SummaryBackgroundIntrahepatic cholestasis of pregnancy, characterised by maternal pruritus and increased 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 without an adequate evidence base. We aimed to evaluate whether ursodeoxycholic acid reduces adverse perinatal outcomes in women with intrahepatic cholestasis of pregnancy.MethodsWe did a double-blind, multicentre, randomised placebo-controlled trial at 33 hospital maternity units in England and Wales. We recruited women with intrahepatic cholestasis of pregnancy, who were aged 18 years or older and with a gestational age between 20 weeks and 40 weeks and 6 days, with a singleton or twin pregnancy and no known lethal fetal anomaly. Participants were randomly assigned 1:1 to ursodeoxycholic acid or placebo, given as two oral tablets a day at an equivalent dose of 500 mg twice a day. The dose could be increased or decreased at the clinician's discretion, to a maximum of four tablets and a minimum of one tablet a day. We recommended that treatment should be continued from enrolment until the infant's birth. The primary outcome was a composite of perinatal death (in-utero fetal death after randomisation or known neonatal death up to 7 days after birth), preterm delivery (<37 weeks' gestation), or neonatal unit admission for at least 4 h (from birth until hospital discharge). Each infant was counted once within this composite. All analyses were done according to the intention-to-treat principle. The trial was prospectively registered with the ISRCTN registry, number 91918806.FindingsBetween Dec 23, 2015, and Aug 7, 2018, 605 women were enrolled and randomly allocated to receive ursodeoxycholic acid (n=305) or placebo (n=300). The primary outcome analysis included 304 women and 322 infants in the ursodeoxycholic acid group, and 300 women and 318 infants in the placebo group (consent to use data was withdrawn for 1 woman and 2 infants). The primary composite outcome occurred in 74 (23%) of 322 infants in the ursodeoxycholic acid group and 85 (27%) of 318 infants in the placebo group (adjusted risk ratio 0·85 [95% CI 0·62–1·15]). Two serious adverse events were reported in the ursodeoxycholic acid group and six serious adverse events were reported in the placebo group; no serious adverse events were regarded as being related to treatment.InterpretationTreatment with ursodeoxycholic acid does not reduce adverse perinatal outcomes in women with intrahepatic cholestasis of pregnancy. Therefore, its routine use for this condition should be reconsidered.FundingNational Institute for Health Research Efficacy and Mechanism Evaluation Programme.

Abstracts Ursodeoxycholic acid improves feto-placental and offspring metabolic outcomes in intrahepatic cholestasis of pregnancy and in a mouse model of hypercholanaemic pregnancy Abstracts 740The correlation between epigenetic change and neonatal plasma glucose level in maternal gestational diabetes offspring

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Background As a pragmatic randomised timing-of-birth trial, WILL adapted its trial procedures in response to the COVID-19 pandemic. These are reviewed here to inform post-pandemic trial methodology. Methods The trial (internal pilot) paused in March 2020, re-opened in July 2020, and is currently recruiting in 37 UK NHS consultant-led maternity units. We evaluated pandemic adaptations made to WILL processes and surveyed sites for their views of these changes (20 sites, videoconference). Results Despite 88% of sites favouring an electronic investigator site file (ISF), information technology requirements and clinical trial unit (CTU) operating procedures mandated the ongoing use of paper ISFs; site start-up delays resulted from restricted access to the CTU. Site initiation visits (SIVs) were conducted remotely; 50% of sites preferred remote SIVs and 44% felt that it was trial-dependent, while few preferred SIVs in-person as standard procedure. The Central team felt remote SIVs provided scheduling and attendance flexibility (for sites and trial staff), the option of recording discussions for missing or future staff, improved efficiency by having multiple sites attend, and time and cost savings; the negative impact on rapport-building and interaction was partially mitigated over time with more familiarity with technology and new ways-of-working. Two methods of remote consent were developed and used by 30/37 sites and for 54/156 recruits. Most (86%) sites using remote consenting felt it improved recruitment. For remote data monitoring (5 sites), advantages were primarily for the monitor (e.g. flexibility, no time constraints, reduced cost), and disadvantages primarily for the sites (e.g. document and access preparation, attendance at a follow-up meeting), but 81% of sites desired having the option of remote monitoring post-pandemic. Conclusions COVID adaptations to WILL trial processes improved the flexibility of trial delivery, for Central and site staff, and participants. Flexibility to use these strategies should be retained post-pandemic. Trial registration ISRCTN77258279. Registered on 05 December 2018.

BackgroundIn healthcare, there is increasing recognition of the importance of developing and testing strategies to scale effective interventions. The NHS long-term plan (2019) acknowledges that often a gold standard approach to a problem already exists somewhere within the NHS, however, it has not been replicated widely across the system.MethodsWe describe the approach and process measures for national scaling of PROMPT (Practical Obstetric Multi-Professional Training) across 12 obstetric-led maternity units in Wales. PROMPT is an evidence-based training package for local maternity staff, previously associated with improvements in maternal and neonatal outcomes, reduction in litigation related to preventable harm and improved safety culture. PROMPT has previously been disseminated internationally using a train-the-trainer model. However, this has been associated with variations in uptake, fidelity and impact. In Wales, the project was supported by Welsh Government, and a structured scaling plan was developed, encompassing ongoing implementation support from a multi-professional team.ResultsPROMPT was successfully implemented in all obstetric led units in Wales, with 326 local PROMPT facilitators trained, and 82.5%–100% of maternity staff attended a local PROMPT course in the first 15 months of the project (January 2019–March 2020). All training courses included evidence-based authentic elements, and 93% of courses in the first year (100/107) were supported by a national implementation team, providing coaching, implementation support and quality assurance.ConclusionsAuthentically scaling up complex interventions is a significant challenge. To replicate the improved outcomes demonstrated by PROMPT, intervention reach and fidelity must first be demonstrated.In this national scaling project, our scaling methodology led to the successful implementation of PROMPT across all health boards in Wales. Additionally, we demonstrated reduced variation in adoption, reach, timescale and intervention fidelity between maternity units with varying readiness for change, which had been difficult in two previous large-scale PROMPT implementation projects.