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infants in the ursodeoxycholic acid group, and 300 women and 318 infants in the placebo group (consent to use data was withdrawn for 1 woman and 2 infants).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.

Much has been written about the benefits and applications of Peer Assisted Learning (PAL) in the literature. Curriculum developers increasingly consider PAL as a vehicle to help undergraduate healthcare students learn to teach; an outcome which has received more attention in the UK since the General Medical Council stated in Tomorrow's Doctors that medical graduates must 'Be able to demonstrate appropriate teaching skills'. This guide is primarily designed to assist curriculum developers, course organisers and educational researchers develop and implement their own PAL initiatives. It is structured around a PAL planning framework consisting of 24 questions. The questions are grouped in threes, around eight themes. Each question is discussed with reference to the PAL literature and other related subjects, and is exemplified by responses from a recent PAL project developed at The University of Edinburgh. Working through the 24 questions, particularly with discussion in a small planning group, will enable readers to efficiently develop their ideas for PAL into comprehensive and practical project plans cognisant of current educational theory, existing PAL literature and the local context. The framework is particularly suitable for those who want to develop healthcare undergraduate PAL initiatives yet have little or no experience of PAL, as it provides an introduction to the relevant literature field and a step-by-step process for the design and implementation of such projects. It will also be of interest to those with experience of PAL and those seeking a structured framework for planning non-PAL curriculum developments in undergraduate healthcare curricula.

Although the potential of metacognitive strategies to reduce medical error is acknowledged, the framework promotes looking beyond the individual to consider the contributions to patient safety of identity issues, role uncertainty and the hierarchical clinical environment. A more distributed approach to situation awareness may help junior doctors to better tolerate complexity and uncertainty. The efficacy of simulation as an educational strategy may be improved by finding ways to recreate the hierarchical and stressful environment in which junior doctors practise. Junior doctors should be aware of the impact of affect and emotion on behaviour, and clinical supervisors should strive to ensure that roles and responsibilities are explicitly discussed.

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

Summary During mammalian ovary formation, the production of ovarian follicles is accompanied by an enormous loss of germ cells. It is not known how this loss is regulated. We have investigated the role of the Trk tyrosine kinase receptors, primarily TrkB, in this process. The ovaries of TrkB−/− and TrkC−/− mice with a mixed (129Sv × C57BL/6) genetic background were examined shortly after birth. Around 50% of TrkB−/− mice had grossly abnormal ovaries that contained greatly reduced numbers of follicles. No defects were found in the ovaries of TrkC−/− mice. Congenic TrkB−/− mice were generated on 129Sv and C57BL/6 backgrounds: whereas the former had a mixed ovarian phenotype similar to that of the original colony of mice, the ovaries of all offspring of the C57BL/6 congenic line contained reduced numbers of follicles. RT-PCR showed that mRNA encoding TrkB and its two ligands, neurotrophin 4 (NT4) and brain-derived neurotrophic factor (BDNF), were present throughout the period of follicle formation in the mouse. In situ hybridisation showed that TrkB was expressed primarily in the germ cells before and after follicle formation. Mouse neonatal and fetal ovaries and human fetal ovaries were cultured in the presence of K252a, a potent inhibitor of all Trk receptors. In mice, K252a inhibited the survival of germ cells in newly formed (primordial) follicles. This effect was rescued by the addition of basic fibroblast growth factor (bFGF) to the culture medium. Combined addition of both BDNF and NT4 blocking antibodies lowered germ-cell survival, indicating that these TrkB ligands are required in this process. The results indicate that signalling through TrkB is an important component of the mechanism that regulates the early survival of female germ cells.