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Objective We evaluated the best time to initiate delivery in late preterm pre-eclampsia in order to optimise long-term infant and maternal outcomes. Design Parallel-group, non-masked, randomised controlled trial. Setting Forty-six maternity units in the UK. Population Women with pre-eclampsia between 34+0 and 36+6 weeks of gestation, without severe disease, were randomised to planned delivery or expectant management. Main outcome measures Infant neurodevelopmental outcome at 2 years of age, using the Parent Report of Children’s Abilities – Revised (PARCA-R) composite score. Results Between 29 September 2014 and 10 December 2018, 901 women were enrolled in the trial, with 450 women allocated to planned delivery and 451 women allocated to expectant management. At the 2-year follow-up, the intention-to-treat analysis population included 276 women (290 infants) allocated to planned delivery and 251 women (256 infants) allocated to expectant management. The mean composite standardised PARCA-R scores were 89.5 (SD 18.2) in the planned delivery group and 91.9 (SD 18.4) in the expectant management group, with an adjusted mean difference of −2.4 points (95% CI −5.4 to 0.5 points). Conclusions In infants of women with late preterm pre-eclampsia, the average neurodevelopmental assessment at 2 years lies within the normal range, regardless of whether planned delivery or expectant management was pursued. With the lower than anticipated follow-up rate there was limited power to demonstrate that these scores did not differ, but the small between-group difference in PARCA-R scores is unlikely to be clinically important.

Background A recent randomized controlled trial of prophylactic antibiotics for the prevention of infection following operative vaginal birth showed that women allocated prophylactic intravenous amoxicillin and clavulanic acid had a significantly lower risk of developing confirmed or suspected infection within 6 weeks after operative vaginal birth (risk ratio [RR], 0.58; 95% confidence interval [CI], 0.49–0.69; P < .001). Some international and national guidelines have subsequently been updated to include prophylactic antibiotics after operative vaginal birth. However, the generalizability of the trial results may be limited in settings where the episiotomy rate is lower (89% of women in the trial had an episiotomy). In addition, there was a high burden of infection in the prophylactic antibiotics group despite the administration of prophylactic antibiotics. It is essential to identify modifiable risk factors for infection after operative vaginal birth, including the timing of antibiotic administration. Objective This study aimed to evaluate if the effectiveness of the prophylactic antibiotic in reducing confirmed or suspected infection was independent of perineal trauma, identify risk factors for infection after operative vaginal birth, and investigate variation in efficacy with the timing of antibiotic administration. Study Design This study was a secondary analysis of 3225 women with primary outcome data from the prophylactic antibiotics for the prevention of infection following operative vaginal birth randomized controlled trial. Women were divided into subgroups according to the perineal trauma experienced (episiotomy and/or perineal tear). The consistency of the prophylactic antibiotics in preventing infection across the subgroups was assessed using log-binomial regression and the likelihood ratio test. Multivariable log-binomial regression was used to investigate factors associated with infection. The multivariable risk factor model was subsequently fitted to the group of women who received amoxicillin and clavulanic acid to investigate the timing of antibiotic administration. Results Of the 3225 women included in the secondary analysis, 2144 (66.5%) had an episiotomy alone, 726 (22.5%) had an episiotomy and a tear, 277 (8.6%) had a tear alone, and 78 (2.4%) had neither episiotomy nor tear. Among women who experienced perineal trauma, amoxicillin and clavulanic acid administration was protective against infection in all subgroups compared with placebo with no significant interaction between subgroup and trial allocation (P=.17). Moreover, 2925 women were included in the multivariable risk factor analysis. The following were associated with adjusted risk ratios of infection: episiotomy, 2.94 (95% confidence interval, 1.62–5.31); forceps, 1.37 (95% confidence interval, 1.12–1.69) compared to vacuum extraction; primiparity, 1.34 (95% confidence interval, 1.05–1.70); amoxicillin and clavulanic acid administration, 0.60 (95% confidence interval, 0.51–0.72); body mass index of 25.0 to 29.9 kg/m2, 1.21 (95% confidence interval, 1.00–1.47), and body mass index of ≥30 kg/m2, 1.22 (95% confidence interval, 0.98–1.52) compared to body mass index of

STUDY QUESTION: Does a policy of elective freezing of embryos, followed by frozen embryo transfer result in a higher healthy baby rate, after first embryo transfer, when compared with the current policy of transferring fresh embryos? SUMMARY ANSWER: This study, although limited by sample size, provides no evidence to support the adoption of a routine policy of elective freeze in preference to fresh embryo transfer in order to improve IVF effectiveness in obtaining a healthy baby. WHAT IS KNOWN ALREADY: The policy of freezing all embryos followed by frozen embryo transfer is associated with a higher live birth rate for high responders but a similar/lower live birth after first embryo transfer and cumulative live birth rate for normal responders. Frozen embryo transfer is associated with a lower risk of ovarian hyperstimulation syndrome (OHSS), preterm delivery and low birthweight babies but a higher risk of large babies and pre-eclampsia. There is also uncertainty about long-term outcomes, hence shifting to a policy of elective freezing for all remains controversial given the delay in treatment and extra costs involved in freezing all embryos. STUDY DESIGN, SIZE, DURATION: A pragmatic two-arm parallel randomized controlled trial (E-Freeze) was conducted across 18 clinics in the UK from 2016 to 2019. A total of 619 couples were randomized (309 to elective freeze/310 to fresh). The primary outcome was a healthy baby after first embryo transfer (term, singleton live birth with appropriate weight for gestation); secondary outcomes included OHSS, live birth, clinical pregnancy, pregnancy complications and cost-effectiveness. PARTICIPANTS/MATERIALS, SETTING, METHODS: Couples undergoing their first, second or third cycle of IVF/ICSI treatment, with at least three good quality embryos on Day 3 where the female partner was ≥18 and MAIN RESULTS AND THE ROLE OF CHANCE: Of the 619 couples randomized, 307 and 309 couples in the elective freeze and fresh transfer arms, respectively, were included in the primary analysis. There was no evidence of a statistically significant difference in outcomes in the elective freeze group compared to the fresh embryo transfer group: healthy baby rate {20.3% (62/307) versus 24.4% (75/309); risk ratio (RR), 95% CI: 0.84, 0.62 to 1.15}; OHSS (3.6% versus 8.1%; RR, 99% CI: 0.44, 0.15 to 1.30); live birth rate (28.3% versus 34.3%; RR, 99% CI 0.83, 0.65 to 1.06); and miscarriage (14.3% versus 12.9%; RR, 99% CI: 1.09, 0.72 to 1.66). Adherence to allocation was poor in the elective freeze group. The elective freeze approach was more costly and was unlikely to be cost-effective in a UK National Health Service context. LIMITATIONS, REASONS FOR CAUTION: We have only reported on first embryo transfer after randomization; data on the cumulative live birth rate requires further follow-up. Planned target sample size was not obtained and the non-adherence to allocation rate was high among couples in the elective freeze arm owing to patient preference for fresh embryo transfer, but an analysis which took non-adherence into account showed similar results. WIDER IMPLICATIONS OF THE FINDINGS: Results from the E-Freeze trial do not lend support to the policy of electively freezing all for everyone, taking both efficacy, safety and costs considerations into account. This method should only be adopted if there is a definite clinical indication. STUDY FUNDING/COMPETING INTEREST(S): NIHR Health Technology Assessment programme (13/115/82). This research was funded by the National Institute for Health Research (NIHR) (NIHR unique award identifier) using UK aid from the UK Government to support global health research. The views expressed in this publication are those of the author(s) and not necessarily those of the NIHR or the UK Department of Health and Social Care. J.L.B., C.C., E.J., P.H., J.J.K., L.L. and G.S. report receipt of funding from NIHR, during the conduct of the study. J.L.B., E.J., P.H., K.S. and L.L. report receipt of funding from NIHR, during the conduct of the study and outside the submitted work. A.M. reports grants from NIHR personal fees from Merck Serono, personal fees for lectures from Merck Serono, Ferring and Cooks outside the submitted work; travel/meeting support from Ferring and Pharmasure and participation in a Ferring advisory board. S.B. reports receipt of royalties and licenses from Cambridge University Press, a board membership role for NHS Grampian and other financial or non-financial interests related to his roles as Editor-in-Chief of Human Reproduction Open and Editor and Contributing Author of Reproductive Medicine for the MRCOG, Cambridge University Press. D.B. reports grants from NIHR, during the conduct of the study; grants from European Commission, grants from Diabetes UK, grants from NIHR, grants from ESHRE, grants from MRC, outside the submitted work. Y.C. reports speaker fees from Merck Serono, and advisory board role for Merck Serono and shares in Complete Fertility. P.H. reports membership of the HTA Commissioning Committee. E.J. reports membership of the NHS England and NIHR Partnership Programme, membership of five Data Monitoring Committees (Chair of two), membership of six Trial Steering Committees (Chair of four), membership of the Northern Ireland Clinical Trials Unit Advisory Group and Chair of the board of Oxford Brain Health Clinical Trials Unit. R.M. reports consulting fees from Gedeon Richter, honorarium from Merck, support fees for attendance at educational events and conferences for Merck, Ferring, Bessins and Gedeon Richter, payments for participation on a Merck Safety or Advisory Board, Chair of the British Fertility Society and payments for an advisory role to the Human Fertilisation and Embryology Authority. G.S. reports travel and accommodation fees for attendance at a health economic advisory board from Merck KGaA, Darmstadt, Germany. N.R.-F. reports shares in Nurture Fertility. Other authors’ competing interests: none declared. TRIAL REGISTRATION NUMBER: ISRCTN: 61225414. TRIAL REGISTRATION DATE: 29 December 2015. DATE OF FIRST PATIENT’S ENROLMENT: 16 February 2016.

BackgroundVancomycin has been used in clinical practice for over 50 years; however, validated, pharmacokinetic (PK) data relating clinical outcomes to different dosing regimens in neonates are lacking. Coagulase negative staphylococci (CoNS) are the most commonly isolated organisms in neonatal, late-onset sepsis (LOS). Optimised use to maximise efficacy while minimising toxicity and resistance selection is imperative to ensure vancomycin’s continued efficacy.MethodsNeoVanc is a European, open-label, Phase IIb, randomised, controlled, non-inferiority trial comparing an optimised vancomycin regimen to a standard vancomycin regimen when treating LOS known/suspected to be caused by Gram-positive organisms (excludingStaphylococcus aureus) in infants aged ≤ 90 days. Three hundred infants will be recruited and randomised in a 1:1 ratio. Infants can be recruited if they have culture confirmed (a positive culture from a normally sterile site and at least one clinical/laboratory criterion) or clinical sepsis (presence of any ≥ 3 clinical/laboratory criteria) in the 24 h before randomisation.The optimised regimen consists of a vancomycin loading dose (25 mg/kg) followed by 5 ± 1 days of 15 mg/kg q12h or q8h, dependent on postmenstrual age (PMA). The standard regimen is a 10 ± 2 day vancomycin course at 15 mg/kg q24h, q12h or q8h, dependent on PMA.The primary endpoint is a successful outcome at the test of cure visit (10 ± 1 days after the end of vancomycin therapy). A successful outcome consists of the patient being alive, having successfully completed study vancomycin therapy and having not had a clinical/microbiological relapse/new infection requiring treatment with vancomycin or other anti-staphylococcal antibiotic for > 24 h.Secondary endpoints include clinical/microbiological relapse/new infection at the short-term follow-up visit (30 ± 5 days after the initiation of vancomycin), evaluation of safety (renal/hearing), vancomycin PK and assessment of a host biomarker panel over the course of vancomycin therapy.DiscussionBased on previous pre-clinical data and a large meta-analysis of neonatal, PK/pharmacodynamic data, NeoVanc was set up to provide evidence on whether a loading dose followed by a short vancomycin course is non-inferior, regarding efficacy, when compared to a standard, longer course. If non-inferiority is demonstrated, this would support adoption of the optimised regimen as a way of safely reducing vancomycin exposure when treating neonatal, Gram-positive LOS.Trial registrationClinicalTrials.gov,NCT02790996. Registered on 7 April 2016.EudraCT, 2015–000203-89. Entered on 18 July 2016.

BACKGROUND: Hydroxychloroquine and chloroquine have been proposed as treatments for coronavirus disease 2019 (Covid-19) on the basis of in vitro activity and data from uncontrolled studies and small, randomized trials. METHODS: In this randomized, controlled, open-label platform trial comparing a range of possible treatments with usual care in patients hospitalized with Covid-19, we randomly assigned 1561 patients to receive hydroxychloroquine and 3155 to receive usual care. The primary outcome was 28-day mortality. RESULTS: The enrollment of patients in the hydroxychloroquine group was closed on June 5, 2020, after an interim analysis determined that there was a lack of efficacy. Death within 28 days occurred in 421 patients (27.0%) in the hydroxychloroquine group and in 790 (25.0%) in the usual-care group (rate ratio, 1.09; 95% confidence interval [CI], 0.97 to 1.23; P=0.15). Consistent results were seen in all prespecified subgroups of patients. The results suggest that patients in the hydroxychloroquine group were less likely to be discharged from the hospital alive within 28 days than those in the usual-care group (59.6% vs. 62.9%; rate ratio, 0.90; 95% CI, 0.83 to 0.98). Among the patients who were not undergoing mechanical ventilation at baseline, those in the hydroxychloroquine group had a higher frequency of invasive mechanical ventilation or death (30.7% vs. 26.9%; risk ratio, 1.14; 95% CI, 1.03 to 1.27). There was a small numerical excess of cardiac deaths (0.4 percentage points) but no difference in the incidence of new major cardiac arrhythmia among the patients who received hydroxychloroquine. CONCLUSIONS: Among patients hospitalized with Covid-19, those who received hydroxychloroquine did not have a lower incidence of death at 28 days than those who received usual care. (Funded by UK Research and Innovation and National Institute for Health Research and others; RECOVERY ISRCTN number, SRCTN50189673; ClinicalTrials .gov number, NCT04381936.)

BACKGROUND Coronavirus disease 2019 (Covid-19) is associated with diffuse lung damage. Glucocorticoids may modulate inflammation-mediated lung injury and thereby reduce progression to respiratory failure and death. METHODS In this controlled, open-label trial comparing a range of possible treatments in patients who were hospitalized with Covid-19, we randomly assigned patients to receive oral or intravenous dexamethasone (at a dose of 6 mg once daily) for up to 10 days or to receive usual care alone. The primary outcome was 28-day mortality. Here, we report the preliminary results of this comparison. RESULTS A total of 2104 patients were assigned to receive dexamethasone and 4321 to receive usual care. Overall, 482 patients (22.9%) in the dexamethasone group and 1110 patients (25.7%) in the usual care group died within 28 days after randomization (age-adjusted rate ratio, 0.83; 95% confidence interval [CI], 0.75 to 0.93; P CONCLUSIONS In patients hospitalized with Covid-19, the use of dexamethasone resulted in lower 28-day mortality among those who were receiving either invasive mechanical ventilation or oxygen alone at randomization but not among those receiving no respiratory support. (Funded by the Medical Research Council and National Institute for Health Research and others; RECOVERY ClinicalTrials.gov number, NCT04381936. opens in new tab; ISRCTN number, 50189673. opens in new tab.)

Objective: Economic evaluation of computerised decision-support software intended to assist in the interpretation of a cardiotocography (CTG) during birth. Design: Individual patient level data from the INFANT study (an unmasked randomised controlled trial). Setting: Maternity units in the UK and Ireland Population: Singleton or twin pregnancy women of 35 weeks’ gestation or more and receiving continuous electronic fetal monitoring during labour. Intervention: Computerised decision-support software. Methods: Cost-consequence analysis presenting costs and outcomes with a time horizon of two years from a government health care perspective. Unit cost data collected from a combination of primary and secondary sources. Main outcome measures: Primary clinical outcomes were (i) composite ‘poor neonatal outcome’ and (ii) developmental assessment at age two years in a subset of surviving children. Mean cost per mother and infant dyad from birth to hospital discharge, and from hospital discharge to 24-months follow-up. Maternal health-related quality of life was assessed at 12 and 24 months follow-up using the EQ-5D-3L. Results: Data were analysed for 46,042 women and 46,614 infants. No statistically significant differences were detected between trial arms in any of the primary clinical outcomes or maternal quality of life. No statistically significant differences in costs were detected in maternal or infant costs from trial entry to hospital discharge or overall from hospital discharge to two-year follow-up. Conclusions: Decision-support software during labour is not associated with additional maternal or infant benefits and over a two-year period the software did not lead to additional costs or savings to the NHS.

BACKGROUND: Risk factors for maternal infection are clearly recognised, including caesarean section and operative vaginal birth. Antibiotic prophylaxis at caesarean section is widely recommended because there is clear systematic review evidence that it reduces incidence of maternal infection. Current WHO guidelines do not recommend routine antibiotic prophylaxis for women undergoing operative vaginal birth because of insufficient evidence of effectiveness. We aimed to investigate whether antibiotic prophylaxis prevented maternal infection after operative vaginal birth. METHODS: In a blinded, randomised controlled trial done at 27 UK obstetric units, women (aged ≥16 years) were allocated to receive a single dose of intravenous amoxicillin and clavulanic acid or placebo (saline) following operative vaginal birth at 36 weeks gestation or later. The primary outcome was confirmed or suspected maternal infection within 6 weeks of delivery defined by a new prescription of antibiotics for specific indications, confirmed systemic infection on culture, or endometritis. We did an intention-to-treat analysis. This trial is registered with ISRCTN, number 11166984, and is closed to accrual. FINDINGS: Between March 13, 2016, and June 13, 2018, 3427 women were randomly assigned to treatment: 1719 to amoxicillin and clavulanic acid, and 1708 to placebo. Seven women withdrew, leaving 1715 in the amoxicillin and clavulanic acid group and 1705 in the placebo groups. Primary outcome data were missing for 195 (6%) women. Significantly fewer women allocated to amoxicillin and clavulanic acid had a confirmed or suspected infection (180 [11%] of 1619) than women allocated to placebo (306 [19%] of 1606; risk ratio 0·58, 95% CI 0·49-0·69; p

Background\ud Infections acquired in hospital are an important cause of morbidity and mortality in very preterm infants. Several small trials have suggested that supplementing the enteral diet of very preterm infants with lactoferrin, an antimicrobial protein processed from cow's milk, prevents infections and associated complications. The aim of this large randomised controlled trial was to collect data to enhance the validity and applicability of the evidence from previous trials to inform practice.\ud \ud Methods\ud In this randomised placebo-controlled trial, we recruited very preterm infants born before 32 weeks' gestation in 37 UK hospitals and younger than 72 h at randomisation. Exclusion criteria were presence of a severe congenital anomaly, anticipated enteral fasting for longer than 14 days, or no realistic prospect of survival. Eligible infants were randomly assigned (1:1) to receive either enteral bovine lactoferrin (150 mg/kg per day; maximum 300 mg/day; lactoferrin group) or sucrose (same dose; control group) once daily until 34 weeks' postmenstrual age. Web-based randomisation minimised for recruitment site, gestation (completed weeks), sex, and single versus multifetal pregnancy. Parents, caregivers, and outcome assessors were unaware of group assignment. The primary outcome was microbiologically confirmed or clinically suspected late-onset infection (occurring >72 h after birth), which was assessed in all participants for whom primary outcome data was available by calculating the relative risk ratio with 95% CI between the two groups. The trial is registered with the International Standard Randomised Controlled Trial Number 88261002.\ud \ud Findings\ud We recruited 2203 participants between May 7, 2014, and Sept 28, 2017, of whom 1099 were assigned to the lactoferrin group and 1104 to the control group. Four infants had consent withdrawn or unconfirmed, leaving 1098 infants in the lactoferrin group and 1101 in the sucrose group. Primary outcome data for 2182 infants (1093 [99·5%] of 1098 in the lactoferrin group and 1089 [99·0] of 1101 in the control group) were available for inclusion in the modified intention-to-treat analyses. 316 (29%) of 1093 infants in the intervention group acquired a late-onset infection versus 334 (31%) of 1089 in the control group. The risk ratio adjusted for minimisation factors was 0·95 (95% CI 0·86–1·04; p=0·233). During the trial there were 16 serious adverse events for infants in the lactoferrin group and 10 for infants in the control group. Two events in the lactoferrin group (one case of blood in stool and one death after intestinal perforation) were assessed as being possibly related to the trial intervention.\ud \ud Interpretation\ud Enteral supplementation with bovine lactoferrin does not reduce the risk of late-onset infection in very preterm infants. These data do not support its routine use to prevent late-onset infection and associated morbidity or mortality in very preterm infants.\ud \ud Funding\ud UK National Institute for Health Research Health Technology Assessment programme (10/57/49).

BackgroundInfections acquired in hospital are an important cause of morbidity and mortality in very preterm infants. Several small trials have suggested that supplementing the enteral diet of very preterm infants with lactoferrin, an antimicrobial protein processed from cow’s milk, prevents infections and associated complications.ObjectiveTo determine whether or not enteral supplementation with bovine lactoferrin (The Tatua Cooperative Dairy Company Ltd, Morrinsville, New Zealand) reduces the risk of late-onset infection (acquired > 72 hours after birth) and other morbidity and mortality in very preterm infants.DesignRandomised, placebo-controlled, parallel-group trial. Randomisation was via a web-based portal and used an algorithm that minimised for recruitment site, weeks of gestation, sex and single versus multiple births.SettingUK neonatal units between May 2014 and September 2017.ParticipantsInfants born at InterventionsEligible infants were allocated individually (1 : 1 ratio) to receive enteral bovine lactoferrin (150 mg/kg/day; maximum 300 mg/day) or sucrose (British Sugar, Peterborough, UK) placebo (same dose) once daily from trial entry until a postmenstrual age of 34 weeks. Parents, caregivers and outcome assessors were unaware of group assignment.OutcomesPrimary outcome – microbiologically confirmed or clinically suspected late-onset infection. Secondary outcomes – microbiologically confirmed infection; all-cause mortality; severe necrotising enterocolitis (NEC); retinopathy of prematurity (ROP); bronchopulmonary dysplasia (BPD); a composite of infection, NEC, ROP, BPD and mortality; days of receipt of antimicrobials until 34 weeks’ postmenstrual age; length of stay in hospital; and length of stay in intensive care, high-dependency and special-care settings.ResultsOf 2203 enrolled infants, primary outcome data were available for 2182 infants (99%). In the intervention group, 316 out of 1093 (28.9%) infants acquired a late-onset infection versus 334 out of 1089 (30.7%) infants in the control group [adjusted risk ratio (RR) 0.95, 95% confidence interval (CI) 0.86 to 1.04]. There were no significant differences in any secondary outcomes: microbiologically confirmed infection (RR 1.05, 99% CI 0.87 to 1.26), mortality (RR 1.05, 99% CI 0.66 to 1.68), NEC (RR 1.13, 99% CI 0.68 to 1.89), ROP (RR 0.89, 99% CI 0.62 to 1.28), BPD (RR 1.01, 99% CI 0.90 to 1.13), or a composite of infection, NEC, ROP, BPD and mortality (RR 1.01, 99% CI 0.94 to 1.08). There were no differences in the number of days of receipt of antimicrobials, length of stay in hospital, or length of stay in intensive care, high-dependency or special-care settings. There were 16 reports of serious adverse events for infants in the lactoferrin group and 10 for infants in the sucrose group.ConclusionsEnteral supplementation with bovine lactoferrin does not reduce the incidence of infection, mortality or other morbidity in very preterm infants.Future workIncrease the precision of the estimates of effect on rarer secondary outcomes by combining the data in a meta-analysis with data from other trials. A mechanistic study is being conducted in a subgroup of trial participants to explore whether or not lactoferrin supplementation affects the intestinal microbiome and metabolite profile of very preterm infants.Trial registrationCurrent Controlled Trials ISRCTN88261002.FundingThis project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full inHealth Technology Assessment; Vol. 22, No. 74. See the NIHR Journals Library website for further project information. This trial was also sponsored by the University of Oxford, Oxford, UK. The funder provided advice and support and monitored study progress but did not have a role in study design or data collection, analysis and interpretation.

Background: The survival rate of preterm children has risen steadily due to advances in obstetric and neonatal intensive care. Children born extremely preterm (≤28 weeks of gestation) are at high risk of long term developmental problems, including cerebral palsy, motor and cognitive impairment, visual and auditory deficits and behavioural problems. This can have serious implications for their quality of life and that of their family and carers. These children take up a disproportionate amount of neonatal intensive care unit resources and overall costs, and as they grow up are more likely to require additional health and social care services beyond routine care to compensate for their functional limitations. The early identification and management of factors that mediate long term outcome is necessary to assist healthcare professionals in selecting appropriate treatment pathways, and to develop, target and evaluate interventions. Many risk factor analyses for neurodevelopmental impairment have been published in preterm populations, but this vast literature has not been formally summarised. Furthermore, there is a dearth of studies reporting longitudinal analysis of neurodevelopmental trajectories from early childhood to adulthood. Objectives: The first aim of this thesis was to perform a comprehensive systematic review of the world literature over the last two decades, to consolidate the evidence about the prognosis of neurodevelopmental outcome in children born very preterm or with very low birth weight. The second aim was to conduct a longitudinal analysis of a cohort of extremely preterm participants followed up into early adulthood to investigate the trajectories of long term sequelae over time, and to examine the association of neurodevelopmental course in relation to the predictive factors identified in the systematic review. Methods: A systematic review was conducted using MEDLINE, EMBASE and PyscINFO databases to identify studies published between January 1 1990 and June 1 2014 reporting multivariable prediction models for the neurodevelopment of children born ≤32 weeks of gestation or with a birth weight ≤1250 grams (protocol registration number CRD42014006943). Seventy-eight studies reporting 222 risk factor models for neurodevelopmental outcome were identified. Two independent reviewers extracted key information about study design, outcome definition, risk factor selection, model development, reporting, and conducted a risk of bias assessment. To address the second objective of the study, a longitudinal analysis of cognitive and behavioural trajectories was conducted using a prospective, population-based cohort study in the United Kingdom and the Republic of Ireland. Three hundred and fifteen surviving infants born less than 26 completed weeks of gestation recruited at birth in 1995 and 160 term-born classroom peers recruited at age six were followed-up to 19 years. Participants were invited for up to four standardized, blinded cognitive assessments and the parent-completed Strengths and Difficulties Questionnaire was used to assess behavioural problems. Results: The systematic review of risk factors for motor impairment in children born very preterm or with very low birth weight provided strong evidence that neonatal brain injury is a robust prognostic factor for cerebral palsy, and some evidence that the use of postnatal steroids increases the risk and the use of antenatal steroids reduces the risk of cerebral palsy. There was moderate evidence that male sex was prognostic for motor impairment at school age in children free of major disability. The systematic review of risk factors for cognitive impairment identified male sex, non-white ethnicity, lower levels of parental education and lower birth weight as significant predictors of global cognitive dysfunction in early infancy, with parental education having a sustained impact after five years of age. There was also evidence that male sex was predictive of delayed language development in early infancy. Gestational age was found to be of limited use as prognostic factor for cerebral palsy, motor and cognitive impairment in cohorts restricted to ≤32 weeks of gestation. There was a dearth of good quality studies investigating risk factors for behavioural problems and psychiatric disorders and the findings of this review were inconclusive. The only factors that appeared to be consistent predictors of general behavioural problems were markers of socio-economic deprivation, neurodevelopmental or cognitive delay, and an abnormal behavioural screen in early infancy. In the longitudinal analysis of the prospective, population-based cohort of extremely preterm children, cognitive trajectories were stable in both the extremely preterm and term-born groups over time with persistent deficit in the extremely preterm group of 25.2 IQ points (95% CI: -27.8 to -22.6, p&LT;0.001) and only minimal catch-up over time. Participants with neonatal brain injury and of male sex had the largest deficits, but a lower level of maternal education and earlier gestational age at birth were also associated with reduced IQ scores. Behavioural problems were also more prevalent among the extremely preterm participants who had a mean Total Difficulties Score of 4.81 points above their term-born peers (95% CI: 3.76 to 5.87, p&LT;0.001) and which persisted over the time period. Behavioural difficulties were mainly due to hyperactivity, inattention and peer problems and were strongly associated with a positive behavioural screen in early infancy. Conclusions: The most robust predictors of poor neurodevelopmental outcome identified by the systematic review were neonatal brain injury, male sex, and markers of social disadvantage. The unclear findings for many risk factors may reflect differences in study design, study population, methodological quality and lack of standardization of measures. Or it may simply reflect the fact that prognostic modelling in such a heterogeneous population is challenging and complex, with multiple risk factors acting sequentially over time, and often with the existence of multiple impairments within the same individual. The main conclusions from the longitudinal analysis of children born extremely preterm is that being born too soon appears to place limits on brain plasticity and function which is not recovered over time; with the most vulnerable being males and those with evidence of brain injury early in life. These structural abnormalities may disturb neurodevelopmental processes and impede the brain from maintaining a normal developmental trajectory. If extremely preterm children fail to achieve optimum levels of cognitive function and are still experiencing behavioural problems once they have reached maturity, then this has implications for health and well-being in later adulthood and old age. Cognitive test scores in infancy and early childhood reflect early adult outcomes and a positive behavioural screen in infancy is strongly associated with early adult behavioural outcomes. Recommendations: The systematic review revealed some shortcomings in methodology and reporting that could be improved in future studies, and confirmed that that there is a dearth of properly designed and well-conducted prognostic modelling studies in this field. The findings and recommendations of this critical review should be used as a basis for the design, analysis and reporting of future studies seeking to develop multivariate risk factor or prognostic models in this population. There is an urgent need for larger population cohorts followed up routinely beyond two years as subtle outcomes such as impairment of executive function and fine motor skills cannot be reliably assessed at this age, and the natural course of some disorders may have their onset later in childhood. Studies with larger sample sizes and greater power are needed for studying less common conditions in preterm populations and there should be more standardisation of outcome and risk factor measurements, particularly with the use of standard diagnostic evaluations to assess psychiatric disorders. Future studies should include a term-born comparison group and adopt appropriate statistical analysis techniques to analyse longitudinal outcome data and the impact of risk factors on these trajectories. Additional research is required to improve the prediction of individual differences, and to identify the neuropathological differences underlying different developmental trajectories and their interaction with environmental influences over time.

Background In the UK, 1–2% of infants are born very preterm ( Methods/design Two thousand eight hundred very preterm or very low birth weight infants will be recruited from approximately 30 hospitals across the UK to a randomised controlled trial. Infants with severe congenital anomaly or no realistic chance of survival will be excluded. Infants will be randomly allocated to either a faster (30 ml/kg/day) or slower (18 ml/kg/day) rate of increase in milk feeds. Data will be collected during the neonatal hospital stay on weight, infection rates, episodes of NEC, length of stay and time to reach full milk feeds. Long term health outcomes comprising vision, hearing, motor and cognitive impairment will be assessed at 24 months of age (corrected for prematurity) using a parent report questionnaire. Discussion Extensive searches have found no active or proposed studies investigating the rate of increasing milk feeds. The results of this trial will have importance for optimising incremental milk feeding for very preterm and/or very low birth weight infants. No additional resources will be required to implement an optimal feeding strategy, and therefore if successful, the trial results could rapidly be adopted across the NHS at low cost. Trial registration ISRCTN Registry; ISRCTN76463425 on 5 March, 2013.

BACKGROUND: The aim of the study was to identify the informational needs of patients with melanoma on disease status and prognosis, and to ascertain their views on the utility of positron emission tomography (PET) and sentinel node biopsy (SNB). PATIENTS AND METHODS: Patients attending the weekly melanoma outpatient clinic at St Thomas' Hospital London UK between February and August 2007 participated in this cross-sectional survey. Views of 106 melanoma patients were elicited using a face-to face semi-structured questionnaire. RESULTS: The majority of participants wanted to know everything about their disease (88%). Prognostic information (> 85%) and information on palliative care input (97%) were highly valued. More than 50% expected the doctor to impart this information without negotiation. Nearly 70% of the responders who had previously had a PET scan felt they should decide if and when the scans should be performed. Fifty three percentage had undergone the SNB because the doctor had suggested it. CONCLUSIONS: Patients with melanoma want detailed and prompt information about their disease including prognosis. Regular PET scans provide reassurance. The role of SNB is not clear to all patients.

BACKGROUND: Knee pain is nearly twice as prevalent as hip pain in elderly people, yet knee replacement is far less common than hip replacement. AIM: To investigate whether systematic differences in the primary care management of hip versus knee problems might explain the disparate rates of joint replacement. DESIGN OF STUDY: Cross-sectional, population-based postal survey. SETTING: Random sample of 5500 Oxfordshire residents aged 65 years and above. METHOD: Screening questions were used to identify symptomatic individuals: "During the past 12 months, have you had pain in or around either of your hips/knees on most days for 1 month or longer?". Standard (Lequesne) severity ratings were obtained for each hip and knee. Logistic regression was used to estimate odds ratios (ORs) for "knee cases" versus "hip cases" for selected healthcare services and attitudes toward replacement. RESULTS: Among 3341 responders, 212 hip cases and 612 knee cases were identified. Knee pain led to a GP consultation more often than hip pain (OR = 1.76, P = 0.04), but specialist referral was no more likely (OR = 0.85, P = 0.57). Similar percentages of hip and knee cases would agree to hip/knee replacement surgery if it was offered, but hip and knee cases differed in their views on the general success of joint replacement. CONCLUSIONS: Some variations in primary care management for hip versus knee pain were apparent. People with hip pain were mostly positive about replacement outcomes, whereas people with knee pain were more uncertain about replacement. Attitudes appeared to be influenced by knowing someone who had undergone such surgery.

Cognitive delay is the most common form of impairment among children born very preterm (VPT) at 32 weeks or less or with very low birth weight (VLBW) of 1250 g or less. It is important to identify factors that are robust predictors of long-term outcome because the ability to predict future prognosis will assist in health care and educational service planning and provision.To identify prognostic factors for poor cognitive development in children born VPT or with VLBW.A systematic review was conducted using MEDLINE, EMBASE, and PyscINFO databases to identify studies published between January 1, 1990, and June 1, 2014, reporting multivariable prediction models for neurodevelopment in VPT or VLBW children. Thirty-one studies comprising 98 risk factor models for cognitive outcome were identified. Two independent reviewers extracted key information on study design, outcome definition, risk factor selection, model development, and reporting and conducted a risk-of-bias assessment.There was evidence that male sex, nonwhite race/ethnicity, lower level of parental education, and lower birth weight were predictive of global cognitive impairment in children younger than 5 years. In older children, only the influence of parental education was sustained. Male sex was also predictive of language impairment in early infancy, but not in middle childhood. Gestational age was a poor predictor of cognitive outcome, probably because of a reduced discriminatory power in cohorts restricted to a narrow gestational age range. The prognostic value of neonatal brain injury was unclear; however, studies adopted mixed strategies for managing children with physical or neurosensory disability.The influence of perinatal risk factors on cognitive development of VPT or VLBW children appears to diminish over time as environmental factors become more important. It is difficult to isolate cognitive outcomes from motor and neurosensory impairment, and the strategy for dealing with untestable children has implications for risk prediction.

Background: The aim of the study was to identify the informational needs of patients with melanoma on disease status and prognosis, and to ascertain their views on the utility of positron emission tomography (PET) and sentinel node biopsy (SNB). Patients and methods: Patients attending the weekly melanoma outpatient clinic at St Thomas' Hospital London UK between February and August 2007 participated in this cross-sectional survey. Views of 106 melanoma patients were elicited using a face-to face semi-structured questionnaire. Results: The majority of participants wanted to know everything about their disease (88%). Prognostic information (> 85%) and information on palliative care input (97%) were highly valued. More than 50% expected the doctor to impart this information without negotiation. Nearly 70% of the responders who had previously had a PET scan felt they should decide if and when the scans should be performed. Fifty three percentage had undergone the SNB because the doctor had suggested it. Conclusions: Patients with melanoma want detailed and prompt information about their disease including prognosis. Regular PET scans provide reassurance. The role of SNB is not clear to all patients. © 2009 Blackwell Publishing Ltd. 63 11 1595 1600