LAparoscopic Versus Abdominal hysterectomy (LAVA): protocol of a randomised controlled trial.

INTRODUCTION: There is uncertainty about the advantages and disadvantages of laparoscopic hysterectomy compared with abdominal hysterectomy, particularly the relative rate of complications of the two procedures. While uptake of laparoscopic hysterectomy has been slow, the situation is changing with greater familiarity, better training, better equipment and increased proficiency in the technique. Thus, a large, robust, multicentre randomised controlled trial (RCT) is needed to compare contemporary laparoscopic hysterectomy with abdominal hysterectomy to determine the safest and most cost-effective technique. METHODS AND ANALYSIS: A parallel, open, non-inferiority, multicentre, randomised controlled, expertise-based surgery trial with integrated health economic evaluation and an internal pilot with an embedded qualitative process evaluation. A within trial-based economic evaluation will explore the cost-effectiveness of laparoscopic hysterectomy compared with open abdominal hysterectomy. We will aim to recruit 3250 women requiring a hysterectomy for a benign gynaecological condition and who were suitable for either laparoscopic or open techniques. The primary outcome is major complications up to six completed weeks postsurgery and the key secondary outcome is time from surgery to resumption of usual activities using the personalised Patient-Reported Outcomes Measurement Information System Physical Function questionnaire. The principal outcome for the economic evaluation is to be cost per QALY at 12 months' postsurgery. A secondary analysis is to be undertaken to generate costs per major surgical complication avoided and costs per return to normal activities. ETHICS AND DISSEMINATION: The study was approved by the West Midlands-Edgbaston Research Ethics Committee, 18 February 2021 (Ethics ref: 21/WM/0019). REC approval for the protocol version 2.0 dated 2 February 2021 was issued on 18 February 2021.We will present the findings in national and international conferences. We will also aim to publish the findings in high impact peer-reviewed journals. We will disseminate the completed paper to the Department of Health, the Scientific Advisory Committees of the RCOG, the Royal College of Nurses (RCN) and the BSGE. TRIAL REGISTRATION NUMBER: ISRCTN14566195.

Planned delivery for pre-eclampsia between 34 and 37 weeks of gestation: the PHOENIX RCT.

BACKGROUND: In women with late preterm pre-eclampsia (i.e. at 34+0 to 36+6 weeks' gestation), the optimal delivery time is unclear because limitation of maternal-fetal disease progression needs to be balanced against infant complications. The aim of this trial was to determine whether or not planned earlier initiation of delivery reduces maternal adverse outcomes without substantial worsening of perinatal or infant outcomes, compared with expectant management, in women with late preterm pre-eclampsia. METHODS: We undertook an individually randomised, triple non-masked controlled trial in 46 maternity units across England and Wales, with an embedded health economic evaluation, comparing planned delivery and expectant management (usual care) in women with late preterm pre-eclampsia. The co-primary maternal outcome was a maternal morbidity composite or recorded systolic blood pressure of ≥ 160 mmHg (superiority hypothesis). The co-primary short-term perinatal outcome was a composite of perinatal deaths or neonatal unit admission (non-inferiority hypothesis). Analyses were by intention to treat, with an additional per-protocol analysis for the perinatal outcome. The primary 2-year infant neurodevelopmental outcome was measured using the PARCA-R (Parent Report of Children's Abilities-Revised) composite score. The planned sample size of the trial was 900 women; the trial is now completed. We undertook two linked substudies. RESULTS: Between 29 September 2014 and 10 December 2018, 901 women were recruited; 450 women [448 women (two withdrew consent) and 471 infants] were allocated to planned delivery and 451 women (451 women and 475 infants) were allocated to expectant management. The incidence of the co-primary maternal outcome was significantly lower in the planned delivery group [289 (65%) women] than in the expectant management group [338 (75%) women] (adjusted relative risk 0.86, 95% confidence interval 0.79 to 0.94; p = 0.0005). The incidence of the co-primary perinatal outcome was significantly higher in the planned delivery group [196 (42%) infants] than in the expectant management group [159 (34%) infants] (adjusted relative risk 1.26, 95% confidence interval 1.08 to 1.47; p = 0.0034), but indicators of neonatal morbidity were similar in both groups. At 2-year follow-up, the mean PARCA-R scores were 89.5 points (standard deviation 18.2 points) for the planned delivery group (290 infants) and 91.9 points (standard deviation 18.4 points) for the expectant management group (256 infants), both within the normal developmental range (adjusted mean difference -2.4 points, 95% confidence interval -5.4 to 0.5 points; non-inferiority p = 0.147). Planned delivery was significantly cost-saving (-£2711, 95% confidence interval -£4840 to -£637) compared with expectant management. There were nine serious adverse events in the planned delivery group and 12 in the expectant management group. CONCLUSION: In women with late preterm pre-eclampsia, planned delivery reduces short-term maternal morbidity compared with expectant management, with more neonatal unit admissions related to prematurity but no indicators of greater short-term neonatal morbidity (such as need for respiratory support). At 2-year follow-up, around 60% of parents reported follow-up scores. Average infant development was within the normal range for both groups; the small between-group mean difference in PARCA-R scores is unlikely to be clinically important. Planned delivery was significantly cost-saving to the health service. These findings should be discussed with women with late preterm pre-eclampsia to allow shared decision-making on timing of delivery. LIMITATIONS: Limitations of the trial include the challenges of finding a perinatal outcome that adequately represented the potential risks of both groups and a maternal outcome that reflects the multiorgan manifestations of pre-eclampsia. The incidences of maternal and perinatal primary outcomes were higher than anticipated on the basis of previous studies, but this did not limit interpretation of the analysis. The trial was limited by a higher loss to follow-up rate than expected, meaning that the extent and direction of bias in outcomes (between responders and non-responders) is uncertain. A longer follow-up period (e.g. up to 5 years) would have enabled us to provide further evidence on long-term infant outcomes, but this runs the risk of greater attrition and increased expense. FUTURE WORK: We identified a number of further questions that could be prioritised through a formal scoping process, including uncertainties around disease-modifying interventions, prognostic factors, longer-term follow-up, the perspectives of women and their families, meta-analysis with other studies, effect of a similar intervention in other health-care settings, and clinical effectiveness and cost-effectiveness of other related policies around neonatal unit admission in late preterm birth. TRIAL REGISTRATION: The trial was prospectively registered as ISRCTN01879376. FUNDING: This project was funded by the National Institute for Health and Care Research ( NIHR ) Health Technology Assessment programme and will be published in Health Technology Assessment. See the NIHR Journals Library website for further project information.

Monofilament suture versus braided suture thread to improve pregnancy outcomes after vaginal cervical cerclage (C-STICH): a pragmatic randomised, controlled, phase 3, superiority trial.

BACKGROUND: Miscarriage in the second trimester and preterm birth are significant global problems. Vaginal cervical cerclage is performed to prevent pregnancy loss and preterm birth. We aimed to determine the effectiveness of a monofilament suture thread compared with braided suture thread on pregnancy loss rates in women undergoing a cervical cerclage. METHODS: C-STICH was a pragmatic, randomised, controlled, superiority trial done at 75 obstetric units in the UK. Women with a singleton pregnancy who received a vaginal cervical cerclage due to a history of pregnancy loss or premature birth, or if indicated by ultrasound, were centrally randomised (1:1) using minimisation to receive a monofilament suture or braided suture thread for their cervical cerclage. Women and outcome assessors were masked to allocation as far as possible. The primary outcome was pregnancy loss, defined as miscarriage, stillbirth, or neonatal death in the first week of life, analysed in the intention-to-treat population (ie, all women who were randomly assigned). Safety was also assessed in the intention-to-treat population. The trial was registered with ISRCTN, ISRCTN15373349. FINDINGS: Between Aug 21, 2015, and Jan 28, 2021, 2049 women were randomly assigned to receive a monofilament suture (n=1025) or braided suture (n=1024). The primary outcome was ascertained in 1003 women in the monofilament suture group and 993 women in the braided suture group. Pregnancy loss occurred in 80 (8·0%) of 1003 women in the monofilament suture group and 75 (7·6%) of 993 women in the braided suture group (adjusted risk ratio 1·05 [95% CI 0·79 to 1·40]; adjusted risk difference 0·002 [95% CI -0·02 to 0·03]). INTERPRETATION: Monofilament suture did not reduce rate of pregnancy loss when compared with a braided suture. Clinicians should use the results of this trial to facilitate discussions around the choice of suture thread to optimise outcomes. FUNDING: National Institute of Health Research Health Technology Assessment Programme.

Long-term impact of pre-incision antibiotics on children born by caesarean section: a longitudinal study based on UK electronic health records.

BACKGROUND: Since changes in the national guidance in 2011, prophylactic antibiotics for women undergoing caesarean section are recommended prior to skin incision, rather than after the baby's umbilical cord has been clamped. Evidence from randomised controlled trials conducted outside the UK has shown that this reduces maternal infectious morbidity; however, the prophylactic antibiotics also cross the placenta, meaning that babies are exposed to them around the time of birth. Antibiotics are known to affect the gut microbiota of the babies, but the long-term effects of exposure to high-dose broad-spectrum antibiotics around the time of birth on allergy and immune-related diseases are unknown. OBJECTIVES: We aimed to examine whether or not in-utero exposure to antibiotics immediately prior to birth compared with no pre-incisional antibiotic exposure increases the risk of (1) asthma and (2) eczema in children born by caesarean section. DESIGN: This was a controlled interrupted time series study. SETTING: The study took place in primary and secondary care. PARTICIPANTS: Children born in the UK during 2006-18 delivered by caesarean section were compared with a control cohort delivered vaginally. INTERVENTIONS: In-utero exposure to antibiotics immediately prior to birth. MAIN OUTCOME MEASURES: Asthma and eczema in children in the first 5 years of life. Additional secondary outcomes, including other allergy-related conditions, autoimmune diseases, infections, other immune system-related diseases and neurodevelopmental conditions, were also assessed. DATA SOURCES: The Health Improvement Network (THIN) and the Clinical Practice Research Datalink (CPRD) primary care databases and the Hospital Episode Statistics (HES) database. Previously published linkage strategies were adapted to link anonymised data on mothers and babies in these databases. Duplicate practices contributing to both THIN and the CPRD databases were removed to create a THIN-CPRD data set. RESULTS: In the THIN-CPRD and HES data sets, records of 515,945 and 3,945,351 mother-baby pairs were analysed, respectively. The risk of asthma was not significantly higher in children born by caesarean section exposed to pre-incision antibiotics than in children whose mothers received post-cord clamping antibiotics, with an incidence rate ratio of 0.91 (95% confidence interval 0.78 to 1.05) for diagnosis of asthma in primary care and an incidence rate ratio of 1.05 (95% confidence interval 0.99 to 1.11) for asthma resulting in a hospital admission. We also did not find an increased risk of eczema, with an incidence rate ratio of 0.98 (95% confidence interval 0.94 to1.03) and an incidence rate ratio of 0.96 (95% confidence interval 0.71 to 1.29) for diagnosis in primary care and hospital admissions, respectively. LIMITATIONS: It was not possible to ascertain the exposure to pre-incision antibiotics at an individual level. The maximum follow-up of children was 5 years. CONCLUSIONS: There was no evidence that the policy change from post-cord clamping to pre-incision prophylactic antibiotics for caesarean sections during 2006-18 had an impact on the incidence of asthma and eczema in early childhood in the UK. FUTURE WORK: There is a need for further research to investigate if pre-incision antibiotics have any impact on developing asthma and other allergy and immune-related conditions in older children. STUDY REGISTRATION: This study is registered as researchregistry3736. FUNDING: This project was funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 26, No. 30. See the NIHR Journals Library website for further project information.

WHAT WAS THE QUESTION?: Women giving birth by caesarean section are at risk of developing infections (such as wound infections) and are offered antibiotics at the time of their operation to reduce this risk. In 2011, the national guidelines changed from recommending antibiotics after cord clamping to giving them before the operation to further reduce the risk of maternal infection. During birth, the newborn gut is colonised by microbes. Antibiotics given to the mother before caesarean section can reach the baby through the placenta and disrupt the normal microbes that colonise the gut. These microbes are believed to play a role in the development of the immune system and altering the normal development of these microbes has been linked to children developing allergic conditions, such as asthma and eczema. This study investigated whether or not giving antibiotics before the caesarean section had a longer-term impact on children's health. WHAT DID WE DO?: We used routine NHS information already collected by hospitals and general practitioners about women who gave birth in the UK between 2006 and 2018, and their children. We compared the risk of asthma, eczema and other health conditions in the first 5 years after birth in children born by caesarean section before and after the change in hospital policies. We also compared their health with children born vaginally. WHAT DID WE FIND?: We found that there was no increased risk of asthma or eczema for children born by caesarean section after the policy decision in 2011 to give the mother antibiotics before the operation. WHAT DOES THIS MEAN?: The study findings provide further evidence for the current recommendation to give preventative antibiotics to women shortly before the caesarean section to reduce the overall risk of infections after birth.

C-STICH2: emergency cervical cerclage to prevent miscarriage and preterm birth-study protocol for a randomised controlled trial.

BACKGROUND: Cervical cerclage is a recognised treatment to prevent late miscarriage and pre-term birth (PTB). Emergency cervical cerclage (ECC) for cervical dilatation with exposed unruptured membranes is less common and the potential benefits of cerclage are less certain. A randomised control trial is needed to accurately assess the effectiveness of ECC in preventing pregnancy loss compared to an expectant approach. METHODS: C-STICH2 is a multicentre randomised controlled trial in which women presenting with cervical dilatation and unruptured exposed membranes at 16 + 0 to 27 + 6 weeks gestation are randomised to ECC or expectant management. Trial design includes 18 month internal pilot with embedded qualitative process evaluation, minimal data set and a within-trial health economic analysis. Inclusion criteria are ≥16 years, singleton pregnancy, exposed membranes at the external os, gestation 16 + 0-27 + 6 weeks, and informed consent. Exclusion criteria are contraindication to cerclage, cerclage in situ or previous cerclage in this pregnancy. Randomisation occurs via an online service in a 1:1 ratio, using a minimisation algorithm to reduce chance imbalances in key prognostic variables (site, gestation and dilatation). Primary outcome is pregnancy loss; a composite including miscarriage, termination of pregnancy and perinatal mortality defined as stillbirth and neonatal death in the first week of life. Secondary outcomes include all core outcomes for PTB. Two-year development outcomes will be assessed using general health and Parent Report of Children's Abilities-Revised (PARCA-R) questionnaires. Intended sample size is 260 participants (130 each arm) based on 60% rate of pregnancy loss in the expectant management arm and 40% in the ECC arm, with 90% power and alpha 0.05. Analysis will be by intention-to-treat. DISCUSSION: To date there has been one small trial of ECC in 23 participants which included twin and singleton pregnancies. This small trial along with the largest observational study (n = 161) found ECC to prolong pregnancy duration and reduce deliveries before 34 weeks gestation. It is important to generate high quality evidence on the effectiveness of ECC in preventing pregnancy loss, and improve understanding of the prevalence of the condition and frequency of complications associated with ECC. An adequately powered RCT will provide the highest quality evidence regarding optimum care for these women and their babies. TRIAL REGISTRATION: ISRCTN Registry ISRCTN12981869 . Registered on 13th June 2018.

Universal late pregnancy ultrasound screening to predict adverse outcomes in nulliparous women: a systematic review and cost-effectiveness analysis.

BACKGROUND: Currently, pregnant women are screened using ultrasound to perform gestational aging, typically at around 12 weeks' gestation, and around the middle of pregnancy. Ultrasound scans thereafter are performed for clinical indications only. OBJECTIVES: We sought to assess the case for offering universal late pregnancy ultrasound to all nulliparous women in the UK. The main questions addressed were the diagnostic effectiveness of universal late pregnancy ultrasound to predict adverse outcomes and the cost-effectiveness of either implementing universal ultrasound or conducting further research in this area. DESIGN: We performed diagnostic test accuracy reviews of five ultrasonic measurements in late pregnancy. We conducted cost-effectiveness and value-of-information analyses of screening for fetal presentation, screening for small for gestational age fetuses and screening for large for gestational age fetuses. Finally, we conducted a survey and a focus group to determine the willingness of women to participate in a future randomised controlled trial. DATA SOURCES: We searched MEDLINE, EMBASE and the Cochrane Library from inception to June 2019. REVIEW METHODS: The protocol for the review was designed a priori and registered. Eligible studies were identified using keywords, with no restrictions for language or location. The risk of bias in studies was assessed using the Quality Assessment of Diagnostic Accuracy Studies 2 (QUADAS-2) tool. Health economic modelling employed a decision tree analysed via Monte Carlo simulation. Health outcomes were from the fetal perspective and presented as quality-adjusted life-years. Costs were from the perspective of the public sector, defined as NHS England, and the costs of special educational needs. All costs and quality-adjusted life-years were discounted by 3.5% per annum and the reference case time horizon was 20 years. RESULTS: Umbilical artery Doppler flow velocimetry, cerebroplacental ratio, severe oligohydramnios and borderline oligohydramnios were all either non-predictive or weakly predictive of the risk of neonatal morbidity (summary positive likelihood ratios between 1 and 2) and were all weakly predictive of the risk of delivering a small for gestational age infant (summary positive likelihood ratios between 2 and 4). Suspicion of fetal macrosomia is strongly predictive of the risk of delivering a large infant, but it is only weakly, albeit statistically significantly, predictive of the risk of shoulder dystocia. Very few studies blinded the result of the ultrasound scan and most studies were rated as being at a high risk of bias as a result of treatment paradox, ascertainment bias or iatrogenic harm. Health economic analysis indicated that universal ultrasound for fetal presentation only may be both clinically and economically justified on the basis of existing evidence. Universal ultrasound including fetal biometry was of borderline cost-effectiveness and was sensitive to assumptions. Value-of-information analysis indicated that the parameter that had the largest impact on decision uncertainty was the net difference in cost between an induced delivery and expectant management. LIMITATIONS: The primary literature on the diagnostic effectiveness of ultrasound in late pregnancy is weak. Value-of-information analysis may have underestimated the uncertainty in the literature as it was focused on the internal validity of parameters, which is quantified, whereas the greatest uncertainty may be in the external validity to the research question, which is unquantified. CONCLUSIONS: Universal screening for presentation at term may be justified on the basis of current knowledge. The current literature does not support universal ultrasonic screening for fetal growth disorders. FUTURE WORK: We describe proof-of-principle randomised controlled trials that could better inform the case for screening using ultrasound in late pregnancy. STUDY REGISTRATION: This study is registered as PROSPERO CRD42017064093. FUNDING: This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 25, No. 15. See the NIHR Journals Library website for further project information.

Ultrasound scans allow doctors to check on the health of an unborn infant. Usually, all pregnant women receive a scan at about 3 months and about 5 months of pregnancy. After that, women are offered a scan during birth only if they have risk factors or if a problem develops. Problems can arise in the later stages of pregnancy, including issues with the infant's growth or whether or not the infant is breech. Some of these problems may be prevented if a scan is carried out, but scans can also be inaccurate. When they are, a woman may receive unnecessary treatment, which could even harm her or her infant. In this study we set out to review previous research about how good ultrasound scanning is at detecting infants who may be born with a condition. This study focused on detecting if the infant was too big or too small. Unfortunately, much of the previous research was not carried out to a high standard. Scanning can detect the size of a infant relatively well, but it is much less clear if scanning can predict complications that may harm the infant during birth. We also studied the costs and outcomes of scanning. We calculated the extra cost required to scan every woman and compared this with the extra benefits from preventing complications. One thing that ultrasound scans detect is whether the infant is presenting head first or bottom first (a 'breech presentation'), as infants presenting breech have high risks of complications. Scanning all women to check whether or not their infant is presenting breech seems to be cost-effective and the cost savings may even be higher than the cost of implementation, although this depends on how much the scan would cost. Whether or not it is worthwhile scanning all infants to see if they are above or below the thresholds for normal size is less clear. A larger research study could provide more reliable numbers from which to draw a conclusion. We show how such a study could be designed, so that a single study could tell us both how well scans can predict adverse outcomes and how helpful this information is.

Economic evaluation of computerised interpretation of fetal heart rate during labour: a cost-consequence analysis alongside the INFANT study.

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 2 years from a government healthcare 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 2 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 EuroQol three-level health-related quality of life instrument (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 2-year follow-up. CONCLUSIONS: Decision-support software during labour is not associated with additional maternal or infant benefits and over a 2-year period the software did not lead to additional costs or savings to the National Health Service. TRIAL REGISTRATION NUMBER: ISRCTN98680152.

Surgical site infection and costs in low- and middle-income countries: A systematic review of the economic burden.

BACKGROUND: Surgical site infection (SSI) is a worldwide problem which has morbidity, mortality and financial consequences. The incidence rate of SSI is high in Low- and Middle-Income countries (LMICs) compared to high income countries, and the costly surgical complication can raise the potential risk of financial catastrophe. OBJECTIVE: The aim of the study is to critically appraise studies on the cost of SSI in a range of LMIC studies and compare these estimates with a reference standard of high income European studies who have explored similar SSI costs. METHODS: A systematic review was undertaken using searches of two electronic databases, EMBASE and MEDLINE In-Process & Other Non-Indexed Citations, up to February 2019. Study characteristics, comparator group, methods and results were extracted by using a standard template. RESULTS: Studies from 15 LMIC and 16 European countries were identified and reviewed in full. The additional cost of SSI range (presented in 2017 international dollars) was similar in the LMIC ($174-$29,610) and European countries ($21-$34,000). Huge study design heterogeneity was encountered across the two settings. DISCUSSION: SSIs were revealed to have a significant cost burden in both LMICs and High Income Countries in Europe. The magnitude of the costs depends on the SSI definition used, severity of SSI, patient population, choice of comparator, hospital setting, and cost items included. Differences in study design affected the comparability across studies. There is need for multicentre studies with standardized data collection methods to capture relevant costs and consequences of the infection across income settings.

Planned early delivery or expectant management for late preterm pre-eclampsia (PHOENIX): a randomised controlled trial.

BACKGROUND: In women with late preterm pre-eclampsia, the optimal time to initiate delivery is unclear because limitation of maternal disease progression needs to be balanced against infant complications. The aim of this trial was to determine whether planned earlier initiation of delivery reduces maternal adverse outcomes without substantial worsening of neonatal or infant outcomes, compared with expectant management (usual care) in women with late preterm pre-eclampsia. METHODS: In this parallel-group, non-masked, multicentre, randomised controlled trial done in 46 maternity units across England and Wales, we compared planned delivery versus expectant management (usual care) with individual randomisation in women with late preterm pre-eclampsia from 34 to less than 37 weeks' gestation and a singleton or dichorionic diamniotic twin pregnancy. The co-primary maternal outcome was a composite of maternal morbidity or recorded systolic blood pressure of at least 160 mm Hg with a superiority hypothesis. The co-primary perinatal outcome was a composite of perinatal deaths or neonatal unit admission up to infant hospital discharge with a non-inferiority hypothesis (non-inferiority margin of 10% difference in incidence). Analyses were by intention to treat, together with a per-protocol analysis for the perinatal outcome. The trial was prospectively registered with the ISRCTN registry, ISRCTN01879376. The trial is closed to recruitment but follow-up is ongoing. FINDINGS: Between Sept 29, 2014, and Dec 10, 2018, 901 women were recruited. 450 women (448 women and 471 infants analysed) were allocated to planned delivery and 451 women (451 women and 475 infants analysed) to expectant management. The incidence of the co-primary maternal outcome was significantly lower in the planned delivery group (289 [65%] women) compared with the expectant management group (338 [75%] women; adjusted relative risk 0·86, 95% CI 0·79-0·94; p=0·0005). The incidence of the co-primary perinatal outcome by intention to treat was significantly higher in the planned delivery group (196 [42%] infants) compared with the expectant management group (159 [34%] infants; 1·26, 1·08-1·47; p=0·0034). The results from the per-protocol analysis were similar. There were nine serious adverse events in the planned delivery group and 12 in the expectant management group. INTERPRETATION: There is strong evidence to suggest that planned delivery reduces maternal morbidity and severe hypertension compared with expectant management, with more neonatal unit admissions related to prematurity but no indicators of greater neonatal morbidity. This trade-off should be discussed with women with late preterm pre-eclampsia to allow shared decision making on timing of delivery. FUNDING: National Institute for Health Research Health Technology Assessment Programme.

Standardisation of the Parent Report of Children's Abilities-Revised (PARCA-R): a norm-referenced assessment of cognitive and language development at age 2 years.

BACKGROUND: The Parent Report of Children's Abilities-Revised (PARCA-R) can be used to identify preterm born children at risk for developmental delay at age 24 months. However, standardised scores for assessing all children in the general population and quantifying development relative to the norm are unavailable, thus limiting the use of the questionnaire. We aimed to develop scores that are standardised by age and sex for the PARCA-R to assess children's cognitive and language development at age 24-27 months. METHODS: Anonymised data from PARCA-R questionnaires that were completed by parents of 2-year-old children in three previous studies were obtained to form a standardisation sample that was representative of the UK general population. Anonymised data were obtained from three further studies to assess the external validity and clinical validity of the standardised scores. We used the lambda-mu-sigma (lambda for skewness, mu for median, sigma for the coefficient of variation) method to develop scores that are standardised by age and sex for three scales (non-verbal cognitive development, language development, and total parent report composite [PRC]) for children in four 1-month age bands, spanning age 23·5-27·5 months. FINDINGS: We included 6402 children (mean age 25 months and 1 day [range 23 months and 16 days to 27 months and 15 days]) in the standardisation sample and 709 (mean age 24 months and 19 days [23 months and 16 days to 27 months and 15 days]) to test the external validity and 1456 (mean age 24 months and 8·5 days [23 months and 16 days to 27 months and 15 days]) to test the clinical validity of the standardised scores. For all PARCA-R scales, mean standardised scores approximated 100 (SD 15) in both sexes and all age groups. These scores were independent of socioeconomic status. Standardised scores were close to 100 (15) in the external validation sample, showing the validity of the scores. Standardised scores for the total PRC scale for children born very preterm (<32 weeks' gestation) were 0·47 SD lower on average than the normative mean, and for children with neonatal sepsis were 0·73 SD lower on average than the normative mean. These scores were equivalent to a standardised score of 93 (95% CI 91-94) for children born very preterm and 89 (88-91) for children with neonatal sepsis, thus showing clinical validity. INTERPRETATION: The PARCA-R provides a norm-referenced, standardised assessment of cognitive and language development at 24-27 months of age. The questionnaire is available non-commercially in English with translations available in 14 other languages, thus providing clinicians and researchers with a cost-effective tool for assessing development and identifying children with delay. FUNDING: Action Medical Research (Ref: GN2580).

Computerised interpretation of the fetal heart rate during labour: a randomised controlled trial (INFANT).

BACKGROUND: Continuous electronic fetal monitoring (EFM) in labour is widely used and computerised interpretation has the potential to increase its utility. OBJECTIVES: This trial aimed to find out whether or not the addition of decision support software to assist in the interpretation of the cardiotocograph (CTG) reduced the number of poor neonatal outcomes, and whether or not it was cost-effective. DESIGN: Two-arm individually randomised controlled trial. The allocations were computer generated using stratified block randomisation employing variable block sizes. The trial was not masked. SETTING: Labour wards in England, Scotland and the Republic of Ireland. PARTICIPANTS: Women in labour having EFM, with a singleton or twin pregnancy, at ≥ 35 weeks' gestation. INTERVENTIONS: Decision support or no decision support. MAIN OUTCOME MEASURES: The primary outcomes were (1) a composite of poor neonatal outcome {intrapartum stillbirth or early neonatal death (excluding lethal congenital anomalies), or neonatal morbidity [defined as neonatal encephalopathy (NNE)], or admission to a neonatal unit within 48 hours for ≥ 48 hours (with evidence of feeding difficulties, respiratory illness or NNE when there was evidence of compromise at birth)}; and (2) developmental assessment at the age of 2 years in a subset of surviving children. RESULTS: Between 6 January 2010 and 31 August 2013, 47,062 women were randomised and 46,042 were included in the primary analysis (22,987 in the decision support group and 23,055 in the no decision support group). The short-term primary outcome event rate was higher than anticipated. There was no evidence of a difference in the incidence of poor neonatal outcome between the groups: 0.7% (n = 172) of babies in the decision support group compared with 0.7% (n = 171) of babies in the no decision support group [adjusted risk ratio 1.01, 95% confidence interval (CI) 0.82 to 1.25]. There was no evidence of a difference in the long-term primary outcome of the Parent Report of Children's Abilities-Revised with a mean score of 98.0 points [standard deviation (SD) 33.8 points] in the decision support group and 97.2 points (SD 33.4 points) in the no decision support group (mean difference 0.63 points, 95% CI -0.98 to 2.25 points). No evidence of a difference was found for health resource use and total costs. There was evidence that decision support did change practice (with increased fetal blood sampling and a lower rate of repeated alerts). LIMITATIONS: Staff in the control group may learn from exposure to the decision support arm of the trial, resulting in improved outcomes in the control arm. This was identified in the planning stage and felt to be unlikely to have a significant effect on the results. As this was a pragmatic trial, the response to CTG alerts was left to the attending clinicians. CONCLUSIONS: This trial does not support the hypothesis that the use of computerised interpretation of the CTG in women who have EFM in labour improves the clinical outcomes for mothers or babies. FUTURE WORK: There continues to be an urgent need to improve knowledge and training about the appropriate response to CTG abnormalities, including timely intervention. TRIAL REGISTRATION: Current Controlled Trials ISRCTN98680152. FUNDING: This project was funded by the National Institute for Health Research (NIHR) HTA programme and will be published in full in Health Technology Assessment; Vol. 22, No. 9. See the NIHR Journals Library website for further project information. Sara Kenyon was part funded by the NIHR Collaboration for Leadership in Applied Health Research and Care West Midlands.

A multicentre, randomised controlled trial of position during the late stages of labour in nulliparous women with an epidural: clinical effectiveness and an economic evaluation (BUMPES).

BACKGROUND: Epidural analgesia leads to increased risk of instrumental vaginal delivery (IVD). There is debate about whether or not posture in second-stage labour influences the incidence of spontaneous vaginal birth (SVB). OBJECTIVES: In nulliparous women with epidural analgesia, does a policy of adopting an 'upright position' throughout second-stage labour increase the incidence of SVB compared with a policy of adopting a 'lying-down' position? DESIGN: Two-arm randomised controlled trial. SETTING: Maternity units in England and Wales. PARTICIPANTS: Nulliparous women aged ≥ 16 years, at ≥ 37 weeks' gestation with singleton cephalic presentation and intended SVB, in second-stage labour with an epidural providing effective pain relief. INTERVENTIONS: (1) Upright position to maintain the pelvis in as vertical a plane as possible; and (2) lying-down position to maintain the pelvis in as horizontal a plane as possible. MAIN OUTCOME MEASURES: The primary outcome measure was incidence of SVB. Secondary outcomes included augmentation, interventions to maintain blood pressure, duration of labour, episiotomy, genital tract trauma, post-partum haemorrhage, maternal satisfaction, neonatal metabolic acidosis, 5-minute Apgar score of < 4, resuscitation at birth and admission to neonatal unit. At 1 year for (1) women: urinary or faecal incontinence, dyspareunia and health-related quality of life; (2) for infants: major morbidity. A cost-consequences analysis with a time horizon of 1 year after the birth from a NHS perspective. RESULTS: Between October 2010 and January 2014, 3236 women were randomised from 41 centres in England and Wales. There was a statistically significant difference in the incidence of SVB between groups, with 35.2% of women achieving a SVB in the upright group, compared with 41.1% in the lying-down group (adjusted risk ratio 0.86, 95% confidence interval 0.78 to 0.94). There was no evidence of differences in most of the secondary maternal or neonatal outcomes, or in long-term outcomes at the 12-month follow-up. No significant overall cost differences were observed between upright and lying-down positions for mothers or their babies. LIMITATIONS: Measurement of adherence was challenging in this unmasked trial, and adherence could be influenced by midwives' beliefs about the allocated positions. If adherence was poor, this would have diluted the difference between the two groups. CONCLUSIONS: There is clear evidence of the benefit of adopting a lying-down position in second-stage labour in nulliparous women with epidural analgesia, with no apparent disadvantages in either short- or long-term outcomes for mother or baby, and this is cost neutral for the NHS. FUTURE WORK: Questions remain about whether or not other positions could increase the incidence of SVB further in this group of women. The results also raise questions about the role of maternal position in second-stage labour in women without an epidural. TRIAL REGISTRATION: Current Controlled Trials ISRCTN35706297. FUNDING: This project was funded by the National Institute for Health Research Health Technology Assessment programme and will be published in Health Technology Assessment, Vol 21, No. 65. See the NIHR Journals Library website for further project information.

A randomised controlled trial of the probiotic Bifidobacterium breve BBG-001 in preterm babies to prevent sepsis, necrotising enterocolitis and death: the Probiotics in Preterm infantS (PiPS) trial.

BACKGROUND: Necrotising enterocolitis (NEC) and late-onset sepsis remain important causes of death and morbidity in preterm babies. Probiotic administration might strengthen intestinal barrier function and provide protection; this is supported by published meta-analyses, but there is a lack of large well-designed trials. OBJECTIVE: To test the use of the probiotic Bifidobacterium breve strain BBG-001 to prevent NEC, late-onset sepsis and death in preterm babies while monitoring probiotic colonisation of participants. DESIGN: Double-blind, randomised, placebo-controlled trial. SETTING: Recruitment was carried out in 24 hospitals, and the randomisation programme used a minimisation algorithm. Parents, clinicians and outcome assessors were blinded to the allocation. PARTICIPANTS: Babies born between 23 and 30 weeks' gestation and randomised within 48 hours of birth. Exclusions included life-threatening or any gastrointestinal malformation detected within 48 hours of birth and no realistic chance of survival. INTERVENTIONS: Active intervention: 1 ml of B. breve BBG-001 in one-eighth-strength infant formula Neocate(®) (Nutricia Ltd, Trowbridge, UK), (6.7 × 10(7) to 6.7 × 10(9) colony-forming units) per dose administered enterally. Placebo: 1 ml of one-eighth-strength infant formula Neocate. Started as soon as practicable and continued daily until 36 weeks' postmenstrual age. MAIN OUTCOME MEASURES: Primary outcomes were an episode of bloodstream infection, with any organism other than a skin commensal, in any baby between 72 hours and 46 weeks' postmenstrual age; an episode of NEC Bell stage ≥ 2 in any baby; and death before discharge from hospital. Secondary outcomes included stool colonisation with B. breve. RESULTS: In total, 654 babies were allocated to receive probiotic and 661 to receive placebo over 37 months from July 2010. Five babies were withdrawn; 650 babies from the probiotic group and 660 from the placebo group were included in the primary analysis. Baseline characteristics were well balanced. There was no evidence of benefit for the primary outcomes {sepsis: 11.2% vs. 11.7% [adjusted relative risk (RR) 0.97, 95% confidence interval (CI) 0.73 to 1.29]; NEC Bell stage ≥ 2: 9.4% vs. 10.0% [adjusted RR 0.93, 95% CI 0.68 to 1.27]; and death: 8.3% vs. 8.5% [adjusted RR 0.93, 95% CI 0.67 to 1.30]}. B. breve colonisation status was available for 1186 (94%) survivors at 2 weeks' postnatal age, of whom 724 (61%) were positive: 85% of the probiotic group and 37% of the placebo group. There were no differences for subgroup analyses by minimisation criteria and by stool colonisation with B. breve at 2 weeks. No harms associated with the interventions were reported. LIMITATIONS: Cross-colonisation of the placebo arm could have reduced statistical power and confounded results; analyses suggest that this did not happen. CONCLUSIONS: This is the largest trial to date of a probiotic intervention. It shows no evidence of benefit and does not support routine use of probiotics for preterm infants. FUTURE WORK RECOMMENDATIONS: The increasing understanding of the pathogenesis of NEC and sepsis will inform the choice of probiotics for testing and better define the target population. Future Phase III trials should incorporate monitoring of the quality and viability of the intervention and colonisation rates of participants; cluster design should be considered. TRIAL REGISTRATION: Current Controlled Trials ISRCTN05511098 and EudraCT 2006-003445-17. FUNDING: This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 20, No. 66. See the NIHR Journals Library website for further project information.

Evaluation of the effects of an offer of a monetary incentive on the rate of questionnaire return during follow-up of a clinical trial: a randomised study within a trial.

BACKGROUND: A systematic review on the use of incentives to promote questionnaire return in clinical trials suggest they are effective, but not all studies have sufficient funds to use them. Promising an incentive once data are returned can reduce the cost-burden of this approach, with possible further cost-savings if the offer were restricted to reminder letters only. This study aimed to evaluate the effect of promising a monetary incentive at first mailout versus a promise on reminder letters only. METHODS: This was a randomised Study Within A Trial (SWAT) nested within BUMPES, a multicentre randomised controlled trial of maternal position in the late stage of labour in women with an epidural. The follow-up questionnaire asked for information on the women's health, wellbeing and health service use one year following the birth of their baby. Women who consented to be contacted were randomised to a promise of a monetary incentive at first mailout or a promise on reminder letters only. Women were given an option of completing the questionnaire on paper or on online. The incentive was posted out on receipt of a completed questionnaire. The primary outcome was the overall return rate, and secondary outcomes were the return rate without any chasing from the study office, and the total cost of the vouchers. RESULTS: A total of 1,029 women were randomised, 508 to the first mailout group and 518 to the reminder group. There was no evidence to suggest a difference between groups in the overall return rate (adjusted RR 1.03 (95 % CI 0.96 to 1.11), however the proportion returned without chasing was higher in the first mailout group (adjusted RR 1.22, 95 % CI 1.07 to 1.39). The total cost of the vouchers per participant was higher in the first mailout group (mean difference £4.56, 95 % CI £4.02 to £5.11). CONCLUSIONS: Offering a monetary incentive when a reminder is required could be cost-effective depending on the sample size of the study and the resources available to administer the reminder letters. TRIAL REGISTRATION: The BUMPES Trial is registered with Current Controlled Trials: ISRCTN35706297 , 26(th) August 2009.

Death, bereavement and randomised controlled trials (BRACELET): a methodological study of policy and practice in neonatal and paediatric intensive care trials.

BACKGROUND: Researchers have seldom included bereaved parents in studies of participants' views of randomised controlled trials (RCTs); hence our understanding of the impact of trials is based on skewed and incomplete samples. Little is known about parental experiences of the death of a child subsequent to their enrolment in a trial or of provision made for this experience by clinicians and trial teams. The Bereavement and RAndomised ControlLEd Trials (BRACELET) study was funded to consider bereavement in the context of paediatric intensive care (PIC) and neonatal intensive care (NIC) trials. DESIGN AND METHODS: The study comprised three interlinked components: a quantitative survey of RCT activity in UK paediatric intensive care units (PICUs) and neonatal intensive care units (NICUs), UK RCT recruitment and mortality rates, and provision for bereavement during 2002-6; a qualitative interview study involving 51 bereaved parents and 59 clinicians and trial team members associated with five neonatal trials; and a methodological study to inform future research. RESULTS: Fifty RCTs were identified as having enrolled babies or children from 2002 to 2006. Approximately 50% of UK NICUs and PICUs (54 NICUs, six PICUs) participated in at least one of these trials. Collectively they enrolled over 3000 children. Most enrolled small numbers, the majority of participants being enrolled by a small group of academic medical units. The proportion of deaths following trial enrolment was 17% in NIC trials and 6% in PIC trials. The qualitative study showed that trial-related decisions were made in a range of circumstances, some after extremely preterm births, others after complicated term deliveries, often under time pressures and in escalating crises. Parents' interest in trials appeared to recede initially but could re-emerge over time. They often valued opportunities to engage with a trial and were interested in more contact and information than they actually received. Clinicians often saw NICU bereavement policies as meeting parental needs, and trial participation as being of relatively minor significance in bereavement. This view may result from the positioning of clinicians' encounters with parents only in the initial stages of grief when trials were not a priority. Trial teams used a range of bereavement strategies, from no further contact to a pioneering multipart follow-up package. Communication with bereaved parents was complicated by limited contact opportunities. Trial teams were obliged to work without knowing whether their communications were appreciated, were problematic, or even whether they were received by parents. The methodological component highlighted strategies for recruitment and data collection in this sensitive setting. Recruitment by unsupported postal contact generally failed and a more personal approach via clinicians was more effective, supplemented by publicity material distributed via trusted organisations. CONCLUSIONS: A co-ordinated response to bereavement is as much a part of the running of trials as recruitment, and needs to be considered at trial inception. BRACELET has demonstrated the value and feasibility of research with bereaved parents involved in NIC trials. In order to respond to bereavement in a fair and sensitive way, as well as to better inform the design of RCTs, it is crucial that we listen to bereaved parents and evaluate new methods for so doing. More research is therefore needed into the experiences of bereavement subsequent to trial enrolment, with study of bereavement strategies in NIC trials as they are introduced. In addition, future studies should determine whether parents and triallists in PIC trials (and trials in adults) face the same issues as in NIC trials. Careful studies are necessary to explore how feedback of trial results are received and understood by bereaved and non-bereaved parents, and how individual trial teams manage this situation. An additional research area for exploring experiences of parenting twins and higher-order births in trials arose from BRACELET. Developmental research should continue to explore means of involving a wider range of parents in future research, including via publicity and specialist websites. Finally, methodological research is needed to ensure that we have the tools to explore, with parents and other relatives, as partners in research, a range of trial-related topics, which might be challenging, as the information is complex or the focus is sensitive. FUNDING: Funding for this study was provided by the Health Technology Assessment programme of the National Institute for Health Research.

Incidence, risk factors, management, and outcomes of stroke in pregnancy.

OBJECTIVE: To estimate the incidence of antenatal stroke in the United Kingdom and to describe risk factors associated with stroke during pregnancy, management, and outcomes. METHODS: A population-based (nationwide) cohort and nested case-control study was conducted using the UK Obstetric Surveillance System between October 2007 and March 2010. We investigated the potential factors associated with antenatal stroke using a logistic regression analysis to estimate odds ratios (ORs) and 95% confidence intervals (CIs). RESULTS: Thirty cases of antenatal stroke were reported giving an estimated incidence of 1.5 cases per 100,000 women delivering (95% CI 1.0-2.1). The incidences of nonhemorrhagic and hemorrhagic stroke were 0.9 (95% CI 0.5-1.3) and 0.6 (95% CI 0.3-1.0) per 100,000 women delivering. Factors associated with increased risk of antenatal stroke were history of migraine (adjusted OR 8.5, 95% CI 1.5-62.1), gestational diabetes (adjusted OR 26.8, 95% CI 3.2-∞), and preeclampsia or eclampsia (adjusted OR 7.7, 95% CI 1.3-55.7). There was wide variation in the use of pharmacologic, surgical, and organized stroke unit care. There were six stroke-related maternal deaths giving a case-fatality rate of 20% of all strokes, 50% of hemorrhagic strokes, and a mortality rate of 0.3 (95% CI 0.1-0.6) per 100,000 women delivering. CONCLUSION: The risk of a stroke during pregnancy is low; however, the poor outcomes in terms of morbidity and mortality and variations in care highlight the importance of such women receiving specialist stroke care. Clinicians should be aware of an association with a history of migraine, gestational diabetes, and preeclampsia or eclampsia. LEVEL OF EVIDENCE: II.

Cost effectiveness of alternative planned places of birth in woman at low risk of complications: evidence from the Birthplace in England national prospective cohort study.

OBJECTIVES: To estimate the cost effectiveness of alternative planned places of birth. DESIGN: Economic evaluation with individual level data from the Birthplace national prospective cohort study. SETTING: 142 of 147 trusts providing home birth services, 53 of 56 freestanding midwifery units, 43 of 51 alongside midwifery units, and a random sample of 36 of 180 obstetric units, stratified by unit size and geographical region, in England, over varying periods of time within the study period 1 April 2008 to 30 April 2010. PARTICIPANTS: 64,538 women at low risk of complications before the onset of labour. INTERVENTIONS: Planned birth in four alternative settings: at home, in freestanding midwifery units, in alongside midwifery units, and in obstetric units. MAIN OUTCOME MEASURES: Incremental cost per adverse perinatal outcome avoided, adverse maternal morbidity avoided, and additional normal birth. The non-parametric bootstrap method was used to generate net monetary benefits and construct cost effectiveness acceptability curves at alternative thresholds for cost effectiveness. RESULTS: The total unadjusted mean costs were £1066, £1435, £1461, and £1631 for births planned at home, in freestanding midwifery units, in alongside midwifery units, and in obstetric units, respectively (equivalent to about €1274, $1701; €1715, $2290; €1747, $2332; and €1950, $2603). Overall, and for multiparous women, planned birth at home generated the greatest mean net benefit with a 100% probability of being the optimal setting across all thresholds of cost effectiveness when perinatal outcomes were considered. There was, however, an increased incidence of adverse perinatal outcome associated with planned birth at home in nulliparous low risk women, resulting in the probability of it being the most cost effective option at a cost effectiveness threshold of £20 000 declining to 0.63. With regards to maternal outcomes in nulliparous and multiparous women, planned birth at home generated the greatest mean net benefit with a 100% probability of being the optimal setting across all thresholds of cost effectiveness. CONCLUSIONS: For multiparous women at low risk of complications, planned birth at home was the most cost effective option. For nulliparous low risk women, planned birth at home is still likely to be the most cost effective option but is associated with an increase in adverse perinatal outcomes.

Social and ethnic inequalities in infant mortality: a perspective from the United kingdom.

Social inequalities in infant mortality can be clearly demonstrated in the countries of the United Kingdom with a social gradient between different groups. Marked variations in infant mortality between ethnic groups are also evident in England and Wales, with the highest rates seen in Pakistani and Caribbean infants and the lowest rates in the white and Bangladeshi groups. Although individual risk factors for infant mortality are well understood, the reasons why certain social and ethnic groups have higher rates remain to be fully elucidated. Policies and interventions to tackle these inequalities are likely to be most effective if they have both universal and targeted components to "level-up" rates to the rate of the most advantaged in society.

Exploring the condom gap: is supply or demand the limiting factor - condom access and use in an urban and a rural setting in Kilifi district, Kenya.

OBJECTIVE: to explore the extent of the condom gap, investigating the relative roles of supply-side and demand-side factors in determining condom use. DESIGN: GPS mapping of condom outlets, and population-based survey. METHODS: an urban and a rural site were selected within the Epidemiological and Demographic Surveillance Site in Kilifi district, Kenya. Potential condom outlets (n = 281) were mapped and surveyed, and questionnaires on condom access and use (n = 630) were administered to a random sample of men and women aged 15-49. Multivariate logistic regression was performed to assess the relative roles of supply-side and demand-side barriers on condom use. RESULTS: the median straight-line distance to free condoms was 18-fold higher in the rural versus urban site. Among sexually active respondents, 42% had ever used a condom, and 23% had used a condom over the past 12 months, with lower levels among rural versus urban respondents (P < 0.05). The mean number of condoms used was 2.2/person per year among all sexually active individuals (condom users and nonusers), amounting to 8.2% protected sex acts/person per year. The adjusted odds of condom use (past 12 months) were 8.1 times greater among individuals experiencing no supply-side or demand-side barriers, compared with individuals experiencing both types of barriers. Despite low levels of usage and the presence of supply-side and demand-side barriers, reported unmet need for condoms was low. CONCLUSIONS: there is an urgent need for renewed condom promotion efforts aimed at building demand, in addition to improving physical access, in resource-limited settings with generalized HIV epidemics in sub-Saharan Africa.