Parent engagement in perinatal mortality reviews: an online survey of clinicians from six high-income countries.

OBJECTIVE: Parent engagement in perinatal mortality review meetings following stillbirth may benefit parents and improve patient safety. We investigated perinatal mortality review meeting practices, including the extent of parent engagement, based on self-reports from healthcare professionals from maternity care facilities in six high-income countries. DESIGN: Cross-sectional online survey. SETTING: Australia, Canada, Ireland, New Zealand, UK and USA. POPULATION: A total of 1104 healthcare professionals, comprising mainly obstetricians, gynaecologists, midwives and nurses. METHODS: Data were drawn from responses to a survey covering stillbirth-related topics. Open- and closed-items that focused on 'Data quality on causes of stillbirth' were analysed. MAIN OUTCOME MEASURES: Healthcare professionals' self-reported practices around perinatal mortality review meetings following stillbirth. RESULTS: Most clinicians (81.0%) were aware of regular audit meetings to review stillbirth at their maternity facility, although this was true for only 35.5% of US respondents. For the 854 respondents whose facility held regular meetings, less than a third (31.1%) reported some form of parent engagement, and this was usually in the form of one-way post-meeting feedback. Across all six countries, only 17.1% of respondents described an explicit approach where parents provided input, received feedback and were represented at meetings. CONCLUSIONS: We found no established practice of involving parents in the perinatal mortality review process in six high-income countries. Parent engagement may hold the key to important lessons for stillbirth prevention and care. Further understanding of approaches, barriers and enablers is warranted. TWEETABLE ABSTRACT: Parent engagement in mortality review after stillbirth is rare, based on data from six countries. We need to understand the barriers.

Intramuscular oxytocin versus Syntometrine® versus carbetocin for prevention of primary postpartum haemorrhage after vaginal birth: a randomised double-blinded clinical trial of effectiveness, side effects and quality of life.

OBJECTIVE: To compare intramuscular oxytocin, Syntometrine® and carbetocin for prevention of postpartum haemorrhage after vaginal birth. DESIGN: Randomised double-blinded clinical trial. SETTING: Six hospitals in England. POPULATION: A total of 5929 normotensive women having a singleton vaginal birth. METHODS: Randomisation when birth was imminent. MAIN OUTCOME MEASURES: Primary: use of additional uterotonic agents. Secondary: weighed blood loss, transfusion, manual removal of placenta, adverse effects, quality of life. RESULTS: Participants receiving additional uterotonics: 368 (19.5%) oxytocin, 298 (15.6%) Syntometrine and 364 (19.1%) carbetocin. When pairwise comparisons were made: women receiving carbetocin were significantly more likely to receive additional uterotonics than those receiving Syntometrine (odds ratio [OR] 1.28, 95% CI 1.08-1.51, P = 0.004); the difference between carbetocin and oxytocin was non-significant (P = 0.78); Participants receiving Syntometrine were significantly less likely to receive additional uterotonics than those receiving oxytocin (OR 0.75, 95% CI 0.65-0.91, P = 0.002). Non-inferiority between carbetocin and Syntometrine was not shown. Use of Syntometrine reduced non-drug PPH treatments compared with oxytocin (OR 0.64, 95% CI 0.42-0.97) but not carbetocin (P = 0.64). Rates of PPH and blood transfusion were not different. Syntometrine was associated with an increase in maternal adverse effects and reduced ability of the mother to bond with her baby. CONCLUSIONS: Non-inferiority of carbetocin to Syntometrine was not shown. Carbetocin is not significantly different to oxytocin for use of additional uterotonics. Use of Syntometrine reduced use of additional uterotonics and need for non-drug PPH treatments compared with oxytocin. Increased maternal adverse effects are a disadvantage of Syntometrine. TWEETABLE ABSTRACT: IM carbetocin does not reduce additional uterotonic use compared with IM Syntometrine or oxytocin.

PARENTS 2 study: consensus report for parental engagement in the perinatal mortality review process.

OBJECTIVE: The PARENTS 1 study (Parents' Active Role and ENgagement in The review of their Stillbirth/perinatal death) found that parents would endorse the opportunity to give feedback into the perinatal mortality review (PNMR) process. In subsequent focus groups, healthcare professionals were positive about parental engagement, although they considered that there may be significant challenges. The objective of this study was to develop core principles and recommendations for parental engagement in PNMR in the UK. METHODS: A two-round Delphi technique was followed to reach consensus on core principles for parental engagement in the PNMR process; Round 1 included a national consensus workshop and Round 2 an online questionnaire. The consensus meeting was attended by a national panel of stakeholders (clinical and academic experts, parent advocates, managers and commissioners) in stillbirth and neonatal and bereavement care. To develop recommendations for parental engagement, participants discussed four key areas comprising: communication with parents, including receiving feedback; the format of the PNMR meeting; the parental engagement pathway; and challenging aspects of engaging with parents in reviews. Content analysis was conducted to generate recommendations from the meeting for a subsequent anonymous web-based survey. Attendees of the consensus workshop and members of the PARENTS 2 Project Advisory Board were asked to rank recommendations using a 9-point Likert scale from 1 (not important) to 9 (critically important). It had been agreed a priori, in compliance with established Grading of Recommendations, Assessment, Development and Evaluation (GRADE) criteria, that 'consensus' would be achieved if over 70% of participants scored the principle as 'critical' (score of 7-9) and fewer than 15% scored the principle as 'not important' (score of 1-3). Principles for which consensus was achieved were included in the core recommendations. RESULTS: Of the 29 invited stakeholders, 22 participated in the consensus meeting and 25 (86% response rate) in the subsequent online questionnaire in June 2017. Consensus was agreed on 12 core principles. Of the 25 participants, 96% agreed that a face-to-face explanation of the PNMR process was of critical importance, 72% considered that parents should be offered the opportunity to nominate a suitable advocate, 92% believed that responses to parents' comments should be formally documented, 96% indicated that it was vital for action plans to be translated into lessons learnt and that this process should be monitored, and 100% of stakeholders voted that a plain-English summary should be produced for the parents following the meeting. There was good agreement on a further seven principles. CONCLUSIONS: Key national stakeholders were unanimously supportive of parental engagement in the PNMR process and agreed on core principles to make this process feasible, meaningful and robust. A 6-month pilot of parental engagement in the PNMR process (PARENTS 2 study) in two UK units took place after the consensus on core principles. In collaboration with the National Perinatal Epidemiology Unit, the findings will inform the national standardized PNMR tool. © 2018 The Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of the International Society of Ultrasound in Obstetrics and Gynecology.

Fetal head position and perineal distension associated with the use of the BD Odon Device™ in operative vaginal birth: a simulation study.

OBJECTIVE: To investigate (1) the placement of the BD Odon Device on the model fetal head and (2) perineal distention during simulated operative vaginal births conducted with the BD Odon Device. DESIGN: Observational simulation study. SETTING: North Bristol NHS Trust, UK. POPULATION OR SAMPLE: Four hundred and forty simulated operative vaginal births. METHODS: Three bespoke fetal mannequins were developed to represent (1) bi-parietal diameter of the 50th centile at term, (2) bi-parietal diameter at the 5th centile at term, and (3) 50th centile head with 2 cm of caput. Siting of the BD Odon Device on model heads was determined before and after 400 simulated operative vaginal births. Variables were analysed to determine their effect on device siting and movement during birth. The fetal mannequins were placed inside a maternal mannequin and the BD Odon Device was placed around the fetal head as per the instructions for use. The location of the air cuff was determined before and after the head was delivered. Perineal distension was determined by recording maximum perineal distention during a simulated operative vaginal birth using the same procedure, as well as scenarios employing an inappropriately non-deflated air cuff (for the BD Odon Device), the Kiwi ventouse and non-rotational forceps. MAIN OUTCOME MEASURES: Site and displacement during birth of the BD Odon Device on a model head. Maximal perineal distension during birth. RESULTS: The BD Odon Device was reliably sited in a standard over the fetal head position (approximately 40 mm above the fetal chin) for all stations, head sizes and positions with no significant displacement. In occipito-posterior births, compared with occipito-anterior or transverse, the BD Odon Device routinely sited further down the fetal head (toward the chin). The BD Odon Device was not associated with more perineal distension compared with forceps or Kiwi ventouse (respectively 21, 26 and 21 mm at posterior fourchette). CONCLUSIONS: The BD Odon Device reliably sited over a safe area of the fetal head in 400 simulated births representative of clinical practice. The BD Odon Device generates similar levels of perineal distension compared with Kiwi ventouse when used correctly. TWEETABLE ABSTRACT: Location of the BD Odon Device on a fetal head in simulation.

Pressure and traction on a model fetal head and neck associated with the use of forceps, Kiwi™ ventouse and the BD Odon Device™ in operative vaginal birth: a simulation study.

OBJECTIVE: To determine the pressure and traction forces exerted on a model fetal head by the BD Odon Device, forceps and Kiwi ventouse during simulated births. DESIGN: Simulation study. SETTING: Simulated operative vaginal birth. POPULATION OR SAMPLE: Eighty-four simulated operative vaginal births. METHODS: A bespoke fetal mannequin with pressure sensors around the head and strain gauge across the neck was used to investigate pressure applied over the head, and traction across the neck during 84 simulated births using the BD Odon Device, non-rotational forceps and Kiwi ventouse. MAIN OUTCOME MEASURES: Peak pressure on the fetal face and lateral aspects of the head during correct use of the BD Odon Device and forceps. Peak pressure on orbits and neck during misplacement of the BD Odon Device and forceps. Peak traction force generated until instrument failure using the BD Odon Device, forceps and Kiwi ventouse. RESULTS: When correctly sited and using 80 kPa inflation pressure on the cuff, the BD Odon Device generated a lower peak pressure on the fetal head than forceps (83 versus 146 kPa). When instruments were purposefully misplaced over the orbits, the BD Odon Device generated a lower peak pressure on the orbits compared with forceps (70 versus 123 kPa). When purposefully misplaced over the neck, the BD Odon Device, compared with forceps, generated a greater peak pressure on the anterio-lateral aspect of the neck (56 versus 17 kPa) and a lower peak pressure on the posterior aspect of the neck (76 versus 93 kPa) than forceps. In cases of true cephalic disproportion, the BD Odon Device 'popped-off' at a lower traction force than did forceps (208 versus 270 N). CONCLUSIONS: In simulated assisted vaginal birth with correctly placed instruments, the peak pressure exerted on the fetal head by a BD Odon Device is lower than the pressure exerted by non-rotational forceps. In cases in which delivery of the fetal head is not possible due to cephalo-pelvic disproportion, lower traction forces could be applied using the BD Odon Device than with forceps before the procedure was abandoned due to device failure. TWEETABLE ABSTRACT: BD Odon Device exerts less pressure on a model fetal head than forceps, but more than Kiwi ventouse.

Usability of virtual-reality simulation training in obstetric ultrasonography: a prospective cohort study.

OBJECTIVE: To assess the usability of virtual-reality (VR) simulation for obstetric ultrasound trainees. METHODS: Twenty-six participants were recruited: 18 obstetric ultrasound trainees (with little formal ultrasonography training) and eight certified experts. All performed five sequential VR-simulated crown-rump length (CRL) scans in a single session and three repetitions of biparietal diameter (BPD), occipitofrontal diameter (OFD) and femur length (FL) measurements. Outcome measures included mean percentage deviation from target for all measurements. Time taken to perform each type of scan was recorded. RESULTS: The mean percentage difference for the first scan was significantly greater for the trainee group than for the expert group for BPD (P = 0.035), OFD (P = 0.010) and FL (P = 0.008) and for time taken for the first CRL (P < 0.001) and fetal biometry (including BPD, OFD and FL measurements) scan (P < 0.001), demonstrating that trainees were initially significantly less accurate and less efficient. Over subsequent scans, the trainees became more accurate for all measurements with a significant improvement shown for OFD and FL (P < 0.05). The time taken for trainees to complete CRL and fetal biometry scans decreased significantly (all P < 0.05) with repetition, to near-expert efficiency. CONCLUSIONS: All participants were able to use the simulator and produce clinically meaningful biometry results. With repetition, beginners quickly approached near-expert levels of accuracy and speed. These data demonstrate that obstetricians with minimal experience can improve their ultrasonographic skills with short-phase VR-simulation training. The speed of improvement suggests that VR simulation might be useful as a warm-up exercise before clinical training sessions in order to reduce their impact on clinical service.

Integration of laparoscopic virtual-reality simulation into gynaecology training.

Surgery carries the risk of serious harm, as well as benefit, to patients. For healthcare organisations, theatre time is an expensive commodity and litigation costs for surgical specialities are very high. Advanced laparoscopic surgery, now widely used in gynaecology for improved outcomes and reduced length of stay, involves longer operation times and a higher rate of complications for surgeons in training. Virtual-reality (VR) simulation is a relatively new training method that has the potential to promote surgical skill development before advancing to surgery on patients themselves. VR simulators have now been on the market for more than 10 years and, yet, few countries in the world have fully integrated VR simulation training into their gynaecology surgical training programmes. In this review, we aim to summarise the VR simulators currently available together with evidence of their effectiveness in gynaecology, to understand their limitations and to discuss their incorporation into national training curricula.

Chlamydia psittaci: a suspected cause of reproductive loss in three Victorian horses.

Chlamydia psittaci was detected by PCR in the lung and equine foetal membranes of two aborted equine foetuses and one weak foal from two different studs in Victoria, Australia. The abortions occurred in September 2019 in two mares sharing a paddock northeast of Melbourne. The weak foal was born in October 2019 in a similar geographical region and died soon after birth despite receiving veterinary care. The detection of C. psittaci DNA in the lung and equine foetal membranes of the aborted or weak foals and the absence of any other factors that are commonly associated with abortion or neonatal death suggest that this pathogen may be the cause of the reproductive loss. The detection of C. psittaci in these cases is consistent with the recent detection of C. psittaci in association with equine abortion in New South Wales. These cases in Victoria show that C. psittaci, and the zoonotic risk it poses, should be considered in association with equine reproductive loss in other areas of Australia.

Analysis of expression and function of the costimulatory molecule 4-1BB in alloimmune responses.

BACKGROUND: 4-1BB (CD137) is a T cell costimulatory molecule that promotes T cell activation. In this study, we investigated the role of 4-1BB costimulation in allogeneic T cell responses. METHODS: Vascularized heart transplantation, allogeneic mixed leukocyte reaction (MLR), and graft versus host disease models were used to examine 4-1BB and 4-1BBL expression. In addition, agonistic anti-4-1BB antibodies were used in MLR to functionally analyze T cell responses. RESULTS: Using a heart transplant model, we found that 4-1BB and 4-1BBL transcripts were both expressed in rejecting cardiac grafts. In the allogeneic MLR, 4-1BB was expressed on both activated CD4 and CD8 T cells and 4-1BB was expressed on T cells after multiple cell divisions in vivo. Functionally, 4-1BB was a potent stimulator of proliferation, cytokine secretion, and CD25 expression by CD8 T cells, but 4-1BB signals had a weak effect on the proliferation of CD4 T cells. Because 4-1BB promoted the secretion of IL-2 and the expression of CD25 on CD8 T cells, we investigated whether IL-2 was the only factor whereby 4-1BB signals induced CD8 T cell proliferation. Although IL-2 was required for optimal CD8 T cell proliferation, 4-1BB also costimulated CD8 T cell proliferation independently of IL-2. CONCLUSIONS: This study demonstrates that 4-1BB is expressed on activated, maximally divided T cells and shows that 4-1BB promotes CD8 T cell proliferation by enhancing signals through the IL-2 receptor and by other mechanisms independent of the IL-2 pathway.

Analysis of the CD40 and CD28 pathways on alloimmune responses by CD4+ T cells in vivo.

BACKGROUND: Blockade of the CD40 and CD28 pathways is a powerful strategy to inhibit CD4-mediated alloimmune responses. In this study, we examine the relative roles of the CD40 and CD28 pathways on CD4-mediated allograft rejection responses, and further characterize the role of these pathways on CD4+ T-cell activation, priming for cytokine production, and cell proliferation in response to alloantigen in vivo. METHODS: BALB/c skin allografts were transplanted onto C57BL/6 Rag 1-/- recipients reconstituted with CD4 cells from CD28-/- or CD40L-/- donors. The popliteal lymph node assay was used to study the role of these pathways on CD4-cell activation and priming in vivo. To investigate the role of CD40 and CD28 blockade on CD4-cell proliferation, the fluorescein dye carboxyfluorescein diacetate succinimidyl ester was used. We performed heterotopic cardiac transplantation using CD40-/- mice to evaluate the role of CD40 on donor versus recipient cells in CD4-mediated rejection. RESULTS: B6 Rag 1-/- recipients reconstituted with CD28-/- CD4+ T cells acutely rejected allografts (median survival time 15 days), whereas recipients reconstituted with CD40L-/- CD4+ T cells had significantly prolonged survival of BALB/c skin grafts (MST 71 days). CD40L blockade was equivalent to or inferior to CD28 blockade in inhibition of in vivo CD4-cell activation, priming for cytokine production, and proliferation responses to alloantigen. BALB/c recipients depleted of CD8 cells promptly rejected donor B6 CD40-/- cardiac allografts, whereas B6 CD40-/- recipients depleted of CD8 cells had significantly prolonged survival of BALB/c wild-type cardiac allografts. CONCLUSIONS: The CD40/CD40L pathway, but not the CD28/B7 pathway, is critical for CD4-mediated rejection responses, however, the responsible mechanisms remain unclear.

Transplantation of the bone marrow microenvironment leads to hematopoietic chimerism without cytoreductive conditioning.

BACKGROUND: It has been hypothesized that regimens to induce transplantation tolerance and long-term hematopoietic chimerism require recipient conditioning with whole body irradiation or a cytoablative regimen to create space within the marrow microenvironment to permit pluripotent stem cell engraftment. The purpose of this study was to determine if transplantation of an intact bone marrow microenvironment in the form of a bone graft would permit stable hematopoietic stem cell engraftment, shape the repertoire of developing T cells, and induce donor-specific unresponsiveness in the absence of a conditioning regimen. METHODS: Fragments of femur were transplanted under the kidney capsule of recipient mice. At defined time points after bone graft transplantation recipients were assayed for chimerism, bone graft viability, and responses to donor and third party alloantigens in vitro and in vivo. RESULTS: In the absence of an immunological barrier, bone graft transplantation resulted in long-term multi-lineage hematopoietic chimerism in the peripheral blood. Nude bone graft transplantation into SCID recipients resulted in development of donor- derived T cells that underwent negative selection on bone graft derived I-E+ cells within the thymus. Across a fully allogeneic barrier in immunocompetent recipients treated with combined blockade of the CD40 and CD28 pathways bone graft transplantation resulted in long-term donor-specific hyporesponsiveness in vitro and acceptance of donor specific skin grafts. CONCLUSIONS: Transplantation of bone marrow in the form of a bone graft may facilitate the production of hematopoietic chimerism and lead to long-term donor-specific hyporesponsiveness in the absence of a cytoreductive conditioning regimen.

Prolonged acceptance of concordant and discordant xenografts with combined CD40 and CD28 pathway blockade.

BACKGROUND: The prompt and vigorous immune response to xenogenic tissue remains a significant barrier to clinical xenotransplantation. Simultaneous blockade of the CD28 and CD40 costimulatory pathways has been shown to dramatically inhibit the immune response to alloantigen. METHODS: . In this study, we investigated the ability of simultaneous blockade of the CD28 and CD40 pathways to inhibit the immune response to xenoantigen in the rat-to-mouse and pig-to-mouse models. RESULTS: Simultaneous blockade of the CD28 and CD40 pathways produced marked inhibition of the cellular response to xenoantigen in vivo and produced long-term acceptance of xenogeneic cardiac and skin grafts (rat-to-mouse), and markedly suppressed an evoked antibody response to xenoantigen. In addition, this strategy significantly prolonged the survival of pig skin on recipient mice. CONCLUSIONS: Long-term hyporesponsiveness to xenoantigen across both a concordant and discordant species barrier, measured by the stringent criterion of skin grafting, can be achieved using a noncytoablative treatment regimen.

Interleukin-6 production and secretion by human parathyroids.

Parathyroid hormone (PTH) stimulates osteoblasts to produce the proinflammatory cytokine interleukin-6 (IL-6), causing bone resorption. In patients with primary hyperparathyroidism, elevated serum levels of IL-6 normalize after resection of parathyroid tumours. Because IL-6 is also expressed in normal parathyroids and in other endocrine cells (adrenal and islet), we hypothesized that parathyroid tumours might contribute directly to the elevated serum IL-6 levels in patients with hyperparathyroidism. Immunohistochemistry identified IL-6, PTH, and chromogranin-A (an endocrine and neuroendocrine tumour marker) in normal, adenomatous and hyperplastic parathyroids. Using immunofluorescence and confocal microscopy, IL-6 co-localized with PTH and with chromogranin-A in parathyroid cells. All cultured parathyroid tumours secreted IL-6 at levels markedly higher than optimally stimulated peripheral blood mononuclear cells. Supernates from cultured parathyroids stimulated proliferation of an IL-6-dependent cell line, and anti-IL-6 MoAb abolished this stimulatory effect. IL-6 mRNA was documented in cultured parathyroid tumours, cultured normal parathyroids, fresh operative parathyroid tumours and fresh operative normal specimens. In conclusion, these data show that parathyroid tumours and normal parathyroids contain, produce and secrete IL-6. Our findings present a novel pathway by which human parathyroids may contribute markedly to IL-6 production and elevation of serum IL-6 levels in patients with hyperparathyroidism. The physiological relevance of IL-6 production by human parathyroids remains to be determined, but IL-6 secretion by parathyroid tumours may contribute to bone loss and to other multi-system complaints observed in these patients.

Vigorous allograft rejection in the absence of danger.

Tolerance to self is a necessary attribute of the immune system. It is thought that most autoreactive T cells are deleted in the thymus during the process of negative selection. However, peripheral tolerance mechanisms also exist to prevent development of autoimmune diseases against peripheral self-Ags. It has been proposed that T cells develop tolerance to peripheral self-Ags encountered in the absence of inflammation or "danger" signals. We have used immunodeficient Rag 1-/- mice to study the response of T cells to neo-self peripheral Ags in the form of well-healed skin and vascularized cardiac allografts. In this paper we report that skin and cardiac allografts without evidence of inflammation are vigorously rejected by transferred T cells or when recipients are reconstituted with T cells at a physiologic rate by nude bone graft transplantation. These results provide new insights into the role of inflammation or "danger" in the initiation of T cell-dependent immune responses. These findings also have profound implications in organ transplantation and suggest that in the absence of central deletional tolerance, peripheral tolerance mechanisms are not sufficient to inhibit alloimmune responses even in the absence of inflammation or danger.

Long-term acceptance of skin and cardiac allografts after blocking CD40 and CD28 pathways.

The receptor-ligand pairs CD28-B7 and CD40-gp39 are essential for the initiation and amplification of T-cell-dependent immune responses. CD28-B7 interactions provide 'second signals' necessary for optimal T-cell activation and IL-2 production, whereas CD40-gp39 signals co-stimulate B-cell, macrophage, endothelial cell and T-cell activation. Nonetheless, blockade of either of these pathways alone is not sufficient to permit engraftment of highly immunogenic allografts. Here we report that simultaneous but not independent blockade of the CD28 and CD40 pathways effectively aborts T-cell clonal expansion in vitro and in vivo, promotes long-term survival of fully allogeneic skin grafts, and inhibits the development of chronic vascular rejection of primarily vascularized cardiac allografts. The requirement for simultaneous blockade of these pathways for effective inhibition of alloimmunity indicates that, although they are interrelated, the CD28 and CD40 pathways are critical independent regulators of T-cell-dependent immune responses.