Trial of Selective Early Treatment of Patent Ductus Arteriosus with Ibuprofen.

BACKGROUND: The cyclooxygenase inhibitor ibuprofen may be used to treat patent ductus arteriosus (PDA) in preterm infants. Whether selective early treatment of large PDAs with ibuprofen would improve short-term outcomes is not known. METHODS: We conducted a multicenter, randomized, double-blind, placebo-controlled trial evaluating early treatment (≤72 hours after birth) with ibuprofen for a large PDA (diameter of ≥1.5 mm with pulsatile flow) in extremely preterm infants (born between 23 weeks 0 days' and 28 weeks 6 days' gestation). The primary outcome was a composite of death or moderate or severe bronchopulmonary dysplasia evaluated at 36 weeks of postmenstrual age. RESULTS: A total of 326 infants were assigned to receive ibuprofen and 327 to receive placebo; 324 and 322, respectively, had data available for outcome analyses. A primary-outcome event occurred in 220 of 318 infants (69.2%) in the ibuprofen group and 202 of 318 infants (63.5%) in the placebo group (adjusted risk ratio, 1.09; 95% confidence interval [CI], 0.98 to 1.20; P = 0.10). A total of 44 of 323 infants (13.6%) in the ibuprofen group and 33 of 321 infants (10.3%) in the placebo group died (adjusted risk ratio, 1.32; 95% CI, 0.92 to 1.90). Among the infants who survived to 36 weeks of postmenstrual age, moderate or severe bronchopulmonary dysplasia occurred in 176 of 274 (64.2%) in the ibuprofen group and 169 of 285 (59.3%) in the placebo group (adjusted risk ratio, 1.09; 95% CI, 0.96 to 1.23). Two unforeseeable serious adverse events occurred that were possibly related to ibuprofen. CONCLUSIONS: The risk of death or moderate or severe bronchopulmonary dysplasia at 36 weeks of postmenstrual age was not significantly lower among infants who received early treatment with ibuprofen than among those who received placebo. (Funded by the National Institute for Health Research Health Technology Assessment Programme; Baby-OSCAR ISRCTN Registry number, ISRCTN84264977.).

Techniques to increase lumbar puncture success in newborn babies: the NeoCLEAR RCT.

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.

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 50­60% 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.

Frenotomy with breastfeeding support versus breastfeeding support alone for infants with tongue-tie and breastfeeding difficulties: the FROSTTIE RCT.

Background: Tongue-tie can be diagnosed in 3-11% of babies, with some studies reporting almost universal breastfeeding difficulties, and others reporting very few feeding difficulties that relate to the tongue-tie itself, instead noting that incorrect positioning and attachment are the primary reasons behind the observed breastfeeding difficulties and not the tongue-tie itself. The only existing trials of frenotomy are small and underpowered and/or include only very short-term or subjective outcomes. Objective: To investigate whether frenotomy is clinically and cost-effective to promote continuation of breastfeeding at 3 months in infants with breastfeeding difficulties diagnosed with tongue-tie. Design: A multicentre, unblinded, randomised, parallel group controlled trial. Setting: Twelve infant feeding services in the UK. Participants: Infants aged up to 10 weeks referred to an infant feeding service (by a parent, midwife or other breastfeeding support service) with breastfeeding difficulties and judged to have tongue-tie. Interventions: Infants were randomly allocated to frenotomy with standard breastfeeding support or standard breastfeeding support without frenotomy. Main outcome measures: Primary outcome was any breastmilk feeding at 3 months according to maternal self-report. Secondary outcomes included mother's pain, exclusive breastmilk feeding, exclusive direct breastfeeding, frenotomy, adverse events, maternal anxiety and depression, maternal and infant NHS health-care resource use, cost-effectiveness, and any breastmilk feeding at 6 months of age. Results: Between March 2019 and November 2020, 169 infants were randomised, 80 to the frenotomy with breastfeeding support arm and 89 to the breastfeeding support arm from a planned sample size of 870 infants. The trial was stopped in the context of the COVID-19 pandemic due to withdrawal of breastfeeding support services, slow recruitment and crossover between arms. In the frenotomy with breastfeeding support arm 74/80 infants (93%) received their allocated intervention, compared to 23/89 (26%) in the breastfeeding support arm. Primary outcome data were available for 163/169 infants (96%). There was no evidence of a difference between the arms in the rate of breastmilk feeding at 3 months, which was high in both groups (67/76, 88% vs. 75/87, 86%; adjusted risk ratio 1.02, 95% confidence interval 0.90 to 1.16). Adverse events were reported for three infants after surgery [bleeding (n = 1), salivary duct damage (n = 1), accidental cut to the tongue and salivary duct damage (n = 1)]. Cost-effectiveness could not be determined with the information available. Limitations: The statistical power of the analysis was extremely limited due to not achieving the target sample size and the high proportion of infants in the breastfeeding support arm who underwent frenotomy. Conclusions: This trial does not provide sufficient information to assess whether frenotomy in addition to breastfeeding support improves breastfeeding rates in infants diagnosed with tongue-tie. Future work: There is a clear lack of equipoise in the UK concerning the use of frenotomy, however, the effectiveness and cost-effectiveness of the procedure still need to be established. Other study designs will need to be considered to address this objective. Trial registration: This trial is registered as ISRCTN 10268851. Funding: This project was funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment Programme (project number 16/143/01) and will be published in full in Health Technology Assessment; Vol. 27, No. 11. See the NIHR Journals Library website for further project information. The funder had no role in study design or data collection, analysis and interpretation. The views expressed are those of the authors and not necessarily those of the NHS, the NIHR or the Department of Health and Social Care.

Many mothers and babies experience difficulties in establishing breastfeeding. In some babies it is thought that their difficulties may be linked to a condition called tongue-tie, in which a piece of skin tightly joins the middle part of the underside of the tongue to the base of the baby's mouth. This can be treated by an operation to divide the tight part/skin in the middle of the underneath of the tongue. We planned to carry out a trial of 870 babies to find out whether an operation together with breastfeeding support helps more mothers and babies with tongue-tie to continue breastfeeding until the baby is 3 months old compared to breastfeeding support on its own and whether the costs were different between the two groups of mothers and babies. We were only able to recruit 169 babies as the trial was stopped because of slow recruitment, changes to services in the COVID-19 pandemic and a high proportion of the babies in the breastfeeding support group going on to have an operation. There were no differences in the rate of breastfeeding at 3 months between the babies in the group who had an operation straightaway and those in the group that had breastfeeding support alone, or had an operation later. More than four in every five babies in both groups were still breastmilk feeding at 3 months. Three babies who had an operation, around 1 in 50 babies, had a complication of the operation (bleeding, scarring or a cut to the tube that makes saliva). Because of the small size of the study, we cannot say whether an operation to divide a tongue-tie along with breastfeeding support helps babies with tongue-tie and breastfeeding difficulties or has different costs. We will need to try different types of research to answer the question.

Mixed-methods feasibility study to inform a randomised controlled trial of proton pump inhibitors to reduce strictures following neonatal surgery for oesophageal atresia.

OBJECTIVES: This mixed-methods feasibility study aimed to explore parents' and medical practitioners' views on the acceptability and design of a clinical trial to determine whether routine prophylactic proton pump inhibitors (PPI) reduce the incidence of anastomotic stricture in infants with oesophageal atresia (OA). DESIGN: Semi-structured interviews with UK parents of an infant with OA and an online survey, telephone interviews and focus groups with clinicians. Data were analysed using reflexive thematic analysis and descriptive statistics. PARTICIPANTS AND SETTING: We interviewed 18 parents of infants with OA. Fifty-one clinicians (49 surgeons, 2 neonatologists) from 20/25 (80%) units involved in OA repair completed an online survey and 10 took part in 1 of 2 focus groups. Interviews were conducted with two clinicians whose survey responses indicated they had concerns about the trial. OUTCOME MEASURES: Parents and clinicians ranked the same top four outcomes ('Severity of anastomotic stricture', 'Incidence of anastomotic stricture', 'Need for treatment of reflux' and 'Presence of symptoms of reflux') as important to measure for the proposed trial. RESULTS: All parents and most clinicians found the use, dose and duration of omeprazole as the intervention medication, and the placebo control, as acceptable. Parents stated they would hypothetically consent to their child's participation in the trial. Concerns of a few parents and clinicians about infants suffering with symptomatic reflux, and the impact of this for study retention, appeared to be alleviated through the symptomatic reflux treatment pathway. Hesitant clinician views appeared to change through discussion of parental support for the study and by highlighting existing research that questions current practice of PPI treatment. CONCLUSIONS: Our findings indicate that parents and most clinicians view the proposed Treating Oesophageal Atresia with prophylactic proton pump inhibitors to prevent STricture (TOAST) trial to be feasible and acceptable so long as infants can be given PPI if clinicians deem it clinically necessary. This insight into parent and clinician views and concerns will inform pilot phase trial monitoring, staff training and the development of the trial protocol.

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.

Comparing the effect of a lactation-specific relaxation and visualisation intervention versus standard care on lactation and mental health outcomes in mothers of very premature infants (the EXPRESS trial): study protocol for a multi-centre, unmasked, randomised, parallel-group trial.

BACKGROUND: Premature birth is the leading cause of neonatal death and can cause major morbidity. Maximising the amount of maternal breastmilk given to very premature infants is important to improve outcomes, but this can be challenging for parents. Parents of infants receiving neonatal care also have high rates of anxiety and distress. There is growing evidence for the impact of maternal relaxation interventions on lactation, as well as mental health. The trial will assess whether a brief self-directed relaxation and visualisation intervention, recommended for use several times a day during expression of milk, improves lactation and mental health outcomes for mothers of very premature infants. METHODS: Multi-centre, randomised, controlled, unmasked, parallel-group trial with planned 132 participants who have experienced premature birth between 23 weeks and 31 weeks and 6 days of gestation and plan to express milk for at least 14 days. The primary outcome is the highest 24-h expressed milk yield recorded on any of day 4, day 14 or day 21 after birth. Secondary outcomes include exclusive breastmilk feeding at 36 weeks post-menstrual age and at 4 months after the estimated date of delivery, Spielberger State Trait Anxiety Index at day 21 and Post-traumatic stress Check List (for DSM 5) at day 21. DISCUSSION: Breastmilk feeding for premature infants is an important research priority, but there are few randomised controlled trials assessing interventions to help parents reach lactation goals in this challenging context. This trial will assess whether a no cost, easily scalable relaxation tool has a role in this setting. Given the lack of harm and potential for immediate dissemination, even a small benefit could have an important global impact. TRIAL REGISTRATION: ISRCTN16356650 . Date assigned: 19/04/2021.

Transfer of thawed frozen embryo versus fresh embryo to improve the healthy baby rate in women undergoing IVF: the E-Freeze RCT.

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 < 42 years. INTERVENTIONS: If at least three good-quality embryos were present on day 3 of embryo development, couples were randomly allocated to either freeze-all (intervention) or fresh-embryo transfer (control). OUTCOMES: The primary outcome was a healthy baby, defined as a live, singleton baby born at term, with an appropriate weight for their gestation. Secondary outcomes included ovarian hyperstimulation, live birth and clinical pregnancy rates, complications of pregnancy and childbirth, health economic outcome, and State-Trait Anxiety Inventory scores. RESULTS: A total of 1578 couples were consented and 619 couples were randomised. Most non-randomisations were because of the non-availability of at least three good-quality embryos (n = 476). Of the couples randomised, 117 (19%) did not adhere to the allocated intervention. The rate of non-adherence was higher in the freeze-all arm, with the leading reason being patient choice. The intention-to-treat analysis showed a healthy baby rate of 20.3% in the freeze-all arm and 24.4% in the fresh-embryo transfer arm (risk ratio 0.84, 95% confidence interval 0.62 to 1.15). Similar results were obtained using complier-average causal effect analysis (risk ratio 0.77, 95% confidence interval 0.44 to 1.10), per-protocol analysis (risk ratio 0.87, 95% confidence interval 0.59 to 1.26) and as-treated analysis (risk ratio 0.91, 95% confidence interval 0.64 to 1.29). The risk of ovarian hyperstimulation was 3.6% in the freeze-all arm and 8.1% in the fresh-embryo transfer arm (risk ratio 0.44, 99% confidence interval 0.15 to 1.30). There were no statistically significant differences between the freeze-all and the fresh-embryo transfer arms in the live birth rates (28.3% vs. 34.3%; risk ratio 0.83, 99% confidence interval 0.65 to 1.06) and clinical pregnancy rates (33.9% vs. 40.1%; risk ratio 0.85, 99% confidence interval 0.65 to 1.11). There was no statistically significant difference in anxiety scores for male participants (mean difference 0.1, 99% confidence interval -2.4 to 2.6) and female participants (mean difference 0.0, 99% confidence interval -2.2 to 2.2) between the arms. The economic analysis showed that freeze-all had a low probability of being cost-effective in terms of the incremental cost per healthy baby and incremental cost per live birth. LIMITATIONS: We were unable to reach the original planned sample size of 1086 and the rate of non-adherence to the allocated intervention was much higher than expected. CONCLUSION: When efficacy, safety and costs are considered, freeze-all is not better than fresh-embryo transfer. TRIAL REGISTRATION: This trial is registered as ISRCTN61225414. 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. 25. See the NIHR Journals Library website for further project information.

During in vitro fertilisation, eggs and sperm are mixed in a laboratory to create embryos. An embryo is placed in the womb 2­5 days later (fresh-embryo transfer) and the remaining embryos are frozen for future use. Initial research suggested that freezing all embryos followed by thawing and replacing them a few weeks later could improve treatment safety and success. Although these data were promising, the data came from small studies and were not enough to change practice and policy. We conducted a large, multicentre, clinical trial to evaluate the two strategies: fresh-embryo transfer compared with later transfer of frozen embryos. We also compared the costs of both strategies during in vitro fertilisation treatment, pregnancy and delivery. This study was conducted across 18 clinics in the UK from 2016 to 2019, and 619 couples participated. Couples were allocated to one of two strategies: immediate fresh-embryo transfer or freezing of all embryos followed later by transfer of frozen embryo. The study's aim was to find out which type of embryo transfer gave participants a higher chance of having a healthy baby. We found that freezing all embryos followed by frozen-embryo transfer did not lead to a higher chance of having a healthy baby. There were no differences between strategies in the number of live births, the miscarriage rate or the number of pregnancy complications. Fresh-embryo transfer was less costly from both a health-care and a patient perspective. A routine strategy of freezing all embryos is not justified given that there was no increase in success rates but there were extra costs and delays to embryo transfer.

Elective freezing of embryos versus fresh embryo transfer in IVF: a multicentre randomized controlled trial in the UK (E-Freeze).

STUDY QUESTION: Does a policy of elective freezing of embryos, followed by frozen embryo transfer result in a higher healthy baby rate, after first embryo transfer, when compared with the current policy of transferring fresh embryos? SUMMARY ANSWER: This study, although limited by sample size, provides no evidence to support the adoption of a routine policy of elective freeze in preference to fresh embryo transfer in order to improve IVF effectiveness in obtaining a healthy baby. WHAT IS KNOWN ALREADY: The policy of freezing all embryos followed by frozen embryo transfer is associated with a higher live birth rate for high responders but a similar/lower live birth after first embryo transfer and cumulative live birth rate for normal responders. Frozen embryo transfer is associated with a lower risk of ovarian hyperstimulation syndrome (OHSS), preterm delivery and low birthweight babies but a higher risk of large babies and pre-eclampsia. There is also uncertainty about long-term outcomes, hence shifting to a policy of elective freezing for all remains controversial given the delay in treatment and extra costs involved in freezing all embryos. STUDY DESIGN, SIZE, DURATION: A pragmatic two-arm parallel randomized controlled trial (E-Freeze) was conducted across 18 clinics in the UK from 2016 to 2019. A total of 619 couples were randomized (309 to elective freeze/310 to fresh). The primary outcome was a healthy baby after first embryo transfer (term, singleton live birth with appropriate weight for gestation); secondary outcomes included OHSS, live birth, clinical pregnancy, pregnancy complications and cost-effectiveness. PARTICIPANTS/MATERIALS, SETTING, METHODS: Couples undergoing their first, second or third cycle of IVF/ICSI treatment, with at least three good quality embryos on Day 3 where the female partner was ≥18 and <42 years of age were eligible. Those using donor gametes, undergoing preimplantation genetic testing or planning to freeze all their embryos were excluded. IVF/ICSI treatment was carried out according to local protocols. Women were followed up for pregnancy outcome after first embryo transfer following randomization. MAIN RESULTS AND THE ROLE OF CHANCE: Of the 619 couples randomized, 307 and 309 couples in the elective freeze and fresh transfer arms, respectively, were included in the primary analysis. There was no evidence of a statistically significant difference in outcomes in the elective freeze group compared to the fresh embryo transfer group: healthy baby rate {20.3% (62/307) versus 24.4% (75/309); risk ratio (RR), 95% CI: 0.84, 0.62 to 1.15}; OHSS (3.6% versus 8.1%; RR, 99% CI: 0.44, 0.15 to 1.30); live birth rate (28.3% versus 34.3%; RR, 99% CI 0.83, 0.65 to 1.06); and miscarriage (14.3% versus 12.9%; RR, 99% CI: 1.09, 0.72 to 1.66). Adherence to allocation was poor in the elective freeze group. The elective freeze approach was more costly and was unlikely to be cost-effective in a UK National Health Service context. LIMITATIONS, REASONS FOR CAUTION: We have only reported on first embryo transfer after randomization; data on the cumulative live birth rate requires further follow-up. Planned target sample size was not obtained and the non-adherence to allocation rate was high among couples in the elective freeze arm owing to patient preference for fresh embryo transfer, but an analysis which took non-adherence into account showed similar results. WIDER IMPLICATIONS OF THE FINDINGS: Results from the E-Freeze trial do not lend support to the policy of electively freezing all for everyone, taking both efficacy, safety and costs considerations into account. This method should only be adopted if there is a definite clinical indication. STUDY FUNDING/COMPETING INTEREST(S): NIHR Health Technology Assessment programme (13/115/82). This research was funded by the National Institute for Health Research (NIHR) (NIHR unique award identifier) using UK aid from the UK Government to support global health research. The views expressed in this publication are those of the author(s) and not necessarily those of the NIHR or the UK Department of Health and Social Care. J.L.B., C.C., E.J., P.H., J.J.K., L.L. and G.S. report receipt of funding from NIHR, during the conduct of the study. J.L.B., E.J., P.H., K.S. and L.L. report receipt of funding from NIHR, during the conduct of the study and outside the submitted work. A.M. reports grants from NIHR personal fees from Merck Serono, personal fees for lectures from Merck Serono, Ferring and Cooks outside the submitted work; travel/meeting support from Ferring and Pharmasure and participation in a Ferring advisory board. S.B. reports receipt of royalties and licenses from Cambridge University Press, a board membership role for NHS Grampian and other financial or non-financial interests related to his roles as Editor-in-Chief of Human Reproduction Open and Editor and Contributing Author of Reproductive Medicine for the MRCOG, Cambridge University Press. D.B. reports grants from NIHR, during the conduct of the study; grants from European Commission, grants from Diabetes UK, grants from NIHR, grants from ESHRE, grants from MRC, outside the submitted work. Y.C. reports speaker fees from Merck Serono, and advisory board role for Merck Serono and shares in Complete Fertility. P.H. reports membership of the HTA Commissioning Committee. E.J. reports membership of the NHS England and NIHR Partnership Programme, membership of five Data Monitoring Committees (Chair of two), membership of six Trial Steering Committees (Chair of four), membership of the Northern Ireland Clinical Trials Unit Advisory Group and Chair of the board of Oxford Brain Health Clinical Trials Unit. R.M. reports consulting fees from Gedeon Richter, honorarium from Merck, support fees for attendance at educational events and conferences for Merck, Ferring, Bessins and Gedeon Richter, payments for participation on a Merck Safety or Advisory Board, Chair of the British Fertility Society and payments for an advisory role to the Human Fertilisation and Embryology Authority. G.S. reports travel and accommodation fees for attendance at a health economic advisory board from Merck KGaA, Darmstadt, Germany. N.R.-F. reports shares in Nurture Fertility. Other authors' competing interests: none declared. TRIAL REGISTRATION NUMBER: ISRCTN: 61225414. TRIAL REGISTRATION DATE: 29 December 2015. DATE OF FIRST PATIENT'S ENROLMENT: 16 February 2016.

Study protocol: baby-OSCAR trial: Outcome after Selective early treatment for Closure of patent ductus ARteriosus in preterm babies, a multicentre, masked, randomised placebo-controlled parallel group trial.

BACKGROUND: The question of whether to treat patent ductus arteriosus (PDA) early or wait until symptoms appear remains high on the research agenda for neonatal medicine. Around 7000 extremely preterm babies under 29 weeks' gestation are born in the UK every year. In 40% of cases the PDA will fail to close spontaneously, even by 4 months of age. Untreated PDA can be associated with several serious and life-threatening short and long-term complications. Reliable data to support clinical decisions about PDA treatment are needed to prevent serious complications in high risk babies, while minimising undue exposure of infants. With the availability of routine bedside echocardiography, babies with a large PDA can be diagnosed before they become symptomatic. METHODS: This is a multicentre, masked, randomised, placebo-controlled parallel group trial to determine if early-targeted treatment of a large PDA with parenteral ibuprofen in extremely preterm babies (23+ 0-28+ 6 weeks' gestation) improves short and long-term health and economic outcomes. With parental informed consent, extremely preterm babies (born between 23+ 0-28+ 6 weeks' gestation) admitted to tertiary neonatal units are screened using echocardiography. Babies with a large PDA on echocardiography, defined by diameter of at least 1.5 mm and unrestricted pulsatile PDA flow pattern, are randomly allocated to either ibuprofen or placebo within 72 h of birth. The primary endpoint is the composite outcome of death by 36 weeks' postmenstrual age or moderate or severe bronchopulmonary dysplasia (BPD) at 36 weeks postmenstrual age. DISCUSSION: Prophylactic pharmacological treatment of all preterm babies unnecessarily exposes them to potentially serious side effects of drug treatment, when their PDA may have closed spontaneously. However, delaying treatment until babies become symptomatic could result in loss of treatment benefit as irreversible damage may have already been done. Targeted, early pharmacological treatment of PDA in asymptomatic babies has the potential to overcome the disadvantages of both prophylactic (overtreatment) and symptomatic approaches (potentially too late). This could result in improvements in the clinically important short-term clinical (mortality and moderate or severe BPD at 36 weeks' postmenstrual age) and long-term health outcomes (moderate or severe neurodevelopment disability and respiratory morbidity) measured at 2 years corrected age. TRIAL REGISTRATION: ISRCTN84264977 . Date assigned: 15/09/2010.

The WHEAT pilot trial-WithHolding Enteral feeds Around packed red cell Transfusion to prevent necrotising enterocolitis in preterm neonates: a multicentre, electronic patient record (EPR), randomised controlled point-of-care pilot trial.

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 <30+0 gestational weeks+days. Primary feasibility outcomes will be rate of recruitment, opt-out, retention, compliance, data completeness and data accuracy; clinical outcomes will include mortality and NEC. The trial will recruit in two neonatal networks in England for 9 months. Data collection will continue until all infants have reached 40+0 corrected gestational weeks or neonatal discharge. Participant identification and recruitment, randomisation and all trial data collection will be embedded within existing neonatal EPR systems (BadgerNet and BadgerEPR); outcome data will be extracted from routinely recorded data held in the National Neonatal Research Database. ETHICS AND DISSEMINATION: This study holds Research Ethics Committee approval to use an opt-out approach to consent. Results will inform future EPR-embedded and data-enabled trials and will be disseminated through conferences, publications and parent-centred information. TRIAL REGISTRATION NUMBER: ISRCTN registry ISRCTN62501859; Pre-results.

Supplemental Iodide for Preterm Infants and Developmental Outcomes at 2 Years: An RCT.

BACKGROUND: The recommendation for enteral iodide intake for preterm infants is 30 to 40 µg/kg per day and 1 µg/kg per day for parenteral intake. Preterm infants are vulnerable to iodide insufficiency and thyroid dysfunction. The hypothesis tested whether, compared with placebo, iodide supplementation of preterm infants improves neurodevelopment. METHODS: A randomized controlled trial of iodide supplementation versus placebo in infants <31 weeks' gestation. Trial solutions (sodium iodide or sodium chloride; dose 30 µg/kg per day) were given within 42 hours of birth to the equivalent of 34 weeks' gestation. The only exclusion criterion was maternal iodide exposure during pregnancy or delivery. Whole blood levels of thyroxine, thyrotropin, and thyroid-binding globulin were measured on 4 specific postnatal days. The primary outcome was neurodevelopmental status at 2 years of age, measured by using the Bayley Scales of Infant Development-III. The primary analyses are by intention-to-treat, and data are presented also for survivors. RESULTS: One thousand two hundred seventy-three infants (637 intervention, 636 placebo) were recruited from 21 UK neonatal units. One hundred thirty-one infants died, and neurodevelopmental assessments were undertaken in 498 iodide and 499 placebo-supplemented infants. There were no significant differences between the intervention and placebo groups in the primary outcome: mean difference cognitive score, -0.34, 95% confidence interval (CI) -2.57 to 1.89; motor composite score, 0.21, 95% CI -2.23 to 2.65; and language composite score, -0.05, 95% CI -2.48 to 2.39. There was evidence of weak interaction between iodide supplementation and hypothyroxinemic status in the language composite score and 1 subtest score. CONCLUSIONS: Overall iodide supplementation provided no benefit to neurodevelopment measured at 2 years of age.

A blinded randomised placebo-controlled trial investigating the efficacy of morphine analgesia for procedural pain in infants: Trial protocol.

Infant pain has both immediate and long-term negative consequences, yet in clinical practice it is often undertreated. To date, few pain-relieving drugs have been tested in infants. Morphine is a potent analgesic that provides effective pain relief in adults, but there is inconclusive evidence for its effectiveness in infants. The purpose of this study is to establish whether oral morphine provides effective analgesia for procedural pain in infants. A blinded, placebo-controlled, parallel-group randomized, phase II, clinical trial will be undertaken to determine whether morphine sulphate administered orally prior to clinically-required retinopathy of prematurity (ROP) screening and heel lancing provides effective analgesia. 156 infants between 34 and 42 weeks' gestational age who require a clinical heel lance and ROP screening on the same test occasion will be included in the trial. Infants will be randomised to receive either a single dose of morphine sulphate (100 µg/kg) or placebo. Each infant will be monitored for 48 hours and safety data will be collected during the 24 hours following drug administration. The primary outcome will be the Premature Infant Pain Profile-revised (PIPP-R) score 30 seconds after ROP screening. The co-primary outcome will be the magnitude of nociceptive-specific brain activity evoked by a clinically-required heel lance. Infant clinical stability will be assessed by comparing the number of episodes of bradycardia, tachycardia, desaturation and apnoea, and changes in respiratory support requirements in the 24-hour periods before and after the clinical intervention. In addition, drug safety will be assessed by considering the occurrence of apnoeic and hypotensive episodes requiring intervention in the 24-hour period following drug administration. This study has been published as an Accepted Protocol Summary by The Lancet.