Intramuscular oxytocin versus oxytocin/ergometrine versus carbetocin for prevention of primary postpartum haemorrhage after vaginal birth:study protocol for a randomised controlled trial (the IMox study)

Abstract Background Postpartum haemorrhage remains a major cause of maternal mortality and morbidity worldwide. Active management of the third stage of labour reduces the risk of postpartum haemorrhage. Oxytocin and oxytocin/ergometrine are commonly used in the UK, with oxytocin/ergometrine being more effective at preventing moderate, but not severe, blood loss. Many guidelines specifically recommend using oxytocin for all vaginal births, as it is associated with fewer adverse events. However, a survey conducted by the Southmead Hospital Maternity Research Team revealed that 71.4% of UK obstetric units still routinely use oxytocin/ergometrine. Carbetocin is a newer medication that may be as effective but has fewer side effects. No studies have directly compared all three medications. Methods The IMox study aims to determine the most effective, acceptable and cost-effective drug for primary prevention of postpartum haemorrhage following vaginal birth. The IMox study is a prospective, multi-centre, double-blind, randomised trial directly comparing oxytocin, oxytocin/ergometrine and carbetocin given intramuscularly for the prevention of postpartum haemorrhage in the third stage of labour. The primary effectiveness outcome is the use of an additional uterotonic drug. Secondary effectiveness outcomes reflect maternal morbidity and mortality within the immediate postpartum period. Participant questionnaires and subjective reporting of side effects will be used to evaluate maternal acceptability. Maternal quality of life utilities will be collected antenatally, and on days 1 and 14 after birth to enable a cost-effectiveness assessment of each studied drug. Participants will be pregnant women planning a vaginal birth in six hospitals in England. Participants will be approached and invited to provide consent to participate from 20 weeks gestation until in established labour. A complete sample of 5712 participants (1904 per arm) providing data for the primary outcome will allow for a robust determination of efficacy between all three study drugs. Data will be collected until participants are discharged from the hospital and on postnatal days 1 and 14 regardless of location. All analyses will be on a modified intention-to-treat basis, and additionally repeated on a per protocol basis. Data collection commenced in Feburary 2015 and was completed in August 2018. Discussion This study is the first to directly compare oxytocin, oxytocin/ergometrine and carbetocin in the same population for the prevention of postpartum haemorrhage following vaginal birth. Furthermore, this study will be the first to directly compute health economic outcomes from such a three-way comparison. This study is limited to using short-term outcomes, and so will not provide evidence for important outcomes such as long-term maternal psychological well-being and time to next conception. Trial registration ClinicalTrials.gov, NCT02216383. Registered on 18 August 2014. EudraCT, 2014-001948-37. Registered on 23 September 2014. ISRCTN, ISRCTN10232550. Retrospectively registered on 6 March 2018)

The IDvIP Trial: A two-centre randomised double-blind controlled trial comparing intramuscular diamorphine and intramuscular pethidine for labour analgesia

<p>Abstract</p> <p>Background</p> <p>Intramuscular pethidine is routinely used throughout the UK for labour analgesia. Studies have suggested that pethidine provides little pain relief in labour and has a number of side effects affecting mother and neonate. It can cause nausea, vomiting and dysphoria in mothers and can cause reduced fetal heart rate variability and accelerations. Neonatal effects include respiratory depression and impaired feeding. There are few large studies comparing the relative side effects and efficacy of different opioids in labour. A small trial comparing intramuscular pethidine with diamorphine, showed diamorphine to have some benefits over pethidine when used for labour analgesia but the study did not investigate the adverse effects of either opioid.</p> <p>Methods</p> <p>The Intramuscular Diamorphine versus Intramuscular Pethidine (IDvIP) trial is a randomised double-blind two centre controlled trial comparing intramuscular diamorphine and pethidine regarding their analgesic efficacy in labour and their side effects in mother, fetus and neonate. Information about the trial will be provided to women in the antenatal period or in early labour. Consent and recruitment to the trial will be obtained when the mother requests opioid analgesia. The sample size requirement is 406 women with data on primary outcomes. The maternal primary outcomes are pain relief during the first 3 hours after trial analgesia and specifically pain relief after 60 minutes. The neonatal primary outcomes are need for resuscitation and Apgar Score <7 at 1 minute. The secondary outcomes are an additional measure of pain relief, maternal sedation, nausea and vomiting, maternal oxygen saturation, satisfaction with analgesia, whether method of analgesia would be used again, use of Entonox, umbilical arterial and venous pH, fetal heart rate, meconium staining, time from delivery to first breath, Apgar scores at 5 mins, naloxone requirement, transfer to neonatal intensive care unit, neonatal haemoglobin oxygen saturation at 30, 60, 90, and 120 mins after delivery, and neonatal sedation and feeding behaviour during first 2 hours.</p> <p>Discussion</p> <p>If the trial demonstrates that diamorphine provides better analgesia with fewer side effects in mother and neonate this could lead to a change in national practice and result in diamorphine becoming the preferred intramuscular opioid for analgesia in labour.</p> <p>Trial Registration</p> <p><a href="http://www.controlled-trials.com/ISRCTN14898678">ISRCTN14898678</a></p> <p>Eudra No: 2006-003250-18, REC Reference No: 06/Q1702/95, MHRA Authorisation No: 1443/0001/001-0001, NIHR UKCRN reference 6895, RfPB grant PB-PG-0407-13170_IR5</p

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

Convalescent plasma in patients admitted to hospital with COVID-19 (RECOVERY): a randomised controlled, open-label, platform trial

SummaryBackground Azithromycin has been proposed as a treatment for COVID-19 on the basis of its immunomodulatoryactions. We aimed to evaluate the safety and efficacy of azithromycin in patients admitted to hospital with COVID-19.Methods In this randomised, controlled, open-label, adaptive platform trial (Randomised Evaluation of COVID-19Therapy [RECOVERY]), several possible treatments were compared with usual care in patients admitted to hospitalwith COVID-19 in the UK. The trial is underway at 176 hospitals in the UK. Eligible and consenting patients wererandomly allocated to either usual standard of care alone or usual standard of care plus azithromycin 500 mg once perday by mouth or intravenously for 10 days or until discharge (or allocation to one of the other RECOVERY treatmentgroups). Patients were assigned via web-based simple (unstratified) randomisation with allocation concealment andwere twice as likely to be randomly assigned to usual care than to any of the active treatment groups. Participants andlocal study staff were not masked to the allocated treatment, but all others involved in the trial were masked to theoutcome data during the trial. The primary outcome was 28-day all-cause mortality, assessed in the intention-to-treatpopulation. The trial is registered with ISRCTN, 50189673, and ClinicalTrials.gov, NCT04381936.Findings Between April 7 and Nov 27, 2020, of 16 442 patients enrolled in the RECOVERY trial, 9433 (57%) wereeligible and 7763 were included in the assessment of azithromycin. The mean age of these study participants was65·3 years (SD 15·7) and approximately a third were women (2944 [38%] of 7763). 2582 patients were randomlyallocated to receive azithromycin and 5181 patients were randomly allocated to usual care alone. Overall,561 (22%) patients allocated to azithromycin and 1162 (22%) patients allocated to usual care died within 28 days(rate ratio 0·97, 95% CI 0·87–1·07; p=0·50). No significant difference was seen in duration of hospital stay (median10 days [IQR 5 to >28] vs 11 days [5 to >28]) or the proportion of patients discharged from hospital alive within 28 days(rate ratio 1·04, 95% CI 0·98–1·10; p=0·19). Among those not on invasive mechanical ventilation at baseline, nosignificant difference was seen in the proportion meeting the composite endpoint of invasive mechanical ventilationor death (risk ratio 0·95, 95% CI 0·87–1·03; p=0·24).Interpretation In patients admitted to hospital with COVID-19, azithromycin did not improve survival or otherprespecified clinical outcomes. Azithromycin use in patients admitted to hospital with COVID-19 should be restrictedto patients in whom there is a clear antimicrobial indication

A mixed-methods stress audit with midwives in the United Kingdom

Problem. UK midwives report high work-related stress, which can negatively impact their health and wellbeing, with many considering leaving the profession. Background. An occupational stress audit guides the implementation of stress management intervention, by identifying which stressors have the most negative impact and why, and highlighting “at risk” groups.Aim. To conduct a concurrent mixed-methods stress audit with UK midwives in an NHS Trust.Methods. Seventy-one midwives (Mage = 39 years, SD = 11) completed a survey assessing stressors (e.g., relationships), stress appraisals (i.e., challenge vs. threat), coping strategies (e.g., avoidance-focused), and outcomes (i.e., mental health, performance, and intention to leave). Ten midwives (Mage = 42 years, SD = 10) participated in semi-structured interviews. Findings. Quantitative data revealed that more work-related demands, poorer peer support and relationships, and threat appraisals predicted worse mental health. Moreover, less control and more work-related demands predicted poorer performance, while less control, poorer manager support, more change-related demands, and threat appraisals predicted greater intention to leave. Qualitative data generated three themes: organisational pressures exacerbated by unexpected changes; individualised responses but largely debilitative emotions; and personal coping and power of social support. Discussion and Conclusion. This study offered a comprehensive and novel insight into the stress experiences of UK midwives, highlighting targets for future stress management interventions, including key stressors (e.g., manager support), underlying mechanisms (e.g., stress appraisals), and “at-risk” groups (e.g., night shift workers). Practical recommendations are provided for stakeholders operating at multiple levels (e.g., midwife, trust, policy) to better support midwives with work-related stress

Effectiveness of interventions on occupational stress, health and well-being, performance, and job satisfaction for midwives: A systematic mixed methods review

Background: Work-related stress is high in midwifery with negative implications for midwives’ health and performance. This systematic review therefore examined which stress management interventions (SMIs) are most effective at reducing occupational stress and improving midwives’ health and well-being, performance, and job satisfaction. Methods: A systematic review included studies if they were: investigating midwives or student midwives; examining an individual- or organisation-level intervention; reporting the intervention effects on at least one outcome (e.g., job performance); peer-reviewed; and published in English. Methodological quality was assessed using the Mixed Methods Appraisal Tool. A narrative synthesis was conducted and data were presented by SMI level (i.e., individual vs. organisation) and modality type (e.g., mindfulness, care model). Sum codes were used to compare the effects of individual- and organisation-level SMIs on outcomes. Findings: From 2605 studies identified, 30 were eligible (18 individual- and 12 organisation-level SMIs). Eight studies were deemed low quality. While individual- and organisation-level SMIs were equally effective in improving job satisfaction and performance, there was a trend for organisation-level SMIs more effectively reducing work stress and improving health and well-being. Specific individual- (i.e., mindfulness, simulation training) and organisation-level (i.e., reflective groups, midwifery care models) SMIs were most beneficial. Conclusion: It is recommended that health practitioners and policy makers implement interventions that target both individual- and organisation-levels to optimally support midwives’ work stress, health, well-being, and performance. Notwithstanding these findings and implications, some studies had poor methodological quality; thus, future research should better follow intervention reporting guidelines

Pregnancy and neonatal outcomes of COVID -19: coreporting of common outcomes from PAN-COVID and AAP-SONPM registries

Objective Few large cohort studies have reported data on maternal, fetal, perinatal and neonatal outcomes associated with severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) infection in pregnancy. We report the outcome of infected pregnancies from a collaboration formed early during the pandemic between the investigators of two registries, the UK and Global Pregnancy and Neonatal outcomes in COVID‐19 (PAN‐COVID) study and the American Academy of Pediatrics (AAP) Section on Neonatal–Perinatal Medicine (SONPM) National Perinatal COVID‐19 Registry. Methods This was an analysis of data from the PAN‐COVID registry (1 January to 25 July 2020), which includes pregnancies with suspected or confirmed maternal SARS‐CoV‐2 infection at any stage in pregnancy, and the AAP‐SONPM National Perinatal COVID‐19 registry (4 April to 8 August 2020), which includes pregnancies with positive maternal testing for SARS‐CoV‐2 from 14 days before delivery to 3 days after delivery. The registries collected data on maternal, fetal, perinatal and neonatal outcomes. The PAN‐COVID results are presented overall for pregnancies with suspected or confirmed SARS‐CoV‐2 infection and separately in those with confirmed infection. Results We report on 4005 pregnant women with suspected or confirmed SARS‐CoV‐2 infection (1606 from PAN‐COVID and 2399 from AAP‐SONPM). For obstetric outcomes, in PAN‐COVID overall and in those with confirmed infection in PAN‐COVID and AAP‐SONPM, respectively, maternal death occurred in 0.5%, 0.5% and 0.2% of cases, early neonatal death in 0.2%, 0.3% and 0.3% of cases and stillbirth in 0.5%, 0.6% and 0.4% of cases. Delivery was preterm (< 37 weeks' gestation) in 12.0% of all women in PAN‐COVID, in 16.1% of those women with confirmed infection in PAN‐COVID and in 15.7% of women in AAP‐SONPM. Extreme preterm delivery (< 27 weeks' gestation) occurred in 0.5% of cases in PAN‐COVID and 0.3% in AAP‐SONPM. Neonatal SARS‐CoV‐2 infection was reported in 0.9% of all deliveries in PAN‐COVID overall, in 2.0% in those with confirmed infection in PAN‐COVID and in 1.8% in AAP‐SONPM; the proportions of neonates tested were 9.5%, 20.7% and 87.2%, respectively. The rates of a small‐for‐gestational‐age (SGA) neonate were 8.2% in PAN‐COVID overall, 9.7% in those with confirmed infection and 9.6% in AAP‐SONPM. Mean gestational‐age‐adjusted birth‐weight Z‐scores were −0.03 in PAN‐COVID and −0.18 in AAP‐SONPM. Conclusions The findings from the UK and USA registries of pregnancies with SARS‐CoV‐2 infection were remarkably concordant. Preterm delivery affected a higher proportion of women than expected based on historical and contemporaneous national data. The proportions of pregnancies affected by stillbirth, a SGA infant or early neonatal death were comparable to those in historical and contemporaneous UK and USA data. Although maternal death was uncommon, the rate was higher than expected based on UK and USA population data, which is likely explained by underascertainment of women affected by milder or asymptomatic infection in pregnancy in the PAN‐COVID study, although not in the AAP‐SONPM study. The data presented support strong guidance for enhanced precautions to prevent SARS‐CoV‐2 infection in pregnancy, particularly in the context of increased risks of preterm delivery and maternal mortality, and for priority vaccination of pregnant women and women planning pregnancy. Copyright © 2021 ISUOG. Published by John Wiley & Sons Ltd