Background Postpartum haemorrhage is a leading cause of maternal mortality. A multicountry, cluster-randomised trial (E-MOTIVE) demonstrated a 60% reduction in adverse postpartum haemorrhage outcomes. The E-MOTIVE intervention included early postpartum haemorrhage detection using calibrated blood-collection drapes, followed by a postpartum haemorrhage treatment bundle (ie, uterine massage, oxytocics, tranexamic acid, intravenous fluids, examination and escalation [MOTIVE]), supported by implementation strategies. We report a mixed-methods process evaluation assessing the implementation of the E-MOTIVE intervention in Kenya, Nigeria, South Africa, and Tanzania. Methods In this mixed-methods process evaluation, data sources were observations of health workers providing clinical care to pregnant women and pregnant people during vaginal birth and postpartum haemorrhage at intervention sites, and surveys and qualitative interviews with health workers at intervention and control sites. Intervention sites received the calibrated drapes, MOTIVE bundle, and implementation strategies and control sites used uncalibrated drapes. Primary implementation outcomes included fidelity, adoption, adaptation, acceptability, feasibility, and contamination to the calibrated drape, MOTIVE bundle, and implementation strategies. Findings Between June 1, 2022, and Jan 31, 2023, 2578 births were observed, 295 pregnant women and people had postpartum haemorrhage, 47 qualitative interviews were done, and 889 surveys were completed. Fidelity to calibrated drape use was high (birth observations 2578 [100%] of 2578; survey 451 [983%] of 459). Among health workers, calibrated drape acceptability was high; however, they reported barriers to pregnant women's and people's acceptability. Fidelity to postpartum haemorrhage treatment bundle delivery was high (birth observations 286 [969%] of 295), with moderate to high fidelity in median time from postpartum haemorrhage diagnosis to final treatment initiation (<= 15 min initiation time in 191 [668%] of 295 birth observations, 16-20 min in 42 [147%] birth observations), and high acceptability and feasibility. Research midwives participated in clinical assessments after birth and bundle delivery in some sites (mixed fidelity). Interpretation This process evaluation shows generally high levels of fidelity, feasibility, and acceptability of the calibrated drape and treatment bundle across evaluation methods and countries. The E-MOTIVE intervention should be included in national policies, with consideration for health workforce, supplies, and medication issues, which might need addressing for successful implementation.

Timely detection and treatment of postpartum hemorrhage (PPH) are crucial to prevent complications or death. A calibrated blood-collection drape can help provide objective, accurate and early diagnosis of PPH, and a treatment bundle can address delays or inconsistencies in the use of effective interventions. Here we conducted an economic evaluation alongside the E-MOTIVE trial, an international, parallel cluster-randomized trial with a baseline control phase involving 210,132 women undergoing vaginal delivery across 78 secondary-level hospitals in Kenya, Nigeria, South Africa and Tanzania. We aimed to assess the cost-effectiveness of the E-MOTIVE intervention, which included a calibrated blood-collection drape for early detection of PPH and a bundle of first-response treatments (uterine massage, oxytocic drugs, tranexamic acid, intravenous fluids, examination and escalation), compared with usual care. We used multilevel modeling to estimate incremental cost-effectiveness ratios from the perspective of the public healthcare system for outcomes of cost per severe PPH (blood loss ≥1,000 ml) avoided and cost per disability-adjusted life-year averted. Our findings suggest that the use of a calibrated blood-collection drape for early detection of PPH and bundled first-response treatment is cost-effective and should be perceived by decision-makers as a worthwhile use of healthcare budgets. ClinicalTrials.gov identifier: NCT04341662.

BACKGROUND:Delays in the detection or treatment of postpartum hemorrhage can result in complications or death. A blood-collection drape can help provide objective, accurate, and early diagnosis of postpartum hemorrhage, and delayed or inconsistent use of effective interventions may be able to be addressed by a treatment bundle. METHODS:We conducted an international, cluster-randomized trial to assess a multicomponent clinical intervention for postpartum hemorrhage in patients having vaginal delivery. The intervention included a calibrated blood-collection drape for early detection of postpartum hemorrhage and a bundle of first-response treatments (uterine massage, oxytocic drugs, tranexamic acid, intravenous fluids, examination, and escalation), supported by an implementation strategy (intervention group). Hospitals in the control group provided usual care. The primary outcome was a composite of severe postpartum hemorrhage (blood loss, ≥1000 ml), laparotomy for bleeding, or maternal death from bleeding. Key secondary implementation outcomes were the detection of postpartum hemorrhage and adherence to the treatment bundle. RESULTS:A total of 80 secondary-level hospitals across Kenya, Nigeria, South Africa, and Tanzania, in which 210,132 patients underwent vaginal delivery, were randomly assigned to the intervention group or the usual-care group. Among hospitals and patients with data, a primary-outcome event occurred in 1.6% of the patients in the intervention group, as compared with 4.3% of those in the usual-care group (risk ratio, 0.40; 95% confidence interval [CI], 0.32 to 0.50; P<0.001). Postpartum hemorrhage was detected in 93.1% of the patients in the intervention group and in 51.1% of those in the usual-care group (rate ratio, 1.58; 95% CI, 1.41 to 1.76), and the treatment bundle was used in 91.2% and 19.4%, respectively (rate ratio, 4.94; 95% CI, 3.88 to 6.28). CONCLUSIONS:Early detection of postpartum hemorrhage and use of bundled treatment led to a lower risk of the primary outcome, a composite of severe postpartum hemorrhage, laparotomy for bleeding, or death from bleeding, than usual care among patients having vaginal delivery. (Funded by the Bill and Melinda Gates Foundation; E-MOTIVE ClinicalTrials.gov number, NCT04341662.).

OBJECTIVE:To explore differences in obstetric practices and clinical outcomes of postpartum hemorrhage (PPH) in Nigerian facilities. METHODS:A descriptive cross-sectional study of public health facilities providing maternal healthcare services in Nigeria. Surveys were conducted across 38 purposively sampled facilities (January 2020-March 2021) to collect information on obstetric practices related to the management of the third stage of labor, treatment of postpartum hemorrhage, and clinical outcomes related to postpartum hemorrhage in the preceding 12 months. RESULTS:The median number of annual births per facility was 2230 (IQR, 1952-3283). The cesarean section rate was 21.6% (range 2.1%-52.6%). There was large variability in PPH rate (median 3%, range 0.4%-16.8%) and blood transfusions for PPH (median 2.8%, range 0.4%-48.6%) after vaginal birth. There was less variability for laparotomies (median 0.25%, range 0%-2.8%) and maternal deaths (median 0.11%, range 0%-0.64%) due to PPH after vaginal birth. The number of maternal deaths from all causes varied (median 0.27%, range 0%-3.5%). The rates of PPH and adverse maternal outcomes did not vary substantially between state or federal facilities, region, type of facility, and the number of clinical staff. CONCLUSION:Across the Nigerian facilities surveyed there was large variation in PPH rates and adverse maternal outcomes due to PPH. This variability remains largely unexplained and requires further insights and detailed data to gain a deeper understanding of the root causes and challenges to implement customized solutions to improve maternal outcomes.

Objective To check the quality of oxytocin and tranexamic acid—two recommended products for prevention and treatment of postpartum hemorrhage (PPH)—used in facilities taking part in an implementation research project to improve PPH diagnosis and management. Methods Between September 2020 and August 2021, oxytocin and tranexamic acid products used in the study facilities in Kenya, Nigeria, South Africa, and Tanzania were collected and transported in cold storage for analysis. Samples were analyzed according to the International (oxytocin) and British Pharmacopeia (tranexamic acid) standards. Results Of the 17 unique oxytocin products, 33 individual measurements were made. Only six unique products had adequate content and no related substances exceeding the recommended limits. Of 14 tranexamic acid samples, 10 showed adequate content. One product in Kenya and two products in Nigeria from different manufacturers had a high content of related substances, which classified them as substandard. Conclusion While we were unable to investigate the origin regarding poor manufacturing or poor storage or both, the high number of substandard oxytocin samples is of great concern. Most of the tranexamic acid samples had adequate content but the presence of impurities in multiple products is worrying and requires further study.

Trial design A randomised, parallel-group, double-blind, placebo-controlled multicentre study with health economic and nested qualitative studies to determine if mifepristone (Mifegyne ® , Exelgyn, Paris, France) plus misoprostol is superior to misoprostol alone for the resolution of missed miscarriage. Methods Women diagnosed with missed miscarriage in the first 14 weeks of pregnancy were randomly assigned (1 : 1 ratio) to receive 200 mg of oral mifepristone or matched placebo, followed by 800 μg of misoprostol 2 days later. A web-based randomisation system allocated the women to the two groups, with minimisation for age, body mass index, parity, gestational age, amount of bleeding and randomising centre. The primary outcome was failure to pass the gestational sac within 7 days after randomisation. The prespecified key secondary outcome was requirement for surgery to resolve the miscarriage. A within-trial cost-effectiveness study and a nested qualitative study were also conducted. Women who completed the trial protocol were purposively approached to take part in an interview to explore their satisfaction with and the acceptability of medical management of missed miscarriage. Results A total of 711 women, from 28 hospitals in the UK, were randomised to receive either mifepristone plus misoprostol (357 women) or placebo plus misoprostol (354 women). The follow-up rate for the primary outcome was 98% (696 out of 711 women). The risk of failure to pass the gestational sac within 7 days was 17% (59 out of 348 women) in the mifepristone plus misoprostol group, compared with 24% (82 out of 348 women) in the placebo plus misoprostol group (risk ratio 0.73, 95% confidence interval 0.54 to 0.98; p = 0.04). Surgical intervention to resolve the miscarriage was needed in 17% (62 out of 355 women) in the mifepristone plus misoprostol group, compared with 25% (87 out of 353 women) in the placebo plus misoprostol group (risk ratio 0.70, 95% confidence interval 0.52 to 0.94; p = 0.02). There was no evidence of a difference in the incidence of adverse events between the two groups. A total of 42 women, 19 in the mifepristone plus misoprostol group and 23 in the placebo plus misoprostol group, took part in an interview. Women appeared to have a preference for active management of their miscarriage. Overall, when women experienced care that supported their psychological well-being throughout the care pathway, and information was delivered in a skilled and sensitive manner such that women felt informed and in control, they were more likely to express satisfaction with medical management. The use of mifepristone and misoprostol showed an absolute effect difference of 6.6% (95% confidence interval 0.7% to 12.5%). The average cost per woman was lower in the mifepristone plus misoprostol group, with a cost saving of £182 (95% confidence interval £26 to £338). Therefore, the use of mifepristone and misoprostol for the medical management of a missed miscarriage dominated the use of misoprostol alone. Limitations The results from this trial are not generalisable to women diagnosed with incomplete miscarriage and the study does not allow for a comparison with expectant or surgical management of miscarriage. Future work Future work should use existing data to assess and rank the relative clinical effectiveness and safety profiles for all methods of management of miscarriage. Conclusions Our trial showed that pre-treatment with mifepristone followed by misoprostol resulted in a higher rate of resolution of missed miscarriage than misoprostol treatment alone. Women were largely satisfied with medical management of missed miscarriage and would choose it again. The mifepristone and misoprostol intervention was shown to be cost-effective in comparison to misoprostol alone. Trial registration Current Controlled Trials ISRCTN17405024. Funding This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment ; Vol. 25, No. 68. See the NIHR Journals Library website for further project information.

BACKGROUND:Miscarriage, defined as the spontaneous loss of a pregnancy before 24 weeks' gestation, is common with approximately 25% of women experiencing a miscarriage in their lifetime. An estimated 15% of pregnancies end in miscarriage. Miscarriage can lead to serious morbidity, including haemorrhage, infection, and even death, particularly in settings without adequate healthcare provision. Early miscarriages occur during the first 14 weeks of pregnancy, and can be managed expectantly, medically or surgically. However, there is uncertainty about the relative effectiveness and risks of each option. OBJECTIVES:To estimate the relative effectiveness and safety profiles for the different management methods for early miscarriage, and to provide rankings of the available methods according to their effectiveness, safety, and side-effect profile using a network meta-analysis. SEARCH METHODS:We searched the Cochrane Pregnancy and Childbirth's Trials Register (9 February 2021), ClinicalTrials.gov and the WHO International Clinical Trials Registry Platform (ICTRP) (12 February 2021), and reference lists of retrieved studies. SELECTION CRITERIA:We included all randomised controlled trials assessing the effectiveness or safety of methods for miscarriage management. Early miscarriage was defined as less than or equal to 14 weeks of gestation, and included missed and incomplete miscarriage. Management of late miscarriages after 14 weeks of gestation (often referred to as intrauterine fetal deaths) was not eligible for inclusion in the review. Cluster- and quasi-randomised trials were eligible for inclusion. Randomised trials published only as abstracts were eligible if sufficient information could be retrieved. We excluded non-randomised trials. DATA COLLECTION AND ANALYSIS:At least three review authors independently assessed the trials for inclusion and risk of bias, extracted data and checked them for accuracy. We estimated the relative effects and rankings for the primary outcomes of complete miscarriage and composite outcome of death or serious complications. The certainty of evidence was assessed using GRADE. Relative effects for the primary outcomes are reported subgrouped by the type of miscarriage (incomplete and missed miscarriage). We also performed pairwise meta-analyses and network meta-analysis to determine the relative effects and rankings of all available methods. MAIN RESULTS:Our network meta-analysis included 78 randomised trials involving 17,795 women from 37 countries. Most trials (71/78) were conducted in hospital settings and included women with missed or incomplete miscarriage. Across 158 trial arms, the following methods were used: 51 trial arms (33%) used misoprostol; 50 (32%) used suction aspiration; 26 (16%) used expectant management or placebo; 17 (11%) used dilatation and curettage; 11 (6%) used mifepristone plus misoprostol; and three (2%) used suction aspiration plus cervical preparation. Of these 78 studies, 71 (90%) contributed data in a usable form for meta-analysis. Complete miscarriage Based on the relative effects from the network meta-analysis of 59 trials (12,591 women), we found that five methods may be more effective than expectant management or placebo for achieving a complete miscarriage: · suction aspiration after cervical preparation (risk ratio (RR) 2.12, 95% confidence interval (CI) 1.41 to 3.20, low-certainty evidence), · dilatation and curettage (RR 1.49, 95% CI 1.26 to 1.75, low-certainty evidence), · suction aspiration (RR 1.44, 95% CI 1.29 to 1.62, low-certainty evidence), · mifepristone plus misoprostol (RR 1.42, 95% CI 1.22 to 1.66, moderate-certainty evidence), · misoprostol (RR 1.30, 95% CI 1.16 to 1.46, low-certainty evidence). The highest ranked surgical method was suction aspiration after cervical preparation. The highest ranked non-surgical treatment was mifepristone plus misoprostol. All surgical methods were ranked higher than medical methods, which in turn ranked above expectant management or placebo. Composite outcome of death and serious complications Based on the relative effects from the network meta-analysis of 35 trials (8161 women), we found that four methods with available data were compatible with a wide range of treatment effects compared with expectant management or placebo: · dilatation and curettage (RR 0.43, 95% CI 0.17 to 1.06, low-certainty evidence), · suction aspiration (RR 0.55, 95% CI 0.23 to 1.32, low-certainty evidence), · misoprostol (RR 0.50, 95% CI 0.22 to 1.15, low-certainty evidence), · mifepristone plus misoprostol (RR 0.76, 95% CI 0.31 to 1.84, low-certainty evidence). Importantly, no deaths were reported in these studies, thus this composite outcome was entirely composed of serious complications, including blood transfusions, uterine perforations, hysterectomies, and intensive care unit admissions. Expectant management and placebo ranked the lowest when compared with alternative treatment interventions. Subgroup analyses by type of miscarriage (missed or incomplete) agreed with the overall analysis in that surgical methods were the most effective treatment, followed by medical methods and then expectant management or placebo, but there are possible subgroup differences in the effectiveness of the available methods.  AUTHORS' CONCLUSIONS: Based on relative effects from the network meta-analysis, all surgical and medical methods for managing a miscarriage may be more effective than expectant management or placebo. Surgical methods were ranked highest for managing a miscarriage, followed by medical methods, which in turn ranked above expectant management or placebo. Expectant management or placebo had the highest chance of serious complications, including the need for unplanned or emergency surgery. A subgroup analysis showed that surgical and medical methods may be more beneficial in women with missed miscarriage compared to women with incomplete miscarriage. Since type of miscarriage (missed and incomplete) appears to be a source of inconsistency and heterogeneity within these data, we acknowledge that the main network meta-analysis may be unreliable. However, we plan to explore this further in future updates and consider the primary analysis as separate networks for missed and incomplete miscarriage.

BackgroundThe anti-progesterone drug mifepristone and the prostaglandin misoprostol can be used to treat missed miscarriage. However, it is unclear whether a combination of mifepristone and misoprostol is more effective than administering misoprostol alone. We investigated whether treatment with mifepristone plus misoprostol would result in a higher rate of completion of missed miscarriage compared with misoprostol alone.MethodsMifeMiso was a multicentre, double-blind, placebo-controlled, randomised trial in 28 UK hospitals. Women were eligible for enrolment if they were aged 16 years and older, diagnosed with a missed miscarriage by pelvic ultrasound scan in the first 14 weeks of pregnancy, chose to have medical management of miscarriage, and were willing and able to give informed consent. Participants were randomly assigned (1:1) to a single dose of oral mifepristone 200 mg or an oral placebo tablet, both followed by a single dose of vaginal, oral, or sublingual misoprostol 800 μg 2 days later. Randomisation was managed via a secure web-based randomisation program, with minimisation to balance study group assignments according to maternal age (<30 years vs ≥30 years), body-mass index (<35 kg/m2 vs ≥35 kg/m2), previous parity (nulliparous women vs parous women), gestational age (<70 days vs ≥70 days), amount of bleeding (Pictorial Blood Assessment Chart score; ≤2 vs ≥3), and randomising centre. Participants, clinicians, pharmacists, trial nurses, and midwives were masked to study group assignment throughout the trial. The primary outcome was failure to spontaneously pass the gestational sac within 7 days after random assignment. Primary analyses were done according to intention-to-treat principles. The trial is registered with the ISRCTN registry, ISRCTN17405024.FindingsBetween Oct 3, 2017, and July 22, 2019, 2595 women were identified as being eligible for the MifeMiso trial. 711 women were randomly assigned to receive either mifepristone and misoprostol (357 women) or placebo and misoprostol (354 women). 696 (98%) of 711 women had available data for the primary outcome. 59 (17%) of 348 women in the mifepristone plus misoprostol group did not pass the gestational sac spontaneously within 7 days versus 82 (24%) of 348 women in the placebo plus misoprostol group (risk ratio [RR] 0·73, 95% CI 0·54–0·99; p=0·043). 62 (17%) of 355 women in the mifepristone plus misoprostol group required surgical intervention to complete the miscarriage versus 87 (25%) of 353 women in the placebo plus misoprostol group (0·71, 0·53–0·95; p=0·021). We found no difference in incidence of adverse events between the study groups.InterpretationTreatment with mifepristone plus misoprostol was more effective than misoprostol alone in the management of missed miscarriage. Women with missed miscarriage should be offered mifepristone pretreatment before misoprostol to increase the chance of successful miscarriage management, while reducing the need for miscarriage surgery.FundingUK National Institute for Health Research Health Technology Assessment Programme.

### What you need to know An early miscarriage is the loss of pregnancy at ≤13 weeks’ gestation.1 It is a major life event and can have a potentially devastating psychological impact on the woman in addition to the physical effects such as bleeding and pain.2 About one in four pregnancies, where a woman has missed a menstrual period and has a positive pregnancy test, ends in early miscarriage.3 Nearly 125 000 early miscarriages occur annually in the UK, accounting for 50 000 hospital admissions.4 Early miscarriage is usually diagnosed by pelvic ultrasound after a woman has experienced vaginal bleeding or abdominal pain. Women with a complete miscarriage, where expulsion of pregnancy tissue is complete, are managed conservatively without further intervention. Women with a missed or incomplete miscarriage (box 1) may require further intervention. Box 1 ### Categories of early miscarriageRETURN TO TEXT Surgery under general anaesthesia used to be the standard treatment for miscarriage,6 but a wider choice of management options is now available (fig 1).3 Over the past two decades there has been a shift towards individualised care and shared decision making between clinician and patient. Up to 70% of women with miscarriage opted for …

ObjectivesTo explore women’s experiences of remifentanil or pethidine for labour pain and infant feeding behaviours at 6weeks post partum.DesignQualitative postnatal sub-study to the randomised controlled trial of remifentanil intravenous patient controlled analgesia (PCA) versus intramuscular pethidine for pain relief in labour (RESPITE). Semistructured telephone interviews were conducted at 6 weeks post partum, and thematic analysis was undertaken.SettingWomen recruited to the RESPITE trial from seven UK hospitals.ParticipantsEighty women consented and 49 (30 remifentanil group and 19 pethidine group) completed the interview.ResultsEight themes emerged which encompassed women’s antenatal plans for pain management (Birth Expectations) through to their future preferences for pain relief (Reflections for Future Choices). Many women who used remifentanil felt it provided effective pain relief (Effectiveness of Pain Relief), whereas women in the pethidine group expressed more mixed views. Both groups described side effects, with women using pethidine frequently reporting nausea (Negative Physiological Responses) and women using remifentanil describing more cognitive effects (Cognitive Effects). Some women who used remifentanil reported restricted movements due to technical aspects of drug administration and fear of analgesia running out (Issues with Drug Administration). Women described how remifentanil enabled them to maintain their ability to stay focused during the birth (Enabling a Sense of Control). There was little difference in reported breastfeeding initiation and continuation between pethidine and remifentanil groups (Impact on Infant Behaviour and Breastfeeding).ConclusionsQualitative insights from a follow-up study to a trial which explored experiences of intravenous remifentanil PCA with intramuscular pethidine injection found that remifentanil appeared to provide effective pain relief while allowing women to remain alert and focused during labour, although as with pethidine, some side effects were noted. Overall, there was little difference in reported breastfeeding initiation and duration between the two groups.Trial registration numberISRCTN29654603.

(Lancet. 2018;392:662–672) While pethidine (meperidine) is widely used for pain relief during labor, there are unfavorable side effects, such as nausea/vomiting, maternal sedation, and possible neonatal depression. In addition, more than a third of women receiving pethidine ultimately request epidural labor analgesia. Remifentanil is a potential alternative to pethidine for labor pain relief. Its rapid onset and short duration of action provide some benefits although its short duration requires administration via intravenous (IV) patient controlled analgesia (PCA). It is not commonly used in maternity units in the United Kingdom, however, as previous trials evaluating remifentanil versus pethidine yielded low-quality evidence. Stronger evidence was required to evaluate the efficacy and safety of remifentanil as compared with pethidine for labor pain management. The RESPITE trial primary outcome compared IV remifentanil PCA with intramuscular pethidine looking at the need to convert to epidural analgesia with secondary outcomes evaluating visual analog scale (VAS) pain scores, mode of delivery and adverse maternal or neonatal outcomes.