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Background Lumbar puncture is an essential tool for diagnosing meningitis. Neonatal lumbar puncture, although frequently performed, has low success rates (50–60%). Standard technique includes lying infants on their side and removing the stylet ‘late’, that is, after the needle is thought to have entered the cerebrospinal fluid. Modifications to this technique include holding infants in the sitting position and removing the stylet ‘early’, that is, following transection of the skin. To the best of our knowledge, modified techniques have not previously been tested in adequately powered trials. Objectives The aim of the Neonatal Champagne Lumbar punctures Every time – An RCT (NeoCLEAR) trial was to compare two modifications to standard lumbar puncture technique, that is, use of the lying position rather than the sitting position and of ‘early’ rather than ‘late’ stylet removal, in terms of success rates and short-term clinical, resource and safety outcomes. Methods This was a multicentre 2 × 2 factorial pragmatic non-blinded randomised controlled trial. Infants requiring lumbar puncture (with a working weight ≥ 1000 g and corrected gestational age from 27+0 to 44+0 weeks), and whose parents provided written consent, were randomised by web-based allocation to lumbar puncture (1) in the sitting or lying position and (2) with early or late stylet removal. The trial was powered to detect a 10% absolute risk difference in the primary outcome, that is, the percentage of infants with a successful lumbar puncture (cerebrospinal fluid containing < 10,000 red cells/mm3). The primary outcome was analysed by modified intention to treat. Results Of 1082 infants randomised (sitting with early stylet removal, n = 275; sitting with late stylet removal, n = 271; lying with early stylet removal, n = 274; lying with late stylet removal, n = 262), 1076 were followed up until discharge. Most infants were term born (950/1076, 88.3%) and were aged < 3 days (936/1076, 87.0%) with a working weight > 2.5 kg (971/1076, 90.2%). Baseline characteristics were balanced across groups. In terms of the primary outcome, the sitting position was significantly more successful than lying [346/543 (63.7%) vs. 307/533 (57.6%), adjusted risk ratio 1.10 (95% confidence interval 1.01 to 1.21); p = 0.029; number needed to treat = 16 (95% confidence interval 9 to 134)]. There was no significant difference in the primary outcome between early stylet removal and late stylet removal [338/545 (62.0%) vs. 315/531 (59.3%), adjusted risk ratio 1.04 (95% confidence interval 0.94 to 1.15); p = 0.447]. Resource consumption was similar in all groups, and all techniques were well tolerated and safe. Limitations This trial predominantly recruited term-born infants who were < 3 days old, with working weights > 2.5 kg. The impact of practitioners’ seniority and previous experience of different lumbar puncture techniques was not investigated. Limited data on resource use were captured, and parent/practitioner preferences were not assessed. Conclusion Lumbar puncture success rate was higher with infants in the sitting position but was not affected by timing of stylet removal. Lumbar puncture is a safe, well-tolerated and simple technique without additional cost, and is easily learned and applied. The results support a paradigm shift towards sitting technique as the standard position for neonatal lumbar puncture, especially for term-born infants during the first 3 days of life. Future work The superiority of the sitting lumbar puncture technique should be tested in larger populations of premature infants, in those aged > 3 days and outside neonatal care settings. The effect of operators’ previous practice and the impact on family experience also require further investigation, alongside in-depth analyses of healthcare resource utilisation. Future studies should also investigate other factors affecting lumbar puncture success, including further modifications to standard technique. Trial registration This trial is registered as ISRCTN14040914 and as Integrated Research Application System registration 223737. Funding This award was funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment programme (NIHR award ref: 15/188/106) and is published in full in Health Technology Assessment; Vol. 27, No. 33. See the NIHR Funding and Awards website for further award information. Plain language summary Newborn babies are more susceptible to getting meningitis, and this can be fatal or have lifelong complications. A lumbar puncture is an essential test for diagnosing meningitis. Lumbar puncture involves taking a small amount of spinal fluid from the lower back using a needle. Analysing the fluid confirms or excludes meningitis, allowing the right treatment to be given. Lumbar punctures are commonly performed in newborns, but are technically difficult. In 50–60% of lumbar punctures in newborns, either no fluid is obtained or the sample is mixed with blood, making analysis less reliable. No-one knows which is the best technique, and so practice varies. The baby can be held lying on their side or sat up, and the ‘stylet’, which is a thin piece of metal that sits inside (and aids insertion of) the needle, can be removed either soon after passing through the skin (i.e. ‘early stylet removal’) or once the tip is thought to have reached the spinal fluid (i.e. ‘late stylet removal’). We wanted to find the best technique for lumbar puncture in newborns. Therefore, we compared sitting with lying position, and ‘early’ with ‘late’ stylet removal. We carried out a large trial in newborn care and maternity wards in 21 UK hospitals. With parental consent, we recruited 1082 full-term and premature babies who needed a lumbar puncture. Our results demonstrated that the sitting position was more successful than lying position, but the timing of stylet removal did not affect success. In summary, the sitting position is an inexpensive, safe, well-tolerated and easily learned way to improve lumbar puncture success rates in newborns. Our results strongly support using this technique in newborn babies worldwide. Scientific summary Background The neonatal period carries the highest risk of bacterial meningitis (≈ 1 per 4000–5000 births), which is associated with significant mortality (≈ 10%) and morbidity (20–50%). Meningitis is diagnosed by analysis of cerebrospinal fluid (CSF), obtained via lumbar puncture (LP). LPs are frequently performed in newborns because of the non-specific clinical features of neonatal meningitis. However, LP success rates in newborns are much lower (50–60%) than in older children (78–87%). Unsuccessful LPs include those with heavily blood-stained CSF or LPs that fail to obtain CSF at all. Treatment for suspected or confirmed neonatal meningitis involves intravenous antibiotics, typically for 14–21 days. Unsuccessful LPs lead to repeated attempts, whereas LPs with equivocal or uninterpretable CSF results often prompt cautious treatment with extended courses of antibiotics. Prolonged antibiotic use is associated with a range of complications, including induced antimicrobial resistance. Consequently, interventions to improve neonatal LP success rates should allow more accurate diagnosis of meningitis, which will help reduce unnecessary courses of antibiotic therapy and extended hospitalisation, and will save healthcare resources. There have been few modifications to the original LP technique. Thus far, the sitting position, as employed for older patients, and ‘early stylet removal’ (ESR) have been suggested. ESR promises advantages because, in neonates, a ‘loss of resistance’ on entering the CSF is often indistinguishable and a needle advanced too far can cause venous puncture and a blood-stained tap, impairing CSF interpretation. We conducted the Neonatal Champagne Lumbar punctures Every time – An RCT (NeoCLEAR) trial to determine the optimal LP technique in neonates in terms of the effect of infant position (sitting vs. lying) and timing of stylet removal [ESR vs. late stylet removal (LSR)] on success [i.e. a CSF red blood cell (RBC) count of < 10,000/mm3] of first LP. Methods Trial design and oversight The NeoCLEAR trial was a 2 × 2 factorial open-label multicentre randomised controlled trial (RCT), with an internal pilot. The study protocol was published previously. The NeoCLEAR trial was co-ordinated by the National Perinatal Epidemiology Unit – Clinical Trials Unit. The University of Oxford (Oxford, UK) sponsored the trial. Trial oversight was conducted by the Trial Steering Committee and an independent Data Monitoring Committee. The funder [i.e. the National Institute for Health and Care Research (NIHR)] did not have a role in study design, conduct, data collection, analysis or interpretation. Ethics approval was obtained. Trial population Eligible infants were inpatients in UK neonatal units and maternity wards who required a LP at a corrected gestational age (CGA) of 27+0 to 44+0 weeks and with a working weight of ≥ 1000 g. Infants were excluded if they had already had a LP for the same indication, if they were unable to be held in sitting position or if sitting was deemed unsafe. Trial procedures Infants whose parents had provided consent were randomised 1 : 1 : 1 : 1 by a one-based system to the following four groups: (1) lying position and LSR, (2) lying position and ESR, (3) sitting position and LSR or (4) sitting position and ESR. Block randomisation was stratified according to site and CGA (four categories: 27+0 to 31+6 weeks, 32+0 to 36+6 weeks, 37+0 to 40+6 weeks and ≥ 41 weeks). Staff were trained in all four techniques. Any second LP required followed the same allocated technique. The need for any further LPs and the techniques used were determined by the clinical team. Blinding of practitioners was impossible, but the primary outcome was based on laboratory tests performed blinded to allocation. Outcomes Participants were followed up until discharge. The primary outcome was the proportion of infants with a successful first LP, defined as a CSF RBC count of < 10,000/mm3. Secondary outcomes included short-term clinical measures (e.g. number of procedures/attempts per infant, proportions with different CSF-based diagnoses, time taken per procedure, infant movement), resources (e.g. duration of antibiotics, length of stay) and safety (e.g. complications, adverse event reporting). Statistics and analysis The NeoCLEAR trial was designed with 90% power to detect a 10% absolute difference in the primary outcome (estimated comparator group event rate 59%), with a 5% two-sided significance level. Four hundred and eighty-three infants were required for each arm of each comparison (i.e. sitting vs. lying position and ESR vs. LSR). Allowing for 5% attrition, the recruitment target was 1020 infants. Outcomes were analysed by modified intention to treat (excluding participants who were withdrawn before collection of trial data or who did not undergo LP). For infant positioning, we compared groups (1) lying/LSR plus (2) lying/ESR with groups (3) sitting/LSR plus, (4) sitting/ESR. To assess the timing of stylet removal, we compared groups (1) plus (3) with groups (2) plus (4). We estimated risk ratios (RRs) for the primary outcome and all other dichotomous outcomes, the mean difference for normally distributed continuous outcomes and the median difference (Med D) for skewed continuous variables. The 95% confidence intervals (CIs) were calculated for all effect estimates. Groups were compared using regression analysis, adjusting for the stratification factors used at randomisation (i.e. centre and CGA) and allocation to the other intervention. The latter adjustment was advised after the final statistical analysis plan was signed off and is a noted deviation. Adjusted risk ratios (aRRs) were estimated using log-binomial regression, or using a Poisson regression model with a robust variance estimator in the event of non-convergence. Linear regression was used for normally distributed outcomes and quantile regression for skewed continuous outcomes. To mitigate multiple testing, inference was restricted to prespecified tested outcomes. A descriptive multiarm analysis was also performed for the primary outcome, other tested outcomes and baseline characteristics (i.e. for each of the four randomised groups). Effect modification between position (i.e. sitting/lying) and the timing of stylet removal (i.e. ESR/LSR) was investigated for the primary outcome using the statistical test for interaction. Prespecified subgroup analyses were conducted for working weight, day of life and CGA at trial entry. Two-sided p-values of ≤ 0.05 were considered to indicate statistical significance. Results From August 2018 to August 2020, 1082 participants from 21 centres in the UK were randomised in a 2 × 2 factorial design, resulting in two principal comparisons: (1) sitting position (n = 546) compared with lying position (n = 536) and (2) ESR (n = 549) compared with LSR (n = 533). A total of 1079 infants had a ‘first’ LP, and 166 (15.4%) infants had a second LP (each of these LP ‘procedures’ involved one or more ‘attempts’). Nine infants were withdrawn during the trial, but in the case of only one of these participants was consent withdrawn before data collection for the primary outcome. Three infants did not receive a LP, and in the case of a further two infants the consent form was missing. Overall, six infants were excluded, leaving 1076 infants for the final (modified intention-to-treat) analysis: (1) sitting position (n = 543) compared with lying position (n = 533) and (2) ESR (n = 545) compared with LSR (n = 531). All infants were followed up until discharge. Baseline characteristics were similar for the two groups in both comparisons, as recorded at trial entry and at time of first LP. The majority of infants were born at term, were < 3 days old and were not receiving respiratory support. Raised C-reactive protein was the most common indication for LP. First comparison: sitting position compared with lying position The primary outcome – a successful first LP – was achieved in 346 of 543 (63.7%) infants in the sitting arm and 307 of 533 (57.6%) infants in the lying arm [aRR 1.10 (95% CI 1.01 to 1.21); p = 0.03; adjusted absolute risk difference 6.1% (95% CI 0.7% to 11.4%), adjusted number needed to treat (NNT) 16 (95% CI 9 to 134)]. Infants allocated to the sitting position were less likely than infants allocated to the lying position to exhibit moderate or severe struggling at the time of needle insertion [169/541 (31.2%) vs. 202/527 (38.4%), aRR 0.82 (95% CI 0.71 to 0.94); p = 0.006]. Other secondary outcomes did not reach statistical significance, but predominantly favoured the sitting position. Based on microscopy of CSF extracted from the first and second LPs (and any culture/polymerase chain reaction results), infants who were sitting were more likely to be ‘negative’ for meningitis than infants who were lying [396/537 (73.7%) vs. 359/521 (68.9%)], and a result of ‘uninterpretable CSF’ (i.e. no sample obtained or CSF not possible to analyse, usually due to a heavily blood contaminated or clotted sample) was more likely to be recorded for infants who were lying than for infants who were sitting [139/521 (26.7%) vs. 114/537 (21.2%)]. Median duration of antibiotic treatment and length of stay were not significantly different in the sitting and lying arms {median 5 [interquartile range (IQR) 4–6] days in each arm, for both duration of antibiotic treatment and length of stay}. Four (0.3%) of 1241 first or second LPs, 1 in ESR and 1 in LSR arms, respectively, were abandoned because of cardiovascular deterioration. Lowest oxygen saturation (SpO2) during the first LP averaged 93% (IQR 89–96%) in the sitting arm and 90% (IQR 85–94%) in the lying arm (adjusted Med D 3.0%, 95% CI 2.1% to 3.9%; p < 0.001). Three of 1075 (0.3%) infants required increased respiratory support within 1 hour of their first LP (sitting arm, n = 1; lying arm, n = 2; not significantly different). The proportion of infants whose lowest SpO2 fell below 80% during the first LP (analysed post hoc) was 6.6% (35 of 532) in the sitting arm and 14.2% (72 of 508) in the lying LP arm, and this pattern was consistent in preterm and term-born babies. In 47 of 543 (8.7%) first LPs in infants allocated to the sitting position, at least one attempt involved switching to the lying position [compared with 4/533 (0.8%) infants allocated to the lying allocation, who were switched to sitting]. Of the 47 LPs where there was at least one attempt in which the allocated technique was not adhered to, the decision to change position was mostly made on the second (22/247) or third (24/257) attempt. The decision to change position was usually made by a clinical (45/47). Similarly, for the second LP, the sitting allocation was less often followed [for at least one attempt in 16/76 (22.5%) of infants allocated to sitting vs. 6/90 (7.0%) of infants allocated to lying]. There were no obvious differences in baseline infant characteristics between LPs that were carried out in the allocated position and those that were not. In prespecified subgroup analyses, the effect of position on the proportion of infants with a successful first LP was consistent across working weight and CGA at trial entry, but a difference in effect was observed between infants enrolled within 3 days of life (n = 836, RR 1.14, 95% CI 1.04 to 1.25) and those enrolled after 3 days (n = 140, RR 0.9, 95% CI 0.78 to 1.05; p = 0.001). Second comparison: early stylet removal compared with late stylet removal The primary outcome was achieved in 338 of 545 (62.0%) infants following ESR and in 315 of 531 (59.3%) infants following LSR. There was no significant difference between the groups (aRR 1.04, 95% CI 0.94 to 1.15; p = 0.45). There were also no obvious differences between the groups in any of the secondary outcomes. Either the first or the second LP (4/1242, 0.3%) was abandoned in four infants receiving LP (two in each arm) because of cardiovascular deterioration. Three of 1076 (0.3%) infants required increased respiratory support within 1 hour of their first LP (ESR, n =1; LSR, n =2; not significantly different). There were no differences in lowest SpO2, lowest heart rate (HR) or highest HR between the two arms. The allocated technique was not adhered to in 35 of 1076 (3.3%) first LPs, with similar numbers in each arm (untested outcome). In 13 of 78 infants allocated to ESR, the second LP involved at least one attempt without ESR, compared with 6 of 79 allocated to LSR; however, denominators were small and this was an untested outcome. The effect of timing of stylet removal on the proportion of infants with successful first LP was consistent across working weight at trial entry, CGA at randomisation and day of life at trial entry. Multiarm analysis: comparing four randomised groups (sitting plus early stylet removal, sitting plus late stylet removal, lying plus early stylet removal and lying plus late stylet removal) No significant interaction between infant position and timing of stylet removal was detected (p = 0.14). Multiarm baseline characteristics and analyses did not reveal any new obvious differences (only those previously described for the sitting position compared with the lying position; see First comparison: sitting position compared with lying position). Serious adverse events Four serious adverse events (SAEs) were reported during the trial. Three SAEs were deemed unrelated to LP. One infant, from the sitting/LSR group, developed a scrotal haematoma 2 days after LP. The infant did not undergo further investigations to identify a cause for this, and so a relationship with the LP could not be ruled out. Therefore, this event was deemed ‘possibly related’. Discussion The NeoCLEAR trial is, to the best of our knowledge, the first adequately powered RCT examining different LP techniques in newborns. The sitting position was superior to the lying position for achieving a successful first LP, with a NNT of 16. Sitting LP was also better tolerated in terms of infant struggling, SpO2 and HR. Timing of stylet removal did not influence LP success. Our results might be explained by the anatomical advantages of sitting position described in neonates: (1) the intervertebral spaces widen when the infants lean forward to adopt a (natural) kyphotic position; (2) the CSF passively sinks to the lowest point of the spinal canal and close to the entry site of the needle; and (3) this position is more comfortable for the baby, as evidenced by the reduced struggling we observed. At the time of the study, the only other paediatric RCT of sitting compared with lying position, by Hanson et al., involved 168 infants who were < 90 days of age in a paediatric emergency room setting.32 In that trial, the success rate did not differ significantly between groups (lateral group 63/82, 77%; sitting group, 61/85, 72%; difference 5.1%, 95% CI −8.2% to 18.3%). The suggestion that higher LP success rates could be achieved with ESR was based on reports of increased success rates with non-styletted needles. However, non-styletted needles are associated with iatrogenic intraspinal epidermoid tumour formation and, therefore, the technique of ESR was introduced. Subsequent observational studies suggested that ESR was associated with increased success rates in infants. At the time of the study, to the best of our knowledge, the NeoCLEAR trial is the first RCT to have investigated ESR and has demonstrated no significant benefit in it for neonatal LP. Therefore, we cannot advise for or against early or late stylet removal in neonates. Our safety analysis showed greater physiological stability for sitting LP, in keeping with previous observations. Other secondary outcomes lacked statistical significance, including resource outcomes. The NeoCLEAR trial has several strengths. To the best of our knowledge, it is the largest RCT, to date, investigating modifications to traditional LP technique, and the only such RCT in newborns. We chose to investigate modifications that came at no additional cost and were easily learned. The results are clear-cut, showing a significantly higher success rate for LPs with more interpretable CSF results when infants were held in a sitting position. Limitations include the fact that many practitioners were unfamiliar with sitting LP before the NeoCLEAR training sessions, and this may have led to more practitioners switching from the allocated sitting position to the lying position following an initially unsuccessful attempt. It could be speculated that success rates would have been even higher if there had been more experience of sitting position LP among practitioners, and if fewer practitioners had switched position. We did not investigate LPs carried out in infants with a CGA of under 27 weeks or over 44 weeks. Furthermore, most infants were born at or near term and had working weights above 2.5 kg and, therefore, we cannot extrapolate our results to infants born extremely pre or post term or to those of significantly different working weights. In addition, in the subgroup analyses of gestational ages, although the inconsistent effect of sitting position may well be a chance finding and/or due to confounders, the NeoCLEAR trial was underpowered to detect a significant difference for those beyond day 3 of life. In conclusion, the NeoCLEAR trial demonstrates that sitting position is superior to lying position for neonatal LP success rates (NNT 16), with no significant benefit for ESR. Adopting the sitting position is cost neutral, safe, well tolerated, and easy to learn. The results would be applicable in similar settings worldwide and should promote the sitting technique becoming the standard for neonatal lumbar puncture. Trial registration This trial is registered as ISRCTN14040914 and as Integrated Research Application System registration 223737. Funding This award was funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment programme (NIHR award ref: 15/188/106) and is published in full in Health Technology Assessment; Vol. 27, No. 33. See the NIHR Funding and Awards website for further award information.

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.

Abstract Background Loss to follow-up resulting in missing outcomes compromises the validity of trial results by reducing statistical power, negatively affecting generalisability and undermining assumptions made at analysis, leading to potentially biased and misleading results. Evidence that incentives are effective at improving response rates exists, but there is little evidence regarding the best approach, especially in the field of perinatal medicine. The NIHR-funded SIFT trial follow-up of infants at 2 years of age provided an ideal opportunity to address this remaining uncertainty. Methods Participants: parents of infants from participating neonatal units in the UK and Ireland followed up for SIFT (multicentre RCT investigating two speeds of feeding in babies with gestational age at birth

Background: Freezing all embryos, followed by thawing and transferring them into the uterine cavity at a later stage (freeze-all), instead of fresh-embryo transfer may lead to improved pregnancy rates and fewer complications during in vitro fertilisation and pregnancies resulting from it. Objective: We aimed to evaluate if a policy of freeze-all results in a higher healthy baby rate than the current policy of transferring fresh embryos. Design: This was a pragmatic, multicentre, two-arm, parallel-group, non-blinded, randomised controlled trial. Setting: Eighteen in vitro fertilisation clinics across the UK participated from February 2016 to April 2019. Participants: Couples undergoing their first, second or third cycle of in vitro fertilisation treatment in which the female partner was aged

Abstract Background The neonatal period carries the highest risk of bacterial meningitis (~ 1 in 5000 births), bearing high mortality (~ 10%) and morbidity (20–50%) rates. Lumbar puncture (LP) remains essential to the diagnosis of meningitis. Though LP is a common procedure in neonates, success rates are lower (50–60%) than in other patient populations. None of the currently-practised neonatal LP techniques are supported by evidence from adequately-powered, randomised controlled trials (RCTs). NeoCLEAR aims to compare two modifications to the traditional technique which are free, accessible, and commonly practised: sitting (as opposed to lying) position, and ‘early’ (as opposed to ‘late’) stylet removal. Methods/design Written parental informed consent permitting, infants in neonatal/maternity wards, of 27+ 0 to 44+ 0 weeks corrected gestational age and weighing ≥1000 g, who require an LP, will be randomly allocated to sitting or lying position, and to early or late stylet removal. The co-primary objectives are to compare success rates (the proportion of infants with cerebrospinal fluid red cell count

Abstract Background Infertility affects one in seven couples; many of these need in vitro fertilisation (IVF). IVF involves external hormones to stimulate a woman’s ovaries to produce eggs which are harvested surgically. Embryos, created in the laboratory by mixing eggs with sperm, are grown in culture for a few days before being replaced within the uterus (fresh embryo transfer). Spare embryos are usually frozen with a view to transfer at a later point in time – especially if the initial fresh transfer does not result in a pregnancy. Despite improvements in technology, IVF success rates remain low with an overall live birth rate of 25–30% per treatment. Additionally, there are concerns about health outcomes for mothers and babies conceived through IVF, particularly after fresh embryo transfer, including maternal ovarian hyperstimulation syndrome (OHSS) and preterm delivery. It is believed that high levels of hormones during ovarian stimulation could create a relatively hostile environment for embryo implantation whilst increasing the risk of OHSS. It has been suggested that freezing all embryos with the intention of thawing and replacing them within the uterus at a later stage (thawed frozen embryo transfer) instead of fresh embryo transfer, may lead to improved pregnancy rates and fewer complications. We aim to compare the clinical and cost effectiveness of fresh and thawed frozen embryo transfer, with the primary aim of identifying any difference in the chance of having a healthy baby. Methods E-Freeze is a pragmatic, multicentre two-arm parallel group randomised controlled trial where women aged ≥18 and

Abstract Background Pre-eclampsia is a pregnancy disorder, characterised by hypertension and multisystem complications in the mother. The adverse outcomes of pre-eclampsia include severe hypertension, stroke, renal and hepatic injury, haemorrhage, fetal growth restriction and even death. The optimal time to instigate delivery to prevent morbidity when pre-eclampsia occurs between 34 and 37 weeks’ gestation, without increasing problems related to infant immaturity or complications, remains unclear. Methods/design The PHOENIX trial is a non-masked, randomised controlled trial, comparing planned early delivery (with initiation of delivery within 48 h of randomisation) with usual care (expectant management) in women with pre-eclampsia between 34+ 0 and 36+ 6 weeks’ gestation. The primary objectives of the trial are to determine if planned delivery reduces adverse maternal outcomes, without increasing the short-term harm to infants (composite of perinatal deaths or neonatal unit admissions up to infant hospital discharge) or impacting long-term infant neurodevelopmental status at 2 years corrected age (Parent Report of Cognitive Abilities-Revised). Discussion Current practice in the UK at the time of trial commencement for management of pre-eclampsia varies by gestation. Previous trials have shown that in women with pre-eclampsia after 37 weeks of gestion, delivery is initiated, as maternal complications are reduced without increasing fetal risks. Prior to 34 weeks of gestation, usual management aims to prolong pregnancy for fetal benefit, unless severe complications occur, necessitating preterm delivery. This trial aims to address the uncertainty for women where the balance of benefits and risks of delivery compared to expectant management are uncertain. Previous trials in this area have been undertaken, but have not provided a definitive answer, and the research question remains active. The results of this trial are expected to influence clinical practice internationally, through direct adoption and by incorporation into guidelines in countries with similar settings. Trial registration ISRCTN01879376. Registered on 25 November 2013.

Background: Intrahepatic cholestasis of pregnancy, characterised by maternal pruritus and raised serum bile acid concentrations, is associated with increased rates of stillbirth, preterm birth and neonatal unit admission. Ursodeoxycholic acid is widely used as a treatment, but without an adequate evidence base. Objective: We aimed to evaluate whether or not ursodeoxycholic acid reduces adverse perinatal outcomes in affected women. Design: Multicentre, masked, randomised, placebo-controlled, two-arm, parallel-group trial. Setting: Thirty-three UK maternity units. Participants: Women with intrahepatic cholestasis of pregnancy aged ≥ 18 years, between 20+0 and 40+6 weeks’ gestation with a singleton or twin pregnancy and no known lethal fetal anomaly. Interventions: Women were randomly assigned (1 : 1 allocation ratio) to take ursodeoxycholic acid tablets or matched placebo tablets, at an equivalent dose of 1000 mg daily, titrated as needed. Main outcome measures: The primary outcome was a composite of perinatal death (in utero fetal death after randomisation or known neonatal death up to 7 days) or preterm delivery (

Background: Observational data suggest that slowly advancing enteral feeds in preterm infants may reduce necrotising enterocolitis but increase late-onset sepsis. The Speed of Increasing milk Feeds Trial (SIFT) compared two rates of feed advancement. Objective: To determine if faster (30 ml/kg/day) or slower (18 ml/kg/day) daily feed increments improve survival without moderate or severe disability and other morbidities in very preterm or very low-birthweight infants. Design: This was a multicentre, two-arm, parallel-group, randomised controlled trial. Randomisation was via a web-hosted minimisation algorithm. It was not possible to safely and completely blind caregivers and parents. Setting: The setting was 55 UK neonatal units, from May 2013 to June 2015. Participants: The participants were infants born at

Abstract Background Intrahepatic cholestasis of pregnancy (ICP) is the most common liver disorder specific to pregnancy and presents with maternal pruritus, raised concentrations of serum bile acids and abnormal liver function tests. ICP is associated with increased rates of spontaneous and iatrogenic preterm labour, fetal hypoxia, meconium-stained amniotic fluid and intrauterine death. Some clinicians treat ICP with ursodeoxycholic acid (UDCA) to improve maternal pruritus and biochemical abnormalities. However, there are currently no data to support the use of UDCA to improve pregnancy outcome as none of the trials performed to date have been powered to address this question. Methods The PITCHES trial is a triple-masked, placebo-controlled randomised trial, to evaluate UDCA versus placebo in women with ICP between 20 + 0 to 40 + 6 weeks’ gestation. The primary objective of the trial is to determine if UDCA treatment of women with ICP between 20 + 0 and 40 + 6 weeks’ gestation reduces the primary perinatal outcome: a composite of perinatal death (as defined by in utero fetal death after randomisation or known neonatal death up to 7 days) or preterm delivery (less than 37 weeks’ gestation) or neonatal unit admission for at least 4 h (from infant delivery until hospital discharge). The secondary objectives of the trial are (1) to investigate the effect of UDCA on other short-term outcomes for both mother and infant and (2) to assess the impact of UDCA on health care resource use, in terms of the total number of nights for mother and infant, together with level of care. Discussion Current practice in the UK at the time of trial commencement for the treatment of ICP is inconsistent, with some units routinely prescribing UDCA, others prescribing very little and the remainder offering it variably. Our previous pilot trial of UDCA in women with ICP demonstrated that the trial would be feasible, and the research question remains active and unanswered. Results are highly likely to influence clinical practice, through direct management and impact on national and international guidelines. Trial registration ISRCTN registry, ID: ISRCTN91918806. Prospectively registered on 27 August 2015.

Background: Sepsis is a leading cause of direct and indirect maternal death in both the UK and globally. All forms of operative delivery are associated with an increased risk of sepsis, and the National Institute for Health and Care Excellence’s guidance recommends the use of prophylactic antibiotics at all caesarean deliveries, based on substantial randomised controlled trial evidence of clinical effectiveness. A Cochrane review, updated in 2017 (Liabsuetrakul T, Choobun T, Peeyananjarassri K, Islam QM. Antibiotic prophylaxis for operative vaginal delivery. Cochrane Database Syst Rev 2017;8:CD004455), identified only one small previous trial of prophylactic antibiotics following operative vaginal birth (forceps or ventouse/vacuum extraction) and, given the small study size and extreme result, suggested that further robust evidence is needed. Objectives: To investigate whether or not a single dose of prophylactic antibiotic following operative vaginal birth is clinically effective for preventing confirmed or presumed maternal infection, and to investigate the associated impact on health-care costs. Design: A multicentre, randomised, blinded, placebo-controlled trial. Setting: Twenty-seven maternity units in the UK. Participants: Women who had an operative vaginal birth at ≥ 36 weeks’ gestation, who were not known to be allergic to penicillin or constituents of co-amoxiclav and who had no indication for ongoing antibiotics. Interventions: A single dose of intravenous co-amoxiclav (1 g of amoxicillin/200 mg of clavulanic acid) or placebo (sterile saline) allocated through sealed, sequentially numbered, indistinguishable packs. Main outcome measures: Primary outcome – confirmed or suspected infection within 6 weeks of giving birth. Secondary outcomes – severe sepsis, perineal wound infection, perineal pain, use of pain relief, hospital bed stay, hospital/general practitioner visits, need for additional perineal care, dyspareunia, ability to sit comfortably to feed the baby, maternal general health, breastfeeding, wound breakdown, occurrence of anaphylaxis and health-care costs. Results: Between March 2016 and June 2018, 3427 women were randomised: 1719 to the antibiotic arm and 1708 to the placebo arm. Seven women withdrew, leaving 1715 women in the antibiotic arm and 1705 in the placebo arm for analysis. Primary outcome data were available for 3225 out of 3420 women (94.3%). Women randomised to the antibiotic arm were significantly less likely to have confirmed or suspected infection within 6 weeks of giving birth (180/1619, 11%) than women randomised to the placebo arm (306/1606, 19%) (relative risk 0.58, 95% confidence interval 0.49 to 0.69). Three serious adverse events were reported: one in the placebo arm and two in the antibiotic arm (one was thought to be causally related to the intervention). Limitations: The follow-up rate achieved for most secondary outcomes was 76%. Conclusions: This trial has shown clear evidence of benefit of a single intravenous dose of prophylactic co-amoxiclav after operative vaginal birth. These results may lead to reconsideration of official policy/guidance. Further analysis of the mechanism of action of this single dose of antibiotic is needed to investigate whether earlier, pre-delivery or repeated administration could be more effective. Until these analyses are completed, there is no indication for administration of more than a single dose of prophylactic antibiotic, or for pre-delivery administration. Trial registration: Current Controlled Trials ISRCTN11166984. Funding: This project was funded by the National Institute for Health Research Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 23, No. 54. See the National Institute for Health Research Journals Library website for further project information.

Introduction Necrotising enterocolitis (NEC) is a potentially devastating neonatal disease. A temporal association between red cell transfusion and NEC is well described. Observational data suggest that withholding enteral feeds around red cell transfusions may reduce the risk of NEC but this has not been tested in randomised trials; current UK practice varies. Prevention of NEC is a research priority but no appropriately powered trials have addressed this question. The use of a simplified opt-out consent model and embedding trial processes within existing electronic patient record (EPR) systems provide opportunities to increase trial efficiency and recruitment.Methods and analysis We will undertake a randomised, controlled, multicentre, unblinded, pilot trial comparing two care pathways: continuing milk feeds (before, during and after red cell transfusions) and withholding milk feeds (for 4 hours before, during and for 4 hours after red cell transfusions), with infants randomly assigned with equal probability. We will use opt-out consent. A nested qualitative study will explore parent and health professional views. Infants will be eligible if born at

Background: 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. Objective: To 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. Design: Randomised, 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. Setting: UK neonatal units between May 2014 and September 2017. Participants: Infants born at

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 × 107 to 6.7 × 109 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.