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ObjectiveIn healthy preterm infants, cortical burst rate and temporal dynamics predict important measures such as brain growth. We hypothesised that in preterm infants with germinal matrix-intraventricular haemorrhage (GM-IVH), cortical bursting could provide prognostic information. We determined how cortical bursting was influenced by the injury, and whether this was related to developmental outcome.MethodsWe identified 47 EEGs from 33 infants with GM-IVH ≥grade II (median gestational age: 25 weeks), acquired between 24-40 weeks corrected gestational age as part of routine clinical care. In a subset of 33 EEGs from 25 infants with asymmetric injury, we used the least-affected hemisphere as an internal control. We tested whether cortical burst rate predicted death or severe motor impairment (median 2 years follow-up; range 1-2 years corrected).ResultsGM-IVH depressed central cortical burst rate. Bursts over the worst-affected hemisphere were less likely to immediately follow (within 1 second) bursts over the least-affected hemisphere than vice versa. Lower burst rate was modestly associated with death or severe motor impairment (specificity 93%, sensitivity 37%).ConclusionsEEG can quantitatively index the functional injury after GM-IVH.SignificanceHigher cortical burst rate is reassuring for a positive motor outcome over the first 2 years.HighlightsGM-IVH depresses cortical burst rateGM-IVH unbalances inter-hemispheric burst dynamicsHigher burst rate following GM-IVH is associated with positive motor outcome at median 2 years

BackgroundSevere early-onset fetal growth restriction (FGR) causes significant fetal and neonatal mortality and morbidity. Predicting the outcome of affected pregnancies at the time of diagnosis is difficult, preventing accurate patient counselling. We investigated the use of maternal serum protein and ultrasound measures at diagnosis to predict fetal or neonatal death and three secondary outcomes: fetal death or delivery ≤28+0 weeks; development of abnormal umbilical artery Doppler velocimetry; slow fetal growth.MethodsWomen with singleton pregnancies (n=142, estimated fetal weights [EFWs] rdcentile, ResultsThe most discriminative model for fetal or neonatal death included EFW z-score (Hadlock 3 formula/Marsal chart), gestational age and umbilical artery Doppler category (AUC 0.91, 95%CI 0.86-0.97) but was less well calibrated than the model containing only EFW z-score (Hadlock3/Marsal). The most discriminative model for fetal death or delivery ≤28+0 weeks included maternal serum placental growth factor (PlGF) concentration and umbilical artery Doppler category (AUC 0.89, 95%CI 0.83-0.94).ConclusionUltrasound measurements and maternal serum PlGF concentration at diagnosis of severe early-onset FGR predict pregnancy outcomes of importance to patients and clinicians.Trial registrationClinicalTrials.govNCT02097667FundingEuropean Union, Rosetrees Trust, Mitchell Charitable Trust.

ObjectiveTo quantify the risks of mortality, morbidity and postnatal characteristics associated with extreme preterm fetal growth restriction (EP-FGR).DesignThe EVERREST (Doesvascular endothelial growth factor gene therapy safely improve outcome in severeearly-onset fetal growth restriction?) prospective multicentre study of women diagnosed with EP-FGR (singleton, estimated fetal weight (EFW) +0–26+6weeks of gestation). The UK subgroup of EP-FGR infants (SettingFour tertiary perinatal units (UK, Germany, Spain, Sweden).Main outcomesAntenatal and postnatal mortality, bronchopulmonary dysplasia (BPD), sepsis, surgically treated necrotising enterocolitis (NEC), treated retinopathy of prematurity (ROP).ResultsOf 135 mothers recruited with EP-FGR, 42 had a stillbirth or termination of pregnancy (31%) and 93 had live births (69%). Postnatal genetic abnormalities were identified in 7/93 (8%) live births. Mean gestational age at birth was 31.4 weeks (SD 4.6). 54 UK-born preterm EP-FGR infants (ConclusionsMortality following diagnosis of EP-FGR is high. Survivors experience increased neonatal morbidity compared with AGA preterm infants.Trial registration numberNCT02097667.

Highlights • Higher power of cortical bursts after postnatal day 3 predicted worse cognitive, language and motor outcomes. • Association between cortical bursts and outcome was independent of structural MRI findings. • EEG may provide additional information by indexing persistent active mechanisms that support recovery or exacerbate damage., Objective Early prediction of neurological deficits following neonatal hypoxic-ischemic encephalopathy (HIE) may help to target support. Neonatal animal models suggest that recovery following hypoxia-ischemia depends upon cortical bursting. To test whether this holds in human neonates, we correlated the magnitude of cortical bursting during recovery (≥postnatal day 3) with neurodevelopmental outcomes. Methods We identified 41 surviving infants who received therapeutic hypothermia for HIE (classification at hospital discharge: 19 mild, 18 moderate, 4 severe) and had 9-channel electroencephalography (EEG) recordings as part of their routine care. We correlated burst power with Bayley-III cognitive, motor and language scores at median 24 months. To examine whether EEG offered additional prognostic information, we controlled for structural MRI findings. Results Higher power of central and occipital cortical bursts predicted worse cognitive and language outcomes, and higher power of central cortical bursts predicted worse motor outcome, all independently of structural MRI findings. Conclusions Clinical EEG after postnatal day 3 may provide additional prognostic information by indexing persistent active mechanisms that either support recovery or exacerbate brain damage, especially in infants with less severe encephalopathy. Significance These findings could allow for the effect of clinical interventions in the neonatal period to be studied instantaneously in the future.

ObjectiveTo describe the cognitive, language and motor developmental trajectories of children born very preterm and to identify perinatal factors that predict the trajectories.DesignData from a cohort of 1142 infants born at Main outcome measuresDevelopmental trajectory SITAR models for Bayley-III cognitive, language (receptive and expressive communication subscales) and motor (fine and gross motor subscales) scores.ResultsThe successfully fitted SITAR models explained 62% of variance in cognitive development, 68% in receptive communication, 53% in fine motor and 68% in the gross motor development. There was too much variation in the expressive communication subscale to fit a SITAR model. The rate of development (gradient of the curve) best explains the variation in trajectories of development in all domains. Lower gestational age, lower birth weight and male sex significantly predicted a slower rate of development.ConclusionThe rate of development, rather than single time point developmental assessment, best predicts the very preterm infant’s developmental trajectory and should be the focus for monitoring and early intervention.

In August 2017, the National Institute for Health and Care Excellence (NICE) published a guideline entitled ‘Developmental follow-up of children and young people born preterm’.1 The 668-page guideline, with similar length in appendices, describes the risks of developmental problems, and the assessments and support recommended for children and young people born before 37+0 weeks’ gestation. The Guideline Committee included paediatric and neonatal clinicians, therapists, psychologists, researchers in neonatology and two lay members. Extensive research has been conducted in the UK on outcomes of prematurity through the EPICure studies,2 and several individual units, regions and networks have developed local guidelines.3 However, there has been no previous standardised guideline on developmental follow-up for these babies. In 2009, the 2-year assessment for those born before 30+0 weeks’ gestation was added to the toolkit in neonatology from the Department of Health,4 and is now in the National Neonatal Audit Programme as a standard of care for the management of children, as well as a measure of perinatal and neonatal outcomes.5 However, there is still wide variation in the provision of the 2-year assessment for premature babies throughout the UK,6 with partial data available for just 60% of these babies.5 This NICE guideline on developmental follow-up of the premature baby is welcome, as there is an urgent need for an adequately funded, equipped, staffed and effective surveillance service for this vulnerable population.

Necrotising enterocolitis (NEC) in preterm babies is a serious gastrointestinal emergency with potentially devastating consequences. Prompt and accurate diagnosis continues to be a challenge for health professionals. Early identification of clinical warning signs is extremely important, but the diagnosis relies heavily on the interpretation of abdominal radiographs. Postgraduate training of paediatricians and neonatologists in neonatal abdominal radiography is scarce, and there is variability of radiological input to neonatal services. Lack of a standardised approach and descriptive terminology for interpretation may result in inadequate communication between clinical and surgical teams, inaccurate diagnosis, inappropriate treatment, and unnecessary cessation of feeds and transfers to surgical units. This paper offers a guide designed for the doctor who on a busy night shift needs to interpret an abdominal radiograph and decide on a differential diagnosis of NEC in a preterm baby. It helps to provide structure and standardisation to interpretation of radiological signs using a comprehensive but simple method to support the clinical diagnosis. Our aim is to enhance the correct diagnosis of NEC.

Hypoxic ischemic encephalopathy (HIE) leads to significant morbidity and mortality. Impaired autoregulation after hypoxia-ischaemia has been suggested to contribute further to injury. Thalamic lactate/N-Acetylasperate (Lac/NAA) peak area ratio of > 0.3 on proton (1H) magnetic resonance spectroscopy (MRS) is associated with poor neurodevelopment outcome following HIE. Cytochrome-c-oxidase (CCO) plays a central role in mitochondrial oxidative metabolism and ATP synthesis. Using a novel broadband NIRS system, we investigated the impact of pressure passivity of cerebral metabolism (CCO), oxygenation (haemoglobin difference (HbD)) and cerebral blood volume (total haemoglobin (HbT)) in 23 term infants following HIE during therapeutic hypothermia (HT). Sixty-minute epochs of data from each infant were studied using wavelet analysis at a mean age of 48 h. Wavelet semblance (a measure of phase difference) was calculated to compare reactivity between mean arterial blood pressure (MABP) with oxCCO, HbD and HbT. OxCCO-MABP semblance correlated with thalamic Lac/NAA (r = 0.48, p = 0.02). OxCCO-MABP semblance also differed between groups of infants with mild to moderate and severe injury measured using brain MRI score (p = 0.04), thalamic Lac/NAA (p = 0.04) and neurodevelopmental outcome at one year (p = 0.04). Pressure passive changes in cerebral metabolism were associated with injury severity indicated by thalamic Lac/NAA, MRI scores and neurodevelopmental assessment at one year of age.

To determine (a) whether diffuse white matter injury of prematurity is associated with an increased choline (Cho)-to-creatine (Cr) ratio and a reduced N-acetylaspartate (NAA)-to-Cho ratio and whether these measures can be used as biomarkers of outcome and (b) if changes in peak area metabolite ratios at magnetic resonance (MR) spectroscopy are associated with changes in T2 and fractional anisotropy (FA) at MR imaging.The local ethics committee approved this study, and informed parental consent was obtained for each infant. At term-equivalent age, 43 infants born at less than 32 weeks gestation underwent conventional and quantitative diffusion-tensor and T2-weighted MR imaging. Single-voxel point-resolved proton (hydrogen 1) MR spectroscopy was performed from a 2-cm(3) voxel centered in the posterior periventricular white matter. Outcome was evaluated by using Bayley scales at a corrected age of 1 year. Associations were investigated with Pearson product moment or Spearman rank order correlation. Differences in ratios in infants with and infants without impairment were tested by using t tests.NAA/Cho and Cho/Cr ratios correlated with the scaled gross motor score and the composite motor score, independent of gestational age (P.05). FA at diffusion-tensor MR imaging and T2 at MR imaging correlated with the NAA/Cho ratio (P.05 for both) but not with the Cho/Cr ratio. Infants with motor scores of less than 85 (impaired) had an increased Cho/Cr ratio (P.03) and a reduced NAA/Cho ratio (P.01) compared to those without impairment. A combination of increased Cho/Cr ratio and decreased NAA/Cho ratio predicted impaired motor outcome at a corrected age of 1 year with a sensitivity of 0.80 (95% confidence interval [CI]: 0.57, 0.94) and a specificity of 0.80 (95% CI: 0.66, 0.88).The combination of Cho/Cr and NAA/Cho ratios measured in the posterior periventricular white matter at term-equivalent age is predictive of motor outcome at 1 year in infants born at less than 32 weeks gestation.

ObjectiveBrain proton (1H) magnetic resonance spectroscopy (MRS) lactate/N-acetylaspartate (Lac/NAA) peak area ratio is used for prognostication in neonatal encephalopathy (NE). At 3 Tesla in NE babies, the objectives were to assess: (1) sensitivity and specificity of basal ganglia and thalamus (BGT) 1H MRS Lac/NAA for the prediction of Bayley III outcomes at 2 years using optimised metabolite fitting (Tarquin) with threonine and total NAA; (2) prediction of motor outcome with diffusion-weighted MRI; (3) BGT Lac/NAA correlation with the National Institute of Child Health and Human Development (NICHD) MRI score.Subjects and methods55 (16 inborn, 39 outborn) infants at 39w+5 d (35w+5d–42w+0d) with NE admitted between February 2012 and August 2014 to University College London Hospitals for therapeutic hypothermia underwent MRI and 1H MRS at 3T on day 2–14 (median day 5). MRIs were scored. Bayley III was assessed at 24 (22–26) months.Results16 babies died (1 inborn, 15 outborn); 20, 19 and 21 babies had poor motor, cognitive and language outcomes. Using a threshold of 0.39, sensitivity and specificity of BGT Lac/NAA for 2-year motor outcome was 100% and 97%, cognition 90% and 97% and language 81% and 97%, respectively. Sensitivity and specificity for motor outcome of mean diffusivity (threshold 0.001 mm2/s) up to day 9 was 72% and 100% and fractional anisotropy (threshold 0.198) was 39% and 94%, respectively. Lac/NAA correlated with BGT injury on NICHD scores (2A, 2B, 3).ConclusionBGT Lac/NAA on 1H MRS at 3T within 14 days accurately predicts 2-year motor, cognitive and language outcome and may be a marker directing decisions for therapies after cooling.

Background Between 4% and 25% of school-age children complain of recurrent abdominal pain (RAP) of sufficient severity to interfere with daily activities. It is unclear whether the diagnosis includes children with different aetiologies for their pain. For the majority no organic cause for their pain can be found on physical examination or investigation. Although most children are likely managed by reassurance and simple measures, a large range of interventions have been recommended. Objectives To determine the effectiveness of dietary interventions for recurrent abdominal pain in school-age children. Search strategy The Cochrane Library (CENTRAL) 2006 (Issue 4), MEDLINE (1966 to Dec 2006), EMBASE (1980 to Dec 2006), CINAHL (1982 to Dec 2007), ERIC (1966 to Dec 2006), PsycINFO (1872 to Dec 2006), LILACS (1982 to Dec 2006), SIGLE (1980 to March 2005), and JICST (1985 to 06/2000) were searched . Where appropriate, search filters were employed. Researchers working in this area were asked to identify relevant studies. Selection criteria Randomised or quasi-randomised studies of any dietary treatment versus placebo or no treatment in school-age children with a diagnosis of RAP or functional gastrointestinal disorder based on the Rome II criteria. Data collection and analysis Two authors independently assessed trials for inclusion, assessed quality and extracted data. Where appropriate studies were pooled using a random effects meta-analysis. Main results Seven trials were included in this review. Two trials, including 83 participants, compared fibre supplements with placebo (Christensen 1982, Feldman 1985), with data from one study reported in two papers (Christensen 1982, Christensen 1986). The pooled odds ratio for improvement in the frequency of abdominal pain was 1.26 (0.25, 6.29). Two trials, including 90 participants (Lebenthal 1981, Dearlove 1983) compared lactose-containing with lactose-free diets. Neither reported data in a form which could be used in the meta-analysis and the former trial had a loss to follow-up of 45%. We were not able to obtain further data for either trial. Three trials (Bausserman 2005, Gavronska 2007, Young 1997) comparing supplementation with Lactobacillus with placebo met the inclusion criteria but only two (Bausserman 2005, Gavronska 2007), including a total of 168 children, provided analysable data. The pooled odds ratio for improvement of symptoms was 1.17 (95% CI 0.62, 2.21). Authors' conclusions There is a lack of high quality evidence on the effectiveness of dietary interventions. This review provides no evidence that fibre supplements, lactose free diets or lactobacillus supplementation are effective in the management of children with RAP. Plain Language Summary Dietary interventions for stomach ache with no identifiable cause in children Recurrent abdominal pain is common in childhood and dietary interventions are often recommended but we found no evidence that they are effective. Between 4% and 25% of school age children complain of stomach aches / recurrent abdominal pain (RAP) which is severe enough to interfere with their daily activities. For most such children, no organic cause for their pain can be found on physical examination or investigation. Although most children are likely to be managed by reassurance and simple measures, a large range of interventions including dietary manipulation has been recommended. Recently it has been suggested that children previously described as having RAP should be classified according to the pattern of symptoms into a series of sub-groups (the Rome II criteria) including irritable bowel syndrome, functional dyspepsia, functional abdominal pain and abdominal migraine. It is not clear whether these categories describe conditions that really differ in either aetiology or responsiveness to treatment but in updating the review we included studies which used these criteria to select participants as well as those using the traditional diagnosis of RAP. This review attempted to determine the effectiveness of dietary interventions. When the original version was published, only four trials fit the inclusion criteria for the review, two of which looked at fibre supplements and two of which looked at lactose-restriction diets. Results suggest little evidence of effect for either treatment. However, as these results were only reported in a few small trials, the reviewers suggested that more research was needed. In this updated version we found three further trials, all testing the effectiveness of probiotics such as lactobacillus which some studies have suggested may be of benefit in adults with irritable bowel syndrome. One was reported only as an abstract that could not be analysed because of lack of data. These trials provided no clear evidence of any benefit from the use of probiotics in these children, including those classified under the Rome II criteria as having irritable bowel syndrome.

Summary Magnetic resonance (MR) techniques have revolutionized the assessment of brain development and injury in the newborn. MR studies at 3 T or above are becoming widespread; however, given the high cost and complexity of high-field MR systems, it is important to assess their benefits and limitations for clinical practice. MR spectroscopy (MRS) studies at high field carry potential benefits such as improved signal-to-noise ratio (SNR) and chemical shift dispersion compared with 1.5 T. However, safety is a very important consideration as radiofrequency (RF) tissue heating and acoustic noise also increase with field strength. Furthermore, increased chemical-shift dependence of the position of the volume of interest (VOI), shorter transverse and longer longitudinal relaxation times constitute additional challenges. We describe the first in-vivo, proton MRS studies of newborn human brain at 4.7 T. Nine infants with neonatal encephalopathy, all ventilated and with continuous physiological monitoring, were studied. We used L-FOCI localization, mostly with a VOI centred on the thalami. The absence of 4.7 T results from healthy infants made it impossible to interpret pathological metabolite peak-area ratios. However, concentration ratios and concentrations should be field-strength independent and interpretable using control values acquired at lower field. Of eight infants with concentration-ratio measurements, seven had low [N-acetylaspartate (NAA)]/[choline (Cho)] and three increased [lactate]/[NAA]. Of the two infants with ‘concentration’ measurements both had low [NAA] and one reduced [creatine]. We used an adult coil and consequent RF power restrictions had repercussions for the minimum magnetization recovery time (TR). A smaller, neonatal coil should improve SNR and, with less RF power, relax TR constraints thereby enabling fuller exploitation of the potential of high-field MRS.

Introduction Despite cooling, adverse outcomes are seen in up to half of the surviving infants after neonatal encephalopathy. A number of novel adjunct drug therapies with cooling have been shown to be highly neuroprotective in animal studies, and are currently awaiting clinical translation. Rigorous evaluation of these therapies in phase II trials using surrogate MR biomarkers may speed up their bench to bedside translation. A recent systematic review of single-centre studies has suggested that MR spectroscopy biomarkers offer the best promise; however, the prognostic accuracy of these biomarkers in cooled encephalopathic babies in a multicentre setting using different MR scan makers is not known. Methods and analysis The MR scanners (3 T; Philips, Siemens, GE) in all the participating sites will be harmonised using phantom experiments and healthy adult volunteers before the start of the study. We will then recruit 180 encephalopathic infants treated with whole body cooling from the participating centres. MRI and spectroscopy will be performed within 2 weeks of birth. Neurodevelopmental outcomes will be assessed at 18–24 months of age. Agreement between MR cerebral biomarkers and neurodevelopmental outcome will be reported. The sample size is calculated using the ‘rule of 10’, generally used to calculate the sample size requirements for developing prognostic models. Considering 9 parameters, we require 9×10 adverse events, which suggest that a total sample size of 180 is required. Ethics and dissemination Human Research Ethics Committee approvals have been received from Brent Research Ethics Committee (London), and from Imperial College London (Sponsor). We will submit the results of the study to relevant journals and offer national and international presentations. Trial registration number Clinical Trials.gov Number: NCT01309711.

Aim To observe signs of gastrointestinal dysmotility [gastric residual volume (GRV*), bile stained aspirates (BSA), abdominal distension (AD^), first passage of meconium (FPOM), and time to regular bowel habit (RBH)] whilst establishing enteral feeds. To examine how these signs were used to suggest diagnosis of NEC. Methods From April–October 2013, intestinal motility data on all preterm infants ≤32 weeks was prospectively observed from birth-14 days old or until tolerating full enteral feeds (150 ml/kg/day) if sooner. Results GRV, BSA and AD were common: (39/65 (60%), 37/65 (57%) and 17/65 (26%) respectively) and significantly prolonged time to full feeds: (median [IQR] (days) 13 [11–18] P = 0.0003, 13 [11–21] P = 0.0002 and 21 [12–28] P = 0.0001 respectively). Cox regression, adjusting for birth weight, showed each sign was a significant independent predictor of time to full feeds. Moreover, the number of signs in the first week following feed introduction predicted time to full feeds (Figure). Neither GRV nor BSA occurred more frequently in the NEC treatment group, but AD did (p = 0.002). Morphine had a stronger effect than gestational age on FPOM (P Conclusion Functional intestinal dysmotility of the preterm infant is readily observed through GRV, BSA and AD soon after birth and should be considered, in the first two weeks of life, as possibly physiological before stopping enteral feeds or commencing NEC treatment.