrhage: A systematic review and meta-analysis

Aim: To undertake a systematic review and meta-analysis exploring school-age neurodevelopmental outcomes of children after low-grade intraventricular haemorrhage (IVH). Method: The published and grey literature was extensively searched to identify observational comparative studies exploring neurodevelopmental outcomes after IVH grades 1 and 2. Our primary outcome was neurodevelopmental impairment after 5 years of age, which included cognitive, motor, speech and language, behavioural, hearing, or visual impairments. Results: This review included 12 studies and over 2036 infants born preterm with low grade IVH. Studies used 30 different neurodevelopmental tools to determine outcomes. There was conflicting evidence of the composite risk of neurodevelopmental impairment after low-grade IVH. There was evidence of an association between low-grade IVH and lower IQ at school age (−4.23, 95% confidence interval [CI] –7.53, −0.92, I2 = 0%) but impact on school performance was unclear. Studies reported an increased crude risk of cerebral palsy after low-grade IVH (odds ratio [OR] 2.92, 95% CI 1.95, 4.37, I2 = 41%). No increased risk of speech and language impairment or behavioural impairment was found. Few studies addressed hearing and visual impairment. Interpretation: This systematic review presents evidence that low-grade IVH is associated with specific neurodevelopmental impairments at school age, lending support to the theory that low-grade IVH is not a benign condition

School-age outcomes of children after perinatal brain injury: a systematic review and meta-analysis

BACKGROUND: Over 3000 children suffer a perinatal brain injury in England every year according to national surveillance. The childhood outcomes of infants with perinatal brain injury are however unknown. METHODS: A systematic review and meta-analyses were undertaken of studies published between 2000 and September 2021 exploring school-aged neurodevelopmental outcomes of children after perinatal brain injury compared with those without perinatal brain injury. The primary outcome was neurodevelopmental impairment, which included cognitive, motor, speech and language, behavioural, hearing or visual impairment after 5 years of age. RESULTS: This review included 42 studies. Preterm infants with intraventricular haemorrhage (IVH) grades 3-4 were found to have a threefold greater risk of moderate-to-severe neurodevelopmental impairment at school age OR 3.69 (95% CI 1.7 to 7.98) compared with preterm infants without IVH. Infants with perinatal stroke had an increased incidence of hemiplegia 61% (95% CI 39.2% to 82.9%) and an increased risk of cognitive impairment (difference in full scale IQ -24.2 (95% CI -30.73 to -17.67) . Perinatal stroke was also associated with poorer academic performance; and lower mean receptive -20.88 (95% CI -36.66 to -5.11) and expressive language scores -20.25 (95% CI -34.36 to -6.13) on the Clinical Evaluation of Language Fundamentals (CELF) assessment. Studies reported an increased risk of persisting neurodevelopmental impairment at school age after neonatal meningitis. Cognitive impairment and special educational needs were highlighted after moderate-to-severe hypoxic-ischaemic encephalopathy. However, there were limited comparative studies providing school-aged outcome data across neurodevelopmental domains and few provided adjusted data. Findings were further limited by the heterogeneity of studies. CONCLUSIONS: Longitudinal population studies exploring childhood outcomes after perinatal brain injury are urgently needed to better enable clinicians to prepare affected families, and to facilitate targeted developmental support to help affected children reach their full potential

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

BACKGROUND: The 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, neonatal research topics have been selected by researchers; prioritisation processes involving wider stakeholder groups have generally identified research themes rather than specific questions amenable to interventional trials. OBJECTIVE: To involve stakeholders including parents, healthcare professionals and researchers to identify and prioritise research questions suitable for answering in neonatal interventional trials in the UK. DESIGN: Research questions were submitted by stakeholders in population, intervention, comparison, outcome format through an online platform. Questions were reviewed by a representative steering group; duplicates and previously answered questions were removed. Eligible questions were entered into a three-round online Delphi survey for prioritisation by all stakeholder groups. PARTICIPANTS: One hundred and eight respondents submitted research questions for consideration; 144 participants completed round one of the Delphi survey, 106 completed all three rounds. RESULTS: Two hundred and sixty-five research questions were submitted and after steering group review, 186 entered into the Delphi survey. The top five ranked research questions related to breast milk fortification, intact cord resuscitation, timing of surgical intervention in necrotising enterocolitis, therapeutic hypothermia for mild hypoxic ischaemic encephalopathy and non-invasive respiratory support. CONCLUSIONS: We have identified and prioritised research questions suitable for practice-changing interventional trials in neonatal medicine in the UK at the present time. Trials targeting these uncertainties have potential to reduce research waste and improve neonatal care

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

Introduction: Methodologically robust clinical trials are required to improve neonatal care and reduce unwanted variations in practice. Previous neonatal research prioritisation processes have identified important research themes rather than specific research questions amenable to clinical trials. Practice-changing trials require well-defined research questions, commonly organised using the Population, Intervention, Comparison, Outcome (PICO) structure. By narrowing the scope of research priorities to those which can be answered in clinical trials and by involving a wide range of different stakeholders, we aim to provide a robust and transparent process to identify and prioritise research questions answerable within the National Healthcare System to inform future practice-changing clinical trials. Methods and analysis: A steering group comprising parents, doctors, nurses, allied health professionals, researchers and representatives from key organisations (Neonatal Society, British Association of Perinatal Medicine, Neonatal Nurses Association and Royal College of Paediatrics and Child Health) was identified to oversee this project. We will invite submissions of research questions formatted using the PICO structure from the following stakeholder groups using an online questionnaire: parents, patients, healthcare professionals and academic researchers. Unanswered, non-duplicate research questions will be entered into a three-round eDelphi survey of all stakeholder groups. Research questions will be ranked by mean aggregate scores. Ethics and dissemination: The final list of prioritised research questions will be disseminated through traditional academic channels, directly to key stakeholder groups through representative organisations and on social media. The outcome of the project will be shared with key research organisations such as the National Institute for Health Research. Research ethics committee approval is not required

Repeat placental growth factor-based testing in women with suspected preterm pre-eclampsia (PARROT-2): a multicentre, parallel-group, superiority, randomised controlled trial.

BackgroundPlacental growth factor (PlGF)-based testing has high diagnostic accuracy for predicting pre-eclampsia needing delivery, significantly reducing time to diagnosis and severe maternal adverse outcomes. The clinical benefit of repeat PlGF-based testing is unclear. We aimed to determine whether repeat PlGF-based testing (using a clinical management algorithm and nationally recommended thresholds) reduces adverse perinatal outcomes in pregnant individuals with suspected preterm pre-eclampsia.MethodsIn this multicentre, parallel-group, superiority, randomised controlled trial, done in 22 maternity units across England, Scotland, and Wales, we recruited women aged 18 years or older with suspected pre-eclampsia between 22 weeks and 0 days of gestation and 35 weeks and 6 days of gestation. Women were randomly assigned (1:1) to revealed repeat PlGF-based testing or concealed repeat testing with usual care. The intervention was not masked to women or partners, or clinicians or data collectors, due to the nature of the trial. The trial statistician was masked to intervention allocation. The primary outcome was a perinatal composite of stillbirth, early neonatal death, or neonatal unit admission. The primary analysis was by the intention-to-treat principle, with a per-protocol analysis restricted to women managed according to their allocation group. The trial was prospectively registered with the ISRCTN registry, ISRCTN 85912420.FindingsBetween Dec 17, 2019, and Sept 30, 2022, 1253 pregnant women were recruited and randomly assigned treatment; one patient was excluded due to randomisation error. 625 women were allocated to revealed repeat PlGF-based testing and 627 women were allocated to usual care with concealed repeat PlGF-based testing (mean age 32·3 [SD 5·7] years; 879 [70%] white). One woman in the concealed repeat PlGF-based testing group was lost to follow-up. There was no significant difference in the primary perinatal composite outcome between the revealed repeat PlGF-based testing group (195 [31·2%]) of 625 women) compared with the concealed repeat PlGF-based testing group (174 [27·8%] of 626 women; relative risk 1·21 [95% CI 0·95-1·33]; p=0·18). The results from the per-protocol analysis were similar. There were four serious adverse events in the revealed repeat PlGF-based testing group and six in the concealed repeat PlGF-based testing group; all serious adverse events were deemed unrelated to the intervention by the site principal investigators and chief investigator.InterpretationRepeat PlGF-based testing in pregnant women with suspected pre-eclampsia was not associated with improved perinatal outcomes. In a high-income setting with a low prevalence of adverse outcomes, universal, routine repeat PlGF-based testing of all individuals with suspected pre-eclampsia is not recommended.FundingTommy's Charity, Jon Moulton Charitable Trust, and National Institute for Health and Care Research Guy's and St Thomas' Biomedical Research Centre

The UK Neonatal Collaborative Necrotising Enterocolitis (NEC) study: testing the utility of operational clinical data to conduct population surveillance, develop an evidence-based case-definition and identify risk factors associated with NEC

Background: Necrotising enterocolitis (NEC) is growing in global relevance. Aetiology and pathophysiology are uncertain; non-invasive diagnostic tests and case-definition lacking; population incidence data scant, and evidence to inform preventive feeding strategies are inadequate. The National Neonatal Research Database (NNRD) comprises data from infants admitted to neonatal units in England and offers opportunities to facilitate population studies. Methods: I performed a systematic review of global NEC incidence; secured the participation of all English neonatal units in a prospective two-year study employing the NNRD as the source of data; quantified the burden of severe NEC (confirmed at laparotomy and/or leading to death); investigated the impact of early maternal breast milk (MBM), and avoidance of bovine products (formula/fortifier) on NEC, and developed a case-definition for NEC suitable for surveillance and research. Statistical methods included multivariate logistic regression, funnel plot and propensity analysis. Results: 118,073 infants (14,678 <32 weeks (w) gestational age (GA)) were admitted to 163 English neonatal units (23 networks) in 2012-2013; 531 (462; 3.15% of infants <32w GA) developed severe NEC; 20% died without a laparotomy; a third who received a laparotomy died. Among infants <32w there was no strong evidence of variation in relation to the adjusted national incidence of 3.13% (95%CI 2.85, 3.42) despite variation in feeding practices. Early vs. late or no MBM (within 7 days) resulted in an Absolute Risk Difference (ARD) of -0.88% (95% CI -1.15, -0.61), Relative Risk (RR) 0.69 (95% CI 0.60, 0.78); equivalent figures for no vs. any bovine products within 14 postnatal days, were ARD -0.65% (95% CI -1.01, 0.29), RR 0.61 (95% CI 0.39, 0.83). The ordinal NEC score allocated three points to pneumatosis, two to blood in stools and one to abdominal tenderness; abdominal discolouration; the composite of increased and/or bilious aspirates AND abdominal distension; one or more of pneumoperitoneum, fixed loop and portal venous gas. Infants with a score of ≥2 (<30 w); ≥3 (30 to <37 w); ≥4 (≥37w GA) were considered to have NEC. Conclusions: This thesis provides, for the first time, population incidence of severe NEC in England. The proposed NEC score and GA-specific case-definition offer opportunity to strengthen research efforts. Commencing MBM early and avoiding bovine products may reduce NEC but effect sizes appear small. The lack of network variation in severe NEC despite differences in feeding practices highlights the need to address ongoing uncertainties.Open Acces

Optimising nutrition during therapeutic hypothermia

There is little evidence to inform provision of enteral or parenteral nutrition to infants with hypoxic ischaemic encephalopathy (HIE) during and soon after therapeutic hypothermia; as a consequence, clinical practice is both variable and changing. A 2014 UK survey found that 79% (33 of 42) of responding neonatal units routinely withheld enteral nutrition during cooling; 3 years later, a similar survey found that 41% (20 of 49) of responding units reported withholding enteral nutrition.1 The latter study also reports wide variation in how, when and how much to feed, and in the use of parenteral nutrition. Internationally, practice is even more variable: withholding enteral feeds is practised almost universally2 in some countries, while in others, milk feeding during hypothermia is routine.3 Here we discuss the limited evidence available to inform enteral and parenteral nutrition during therapeutic hypothermia

Administration of parenteral nutrition during therapeutic hypothermia: a population level observational study using routinely collected data held in the National Neonatal Research Database

Background: parenteral nutrition is commonly administered during therapeutic hypothermia. Randomised trials in critically ill children indicate that parenteral nutrition may be harmful. Objective: to examine the association between parenteral nutrition during therapeutic hypothermia and clinically important outcomes. Design: retrospective, population-based cohort study using the National Neonatal Research Database; propensity scores were used to create matched groups for comparison. Setting: National Health Service neonatal units in England, Scotland and Wales.Participants: 6030 term and near-term babies, born 1/1/2010 and 31/12/2017, who received therapeutic hypothermia; 2480 babies in the matched analysis. Exposure: we compared babies that received any parenteral nutrition during therapeutic hypothermia with babies that did not. Main outcome: measures Primary outcome: blood culture confirmed late-onset infection; secondary outcomes: treatment for late onset infection, necrotising enterocolitis, survival, length of stay, measures of breast feeding, hypoglycaemia, central line days, time to full enteral feeds, discharge weight.Results: 1475/6030 babies (25%) received parenteral nutrition. In comparative matched analyses, the rate of culture positive late onset infection was higher in babies that received parenteral nutrition (0.3% vs 0.9%; difference 0.6; 95% CI 0.1, 1.2; p=0.03), but treatment for presumed infection was not (difference 0.8%, 95% CI -2.1 to 3.6, p=0.61). Survival was higher in babies that received parenteral nutrition (93.1% vs 90.0%; rate difference 3.1, 95% CI 1.5, 4.7; p&lt;0.001). Conclusions: receipt of parenteral nutrition during therapeutic hypothermia is associated with higher late-onset infection but lower mortality. This finding may be explained by residual confounding. Research should address the risks and benefits of parenteral nutrition in this population.</p

Study protocol: optimising newborn nutrition during and after neonatal therapeutic hypothermia in the United Kingdom: observational study of routinely collected data using propensity matching

Introduction: therapeutic hypothermia is standard of care for infants born ≥36 weeks gestation with hypoxic ischaemic encephalopathy (HIE); consensus on optimum nutrition during therapeutic hypothermia is lacking. This results in variation in enteral feeding and parenteral nutrition (PN) for these infants. In this study, we aim to determine the optimum enteral nutrition and PN strategy for newborns with HIE during therapeutic hypothermia.Methods and analysis: we will undertake a retrospective cohort study using routinely recorded electronic patient data held on the United Kingdom (UK) National Neonatal Research Database (NNRD). We will extract data from infants born ≥36 weeks gestational age between 1 January 2008 and 31 December 2016, who received therapeutic hypothermia for at least 72 hours or died during therapeutic hypothermia, in neonatal units in England, Wales and Scotland. We will form matched groups in order to perform two comparisons examining: (1) the risk of NEC between infants enterally fed and infants not enterally fed, during therapeutic hypothermia; (2) the risk of late-onset blood stream infections between infants who received intravenous dextrose without any PN and infants who received PN, during therapeutic hypothermia. The following secondary outcomes will also be examined: Survival, length of stay, breast feeding at discharge, hypoglycaemia, time to full enteral feeds and growth. Comparison groups will be matched on demographic, maternal, infant and organisational factors using propensity score matching.Ethics and dissemination: in this study, we will use deidentifed data held in the NNRD, an established national population database; parents can opt out of their baby's data being held in the NNRD. This study holds study-specific Research Ethics Committee approval (East Midlands Leicester Central, 17/EM/0307). These results will help inform optimum nutritional management in infants with HIE receiving therapeutic hypothermia; results will be disseminated through conferences, scientific publications and parent-centred information produced in partnership with parents.</p