Essential variables for reporting research studies on fetal growth restriction: a Delphi consensus.

OBJECTIVE: To determine, by expert consensus using a Delphi procedure, a minimum reporting set of study variables for fetal growth restriction (FGR) research studies. METHODS: A panel of experts, identified based on their publication record as lead or senior author of studies on FGR, was asked to select a set of essential reporting study parameters from a literature-based list of variables, utilizing the Delphi consensus methodology. Responses were collected in four consecutive rounds by online questionnaires presented to the panelists through a unique token-secured link for each round. The experts were asked to rate the importance of each parameter on a five-point Likert scale. Variables were selected in the three first rounds based on a 70% threshold for agreement on the Likert-scale scoring. In the final round, retained parameters were categorized as essential (to be reported in all FGR studies) or recommended (important but not mandatory). RESULTS: Of the 100 invited experts, 87 agreed to participate and of these 62 (71%) completed all four rounds. Agreement was reached for 16 essential and 30 recommended parameters including maternal characteristics, prenatal investigations, prenatal management and pregnancy/neonatal outcomes. Essential parameters included hypertensive complication in the current pregnancy, smoking, parity, maternal age, fetal abdominal circumference, estimated fetal weight, umbilical artery Doppler (pulsatility index and end-diastolic flow), fetal middle cerebral artery Doppler, indications for intervention, pregnancy outcome (live birth, stillbirth or neonatal death), gestational age at delivery, birth weight, birth-weight centile, mode of delivery and 5-min Apgar score. CONCLUSIONS: We present a list of essential and recommended parameters that characterize FGR independent of study hypotheses. Uniform reporting of these variables in prospective clinical research is expected to improve data quality, study consistency and ultimately our understanding of FGR. Copyright © 2018 ISUOG. Published by John Wiley & Sons Ltd.

Somatosensory function and pain in extremely preterm young adults from the UK EPICure cohort: sex-dependent differences and impact of neonatal surgery.

BACKGROUND: Surgery or multiple procedural interventions in extremely preterm neonates influence neurodevelopmental outcome and may be associated with long-term changes in somatosensory function or pain response. METHODS: This observational study recruited extremely preterm (EP, <26 weeks' gestation; n=102, 60% female) and term-born controls (TC; n=48) aged 18-20 yr from the UK EPICure cohort. Thirty EP but no TC participants had neonatal surgery. Evaluation included: quantitative sensory testing (thenar eminence, chest wall); clinical pain history; questionnaires (intelligence quotient; pain catastrophising; anxiety); and structural brain imaging. RESULTS: Reduced thermal threshold sensitivity in EP vs TC participants persisted at age 18-20 yr. Sex-dependent effects varied with stimulus intensity and were enhanced by neonatal surgery, with reduced threshold sensitivity in EP surgery males but increased sensitivity to prolonged noxious cold in EP surgery females (P<0.01). Sex-dependent differences in thermal sensitivity correlated with smaller amygdala volume (P<0.05) but not current intelligence quotient. While generalised decreased sensitivity encompassed mechanical and thermal modalities in EP surgery males, a mixed pattern of sensory loss and sensory gain persisted adjacent to neonatal scars in males and females. More EP participants reported moderate-severe recurrent pain (22/101 vs 4/48; χ2=0.04) and increased pain intensity correlated with higher anxiety and pain catastrophising. CONCLUSIONS: After preterm birth and neonatal surgery, different patterns of generalised and local scar-related alterations in somatosensory function persist into early adulthood. Sex-dependent changes in generalised sensitivity may reflect central modulation by affective circuits. Early life experience and sex/gender should be considered when evaluating somatosensory function, pain experience, or future chronic pain risk.

The future of UK healthcare: problems and potential solutions to a system in crisis.

The UK's Health System is in crisis, central funding no longer keeping pace with demand. Traditional responses-spending more, seeking efficiency savings or invoking market forces-are not solutions. The health of our nation demands urgent delivery of a radical new model, negotiated openly between public, policymakers and healthcare professionals. Such a model could focus on disease prevention, modifying health behaviour and implementing change in public policy in fields traditionally considered unrelated to health such as transport, food and advertising. The true cost-effectiveness of healthcare interventions must be balanced against the opportunity cost of their implementation, bolstering the central role of NICE in such decisions. Without such action, the prognosis for our healthcare system-and for the health of the individuals it serves-may be poor. Here, we explore such a new prescription for our national health.

Non-technical skills of surgical trainees and experienced surgeons.

BACKGROUND: In addition to technical expertise, surgical competence requires effective non-technical skills to ensure patient safety and maintenance of standards. Recently the Royal Australasian College of Surgeons implemented a new Surgical Education and Training (SET) curriculum that incorporated non-technical skills considered essential for a competent surgeon. This study sought to compare the non-technical skills of experienced surgeons who completed their training before the introduction of SET with the non-technical skills of more recent trainees. METHODS: Surgical trainees and experienced surgeons undertook a simulated scenario designed to challenge their non-technical skills. Scenarios were video recorded and participants were assessed using the Non-Technical Skills for Surgeons (NOTSS) scoring system. Participants were divided into subgroups according to years of experience and their NOTSS scores were compared. RESULTS: For most NOTSS elements, mean scores increased initially, peaking around the time of Fellowship, before decreasing roughly linearly over time. There was a significant downward trend in score with increasing years since being awarded Fellowship for six of the 12 NOTSS elements: considering options (score -0·015 units per year), implementing and reviewing decisions (-0·020 per year), establishing a shared understanding (-0·014 per year), setting and maintaining standards (-0·024 per year), supporting others (-0·031 per year) and coping with pressure (-0·015 per year). CONCLUSION: The drop in NOTSS score was unexpected and highlights that even experienced surgeons are not immune to deficiencies in non-technical skills. Consideration should be given to continuing professional development programmes focusing on non-technical skills, regardless of the level of professional experience.

The association of neonatal morbidity with long-term neurological outcome in infants who were growth restricted and preterm at birth: secondary analyses from TRUFFLE (Trial of Randomized Umbilical and Fetal Flow in Europe).

OBJECTIVE: To study the relationship between neonatal morbidity (NNM) and two-year neurodevelopmental impairment (NDI) in surviving children after early fetal growth restriction (FGR). DESIGN: Secondary analysis of a European randomised trial (TRUFFLE) of delivery for very preterm fetuses dependent on venous Doppler or cardiotocographic criteria. SETTING: Tertiary perinatal centres, participants in TRUFFLE. POPULATION: 402 surviving children after early FGR. METHODS: Prospective data were collection from the recognition of FGR until the corrected age of two years. We studied the association between NNM and NDI, retaining trial allocation in all statistical models. NNM included any of bronchopulmonary dysplasia, brain injury, sepsis or necrotising enterocolitis. NDI was a composite of Bayley cognitive score < 85, cerebral palsy or severe sensory impairment. MAIN OUTCOME MEASURE: NDI in relation to NNM. RESULTS: NNM occurred in 104 cases (26%) and was more frequent in 17 of 39 infants with NDI (44%) than in the 87 of 363 infants with normal outcome (24%) [odds ratio 2.5 (95% CI, 1.3-4.8); P = 0.01]. In 22 of 39 NDI cases (56%) there was no preceding NNM. NNM was inversely related to gestational age, but NDI did not vary by gestational age. In multivariable analyses, cerebral ultrasound abnormalities were most strongly associated with NDI, together with trial group allocation, birthweight ratio, infant sex and Apgar score. CONCLUSIONS: With the exception of cerebral ultrasound abnormalities, commonly used NNMs are poor markers of later NDI and should not be used as surrogate outcomes for NDI. TWEETABLE ABSTRACT: Neonatal morbidities cannot be used as surrogate outcomes for neurodevelopmental impairment.

The effects of designation and volume of neonatal care on mortality and morbidity outcomes of very preterm infants in England: retrospective population-based cohort study.

OBJECTIVE: To examine the effects of designation and volume of neonatal care at the hospital of birth on mortality and morbidity outcomes in very preterm infants in a managed clinical network setting. DESIGN: A retrospective, population-based analysis of operational clinical data using adjusted logistic regression and instrumental variables (IV) analyses. SETTING: 165 National Health Service neonatal units in England contributing data to the National Neonatal Research Database at the Neonatal Data Analysis Unit and participating in the Neonatal Economic, Staffing and Clinical Outcomes Project. PARTICIPANTS: 20 554 infants born at <33 weeks completed gestation (17 995 born at 27-32 weeks; 2559 born at <27 weeks), admitted to neonatal care and either discharged or died, over the period 1 January 2009-31 December 2011. INTERVENTION: Tertiary designation or high-volume neonatal care at the hospital of birth. OUTCOMES: Neonatal mortality, any in-hospital mortality, surgery for necrotising enterocolitis, surgery for retinopathy of prematurity, bronchopulmonary dysplasia and postmenstrual age at discharge. RESULTS: Infants born at <33 weeks gestation and admitted to a high-volume neonatal unit at the hospital of birth were at reduced odds of neonatal mortality (IV regression odds ratio (OR) 0.70, 95% CI 0.53 to 0.92) and any in-hospital mortality (IV regression OR 0.68, 95% CI 0.54 to 0.85). The effect of volume on any in-hospital mortality was most acute among infants born at <27 weeks gestation (IV regression OR 0.51, 95% CI 0.33 to 0.79). A negative association between tertiary-level unit designation and mortality was also observed with adjusted logistic regression for infants born at <27 weeks gestation. CONCLUSIONS: High-volume neonatal care provided at the hospital of birth may protect against in-hospital mortality in very preterm infants. Future developments of neonatal services should promote delivery of very preterm infants at hospitals with high-volume neonatal units.

Perinatal morbidity and mortality in early-onset fetal growth restriction: cohort outcomes of the trial of randomized umbilical and fetal flow in Europe (TRUFFLE).

OBJECTIVES: Few data exist for counseling and perinatal management of women after an antenatal diagnosis of early-onset fetal growth restriction. Yet, the consequences of preterm delivery and its attendant morbidity for both mother and baby are far reaching. The objective of this study was to describe perinatal morbidity and mortality following early-onset fetal growth restriction based on time of antenatal diagnosis and delivery. METHODS: We report cohort outcomes for a prospective multicenter randomized management study of fetal growth restriction (Trial of Randomized Umbilical and Fetal Flow in Europe (TRUFFLE)) performed in 20 European perinatal centers between 2005 and 2010. Women with a singleton fetus at 26-32 weeks of gestation, with abdominal circumference < 10(th) percentile and umbilical artery Doppler pulsatility index > 95(th) percentile, were recruited. The main outcome measure was a composite of fetal or neonatal death or severe morbidity: survival to discharge with severe brain injury, bronchopulmonary dysplasia, proven neonatal sepsis or necrotizing enterocolitis. RESULTS: Five-hundred and three of 542 eligible women formed the study group. Mean ± SD gestational age at diagnosis was 29 ± 1.6 weeks and mean ± SD estimated fetal weight was 881 ± 217 g; 12 (2.4%) babies died in utero. Gestational age at delivery was 30.7 ± 2.3 weeks, and birth weight was 1013 ± 321 g. Overall, 81% of deliveries were indicated by fetal condition and 97% were by Cesarean section. Of 491 liveborn babies, outcomes were available for 490 amongst whom there were 27 (5.5%) deaths and 118 (24%) babies suffered severe morbidity. These babies were smaller at birth (867 ± 251 g) and born earlier (29.6 ± 2.0 weeks). Death and severe morbidity were significantly related to gestational age, both at study entry and delivery and also with the presence of maternal hypertensive morbidity. The median time to delivery was 13 days for women without hypertension, 8 days for those with gestational hypertension, 4 days for pre-eclampsia and 3 days for HELLP syndrome. CONCLUSIONS: Fetal outcome in this study was better than expected from contemporary reports: perinatal death was uncommon (8%) and 70% survived without severe neonatal morbidity. The intervals to delivery, death and severe morbidity were related to the presence and severity of maternal hypertensive conditions.

Nature and severity of lung function abnormalities in extremely pre-term children at 11 years of age.

Advances in neonatal care have resulted in increased survival of children born extremely pre-term (EP). Nevertheless the incidence of bronchopulmonary dysplasia and long-term respiratory morbidity remains high. We investigated the nature of pathophysiological changes at 11 yrs of age to ascertain whether respiratory morbidity in EP children primarily reflects alterations in the lung periphery or more centralised airway function in this population. Spirometry, plethysmography, diffusing capacity, exhaled nitric oxide, multiple-breath washout, skin tests and methacholine challenge were used during laboratory-based assessments in a subgroup of the 1995 EPICure cohort and in controls. Results were obtained in 49 EP and 52 control children. Lung function abnormalities were found in 78% of EP children, with evidence of airway obstruction, ventilation inhomogeneity, gas trapping and airway hyperresponsiveness. Levels of atopy and exhaled nitric oxide were similar between the groups. Prior wheeze was associated with significant reductions in forced flows and volumes. By contrast, abnormalities of the lung periphery appear to be mediated primarily through EP birth per se. The prevalence of lung function abnormalities, which is largely obstructive in nature and likely to have long-term implications, remains high among 11-yr-old children born EP. Spirometry proved an effective means of detecting these persistent abnormalities.

Effect of hospital and surgeon volume on patient outcomes following treatment of abdominal aortic aneurysms: a systematic review.

OBJECTIVES: This systematic review assessed the efficacy of centralisation for the treatment of unruptured and ruptured abdominal aortic aneurysms. Patient outcomes achieved by low and high volume hospitals/surgeons, including morbidity, mortality and length of hospital stay, were used as proxy measures of efficacy. DESIGN: Systematic review was designed to identify, assess and report on peer-reviewed articles reporting outcomes from unruptured and ruptured abdominal aortic aneurysms. No language restriction was placed on the databases searched. MATERIALS: Only peer-reviewed journals articles were included. METHODS: To ensure the contemporary nature of this review, only studies published between January 1997 and June 2007 were sought. Studies were included if they reported on at least one volume type and patient outcome. RESULTS: Twenty two studies were included in this review. In the majority of group assessments, the number of studies reporting statistical significance was similar to the number of studies reporting no statistical significance. CONCLUSION: The paucity of studies reporting statistically significant results demonstrates that although this evidence exists, its potential to be overstated must also be taken into account when drawing conclusions as to its efficacy for twenty first century healthcare systems.

Respiratory health in pre-school and school age children following extremely preterm birth.

RATIONALE: Increasing survival at extremely low gestational ages is associated with very high rates of bronchopulmonary dysplasia (BPD) but is rarely quantified. OBJECTIVES: To identify respiratory morbidity and risk factors in the EPICure cohort over the first 6 years of life. METHODS: 308 babies born at < or =25 weeks' gestation in 1995 were followed up at 30 months and 6 years of age. Respiratory outcome was evaluated using clinical assessment, parental questionnaire and peak expiratory flow (PEF) at 6 years. RESULTS: 74% of this population received supplemental oxygen at 36 weeks postmenstrual age and 36% were discharged with supplemental oxygen which continued for a median of 2.5 months (75th percentile: 8.5 months). 236 children were followed to 6 years. Respiratory symptoms and medication use were more prevalent at 30 months and 6 years in children with BPD compared to those without. Children without BPD (n = 56) were not significantly different from their classmates but had consistently higher prevalence of poor respiratory health. Symptoms, need for hospital admission and medication use declined between 30 months and 6 years. 200 index children completed three PEF measures; PEF was lower than in classmates (mean adjusted difference: 39 l/min (95% CI 30 to 47)) and was lowest in children discharged home with oxygen and in those with BPD. Gestational age, BPD and maternal smoking at home and in pregnancy were independent risk factors for symptoms, but BPD was the only independent associate of PEF. CONCLUSION: Extremely preterm children have a continuum of poor respiratory health over the first 6 years, which is exacerbated by smoking during pregnancy and in the home.

The EPICure study: growth and blood pressure at 6 years of age following extremely preterm birth.

BACKGROUND: Preterm children are at risk for reduced growth in early childhood, which may predispose them to later changes in blood pressure (BP). OBJECTIVE: To study growth and BP in extremely preterm (EP) children at age 6 years. METHODS: Children who were born at 25 completed weeks of gestation or less in the United Kingdom and Ireland in 1995 were evaluated when they reached early school age. Children underwent standardised assessments, including auxology and sitting BP. RESULTS: Of 308 surviving children, 241 (78%) were assessed at a median age of 6 years 4 months; 160 full-term classmates acted as a comparison group. Compared with classmates, EP children were 1.2 standard deviations (SDs) lighter, 0.97 SD shorter, body mass index (BMI) was 0.95 SD lower and head circumference 1.3 SD lower. Compared with 2.5 years of age, EP children had shown "catch-up" in their weight by 0.37 SD, height by 0.42 SD and head circumference by 0.13 SD. Systolic and diastolic BP were lower by 2.3 mm Hg and 2.4 mm Hg, respectively, in EP children, but these differences were accounted for by differences in height and BMI. Maternal smoking in pregnancy was associated with lower BP. Children born before 24 weeks had higher systolic pressures and children given postnatal steroids higher diastolic pressures. CONCLUSIONS: Poor postnatal growth seen after birth and in the third year persists into school age. Catch-up growth reduces some of the early deficit but is least for head growth. Despite serious postnatal growth restriction BP appears similar in both EP and term classmates.

Frequent wheeze at follow up of very preterm infants: which factors are predictive?

OBJECTIVE: To determine if chest radiograph appearance at 28 days or 36 weeks postmenstrual age (PMA) can predict recurrent wheeze or cough at follow up in prematurely born infants more effectively than readily available clinical data. DESIGN: Chest radiographs of infants entered into the UKOS trial, who had had a chest radiograph at 28 days and 36 weeks PMA and completed six months of follow up, were assessed for the presence of fibrosis, interstitial shadows, cystic elements, and hyperinflation. At 6 months of corrected age, the occurrence and frequency of wheeze and cough since discharge were determined using a symptom questionnaire. PATIENTS: A total of 185 infants with a median gestational age of 26 (range 23-28) weeks. RESULTS: Thirty seven infants wheezed more than once a week, compared with the rest of the cohort. These infants had significantly higher chest radiograph scores at 28 days (p = 0.020) and 36 weeks PMA (p = 0.005), with significantly higher scores at 28 days for fibrosis (p = 0.017) and at 36 weeks PMA for fibrosis (p = 0.001) and cystic elements (p = 0.0007). They had also been ventilated for longer (p = 0.013). Forty four infants coughed more than once a week; they did not differ significantly from the rest of the cohort. An abnormal chest radiograph score at 36 weeks PMA had the largest area under the receiver operator characteristic curve with regard to prediction of frequent wheeze. CONCLUSION: An abnormal chest radiograph appearance at 36 weeks PMA predicts frequent wheeze at follow up and appears to be a better predictor than readily available clinical data.

The EPICure study: outcomes to discharge from hospital for infants born at the threshold of viability.

OBJECTIVE: To evaluate the outcome for all infants born before 26 weeks of gestation in the United Kingdom and the Republic of Ireland. This report is of survival and complications up until discharge from hospital. METHODOLOGY: A prospective observational study of all births between March 1, 1995 and December 31, 1995 from 20 to 25 weeks of gestation. RESULTS: A total of 4004 births were recorded, and 811 infants were admitted for intensive care. Overall survival was 39% (n = 314). Male sex, no reported chorioamnionitis, no antenatal steroids, persistent bradycardia at 5 minutes, hypothermia, and high Clinical Risk Index for Babies (CRIB) score were all independently associated with death. Of the survivors, 17% had parenchymal cysts and/or hydrocephalus, 14% received treatment for retinopathy of prematurity (ROP), and 51% needed supplementary oxygen at the expected date of delivery. Failure to administer antenatal steroids and postnatal transfer for intensive care within 24 hours of birth were predictive of major scan abnormality; lower gestation was predictive of severe ROP, while being born to a black mother was protective. Being of lower gestation, male sex, tocolysis, low maternal age, neonatal hypothermia, a high CRIB score, and surfactant therapy were all predictive of oxygen dependency. Intensive care was provided in 137 units, only 8 of which had >5 survivors. There was no difference in survival between institutions when divided into quintiles based on their numbers of extremely preterm births or admissions. CONCLUSIONS: This study provides outcome data for this geographically defined cohort; survival and neonatal morbidity are consistent with previous data from the United Kingdom and facilitate comparison with other geographically based data.

Phase I study of intraventricular recombinant tissue plasminogen activator for treatment of posthaemorrhagic hydrocephalus.

AIM: Phase I study to evaluate intraventricular fibrinolytic treatment with recombinant tissue plasminogen activator (tPA) as a method of clearing blood from the cerebrospinal fluid, and thus preventing permanent hydrocephalus. METHODS: Twenty two preterm infants, aged 7 to 26 days, with progressive posthaemorrhagic ventricular dilatation (ventricular width > 4 mm over 97th centile) received one to five intraventricular bolus injections of 1.0 mg or 0.5 mg tPA at intervals of one to seven days. RESULTS: The mean cerebrospinal fluid concentration of tPA 24 hours after 1 mg was 1860 micrograms/ml. The half life of tPA in cerebrospinal fluid was about 24 hours. Twenty one (95%) infants survived, 12 (55%) without shunt surgery. One infant had secondary intraventricular haemorrhage. CONCLUSION: Intraventricular tPA resulted in survival without a shunt for most of the infants, but with some risk. Failure may have been due to plasminogen deficiency, an inhibitor, or late intervention.

Omenn's disease.

The importance of accurate pathological diagnosis is emphasised in the case of a newborn infant who presented with alopecia, a generalised erythrodermatous skin eruption, and hepatosplenomegaly. She subsequently developed generalised lymphadenopathy and recurrent septicaemia and died aged 2 months. The histological findings of widespread lymphocytic, histiocytic, and eosinophilic tissue infiltration, associated with thymic hypoplasia, were consistent with autosomal recessive Omenn's disease.