OBJECTIVE:To compare the frequency and timing of postpartum haemorrhage (PPH) treatment initiation between hospitals implementing the MOTIVE treatment bundle (which consisted of uterine Massage, Oxytocic drugs, Tranexamic acid, IntraVenous fluids and Examination) and those following usual care. DESIGN:Nested prospective observational study. SETTING:Hospitals in Nigeria, Kenya, Tanzania and South Africa participating in the E-MOTIVE trial. POPULATION OR SAMPLE:Healthcare workers treating PPH. METHODS:Between June and December 2022, we observed healthcare workers for 1-2 weeks in 39 E-MOTIVE and 39 usual care hospitals across Nigeria, Kenya, Tanzania, and South Africa managing vaginal birth and treating PPH. We descriptively compared the frequency and timing from PPH detection to treatment initiation of individual treatments and the MOTIVE bundle, between E-MOTIVE care and usual care. RESULTS:Among 2578 observations in E-MOTIVE care hospitals, 295 (11%) PPHs were treated, and among 2834 observations in usual care hospitals, 219 (8%) PPHs were treated. In E-MOTIVE care hospitals, 97% (286/295) of women with PPH received the MOTIVE bundle, compared to 36% (79/219) in usual care. Median initiation times for the first component were similar (0 vs. 1 min), but E-MOTIVE care hospitals achieved faster initiation of all components (13 min, IQR 6-18) compared to usual care (18 min, IQR 10-25). In total, 79% (233/295) of women in E-MOTIVE care had all components initiated within 20 min, compared to 22% (48/219) in usual care. CONCLUSIONS:Timely and comprehensive management of PPH using the MOTIVE bundle, particularly initiating all components within 15-20 min, was commonly observed in the E-MOTIVE care hospitals. Scaling up E-MOTIVE care should emphasise timely bundle initiation to strengthen PPH treatment and improve maternal health outcomes in low-and-middle-income countries.

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.

BACKGROUND:Postpartum haemorrhage (PPH) is the leading cause of maternal mortality worldwide. Accurate diagnosis of PPH can prevent adverse outcomes by enabling early treatment. OBJECTIVES:What is the accuracy of methods (index tests) for diagnosing primary PPH (blood loss ≥ 500 mL in the first 24 hours after birth) and severe primary PPH (blood loss ≥ 1000 mL in the first 24 hours after birth) (target conditions) in women giving birth vaginally (participants) compared to weighed blood loss measurement or other objective measurements of blood loss (reference standards)? SEARCH METHODS:We searched CENTRAL, MEDLINE, Embase, Web of Science Core Collection, ClinicalTrials.gov, and the World Health Organization International Clinical Trials Registry Platform to 24 May 2024. SELECTION CRITERIA:We included women who gave birth vaginally in any setting. Study types included diagnostic cohort studies and cross-sectional studies that reported 2 x 2 data (number of true positive, false positive, false negative, and true negative results) or where the 2 x 2 data could be derived from test accuracy estimates. Eligible index tests included: visual estimation; calibrated blood collection devices; approach with calibrated drape and observations; blood loss estimation using the SAPHE (Signalling a Postpartum Hemorrhage Emergency) Mat; blood loss field image analysis and other technologies; uterine atony assessment; clinical variables (e.g. heart rate, blood pressure, shock index); early warning charts; haemoglobin levels; and predelivery fibrinogen levels. Eligible reference standards included objective methods such as: gravimetric blood loss measurement, which involves weighing collected blood, as well as weighing blood-soaked pads, gauze and sheets, and subtracting their dry weight; calibrated devices to measure blood volume (volumetric blood loss measurement); the alkaline-haematin method of blood loss estimation; and blood extracted using machine-extraction and measured spectrometrically as oxyhaemoglobin. DATA COLLECTION AND ANALYSIS:At least two review authors, working independently, undertook study screening, selection, data extraction, assessment of risk of bias, and assessment of the certainty of the evidence. We resolved any differences through consensus or with input from another author. We generated 2 x 2 tables of the true positives, true negatives, false positives, and false negatives to calculate the sensitivity, specificity, and 95% confidence intervals for each index test. We presented sensitivity and specificity estimates from studies in forest plots. Where possible, we conducted meta-analyses for each index test and reference standard combination for each target condition. We examined heterogeneity by visual inspection of the forest plots. MAIN RESULTS:Our review included 18 studies with a total of 291,040 participants. Fourteen studies evaluated PPH and seven studies evaluated severe PPH. Most studies were conducted in a hospital setting (16 of 18). There were four studies at high risk of bias for the patient selection domain and 14 studies at low risk. For the index test domain, 10 studies were at low risk of bias, seven studies at high risk, and one study at uncertain risk. For the reference standard domain, one study was at high risk of bias and 17 studies at low risk. For the flow and timing domain, three studies were at high risk of bias and 15 studies at low risk. The applicability concerns were low for all studies across the domains. In the abstract, we have prioritised reporting results for common, important thresholds for index tests or where the certainty of the evidence for the sensitivity estimate was at least moderate. Full results are in the main body of the review. PPH (blood loss ≥ 500 mL) For PPH, visual estimation with gravimetric blood loss measurement as the reference standard had 48% sensitivity (95% confidence interval (CI) 44% to 53%; moderate certainty) and 97% specificity (95% CI 95% to 99%; high certainty) (4 studies, 196,305 participants). Visual estimation with volumetric blood loss measurement as the reference standard showed 22% sensitivity (95% CI 12% to 37%; moderate certainty) and 99% specificity (95% CI 97% to 100%; moderate certainty) (2 studies, 514 participants). The diagnostic approach with calibrated drape plus observations, with gravimetric blood loss measurement as the reference standard for PPH, showed 93% sensitivity (95% CI 92% to 94%; high certainty) and 95% specificity (95% CI 95% to 96%; high certainty) (2 studies, 53,762 participants). A haemoglobin level of less than 10 g/dL with gravimetric blood loss measurement as the reference standard showed 37% sensitivity (95% CI 30% to 44%; high certainty) and 79% specificity (95% CI 76% to 82%; high certainty) (1 study, 1058 participants). Severe PPH (blood loss ≥ 1000 mL) For severe PPH, visual estimation, with volumetric plus gravimetric blood loss measurement as the reference standard, showed 9% sensitivity (95% CI 0% to 41%; low certainty) and 100% specificity (95% CI 99% to 100%; moderate certainty) (1 study, 274 participants). A shock index level of 1.0 or higher (commonly used as a threshold for severe PPH) up to two hours after birth, with gravimetric blood loss measurement as the reference standard, showed 30% sensitivity (95% CI 27% to 33%; moderate certainty) and 93% specificity (95% CI 92% to 93%; moderate certainty) (1 study, 30,820 participants). A haemoglobin level of less than 10 g/dL, with gravimetric blood loss measurement as the reference standard, showed 71% sensitivity (95% CI 51% to 87%; moderate certainty) and 77% specificity (95% CI 75% to 80%; high certainty) (1 study, 1058 participants). AUTHORS' CONCLUSIONS:Visual estimation of blood loss to diagnose PPH showed low sensitivity and is likely to miss the diagnosis in half of women giving birth vaginally. A diagnostic approach using a calibrated drape to objectively measure blood loss plus clinical observations showed high sensitivity and specificity for diagnosing PPH. Other index tests showed low to moderate sensitivities in diagnosing PPH and severe PPH. Future research should determine the accuracy of diagnostic tests in non-hospital settings and consider combining index tests to increase the sensitivity of PPH diagnosis. FUNDING:Bill and Melinda Gates Foundation REGISTRATION: PROSPERO (CRD42024541874).

RATIONALE:Postpartum haemorrhage (PPH) is a major cause of maternal mortality worldwide. The combination of accurate diagnosis and effective treatment is necessary to improve outcomes. There is uncertainty about which combination of diagnostic and treatment strategies is most effective. OBJECTIVES:To assess the comparative effectiveness of various combinations of 'diagnostic and treatment' strategies for PPH in women giving birth, and rank them. To explore the relative effects of various diagnostic strategies, when the treatment strategies are the same or similar. To explore the relative effects of various treatment strategies, when the diagnostic strategies are the same or similar. SEARCH METHODS:We searched CENTRAL, MEDLINE, Embase, ClinicalTrials.gov, and the World Health Organization International Clinical Trials Registry Platform to 18 October 2024. ELIGIBILITY CRITERIA:Randomised controlled trials or cluster-randomised trials comparing the effects of different combinations of 'diagnostic and treatment' strategies for PPH were eligible. We included studies of women having vaginal or caesarean birth in any setting. OUTCOMES:Critical outcomes were: PPH ≥ 500 mL within 24 hours after birth; additional blood loss of ≥ 500 mL following diagnosis of PPH and within 24 hours after birth; PPH ≥ 1000 mL within 24 hours after birth; need for blood transfusion; use of additional uterotonics, and PPH treatment rate. Important outcomes included maternal death. RISK OF BIAS:We used the Cochrane risk of bias tool (RoB 1). SYNTHESIS METHODS:At least two review authors independently assessed trials for inclusion, trustworthiness, risk of bias, and certainty of the evidence using GRADE. We calculated direct and indirect effect estimates, where possible, for critical and important outcomes. Due to limited data, we were unable to perform pairwise meta-analyses and network meta-analyses for the available combinations, or generate rankings. INCLUDED STUDIES:We included five trials (10 trial arms, 236,771 women); all included women giving birth vaginally and four had a hospital setting. The combinations of diagnostic and treatment strategies were: visual estimation-based diagnosis plus usual care for treatment; 3-option trigger PPH diagnosis with calibrated drape (1. clinical concern, or 2. blood loss ≥ 300 mL to < 500 mL plus abnormal observations, or 3. blood loss ≥ 500 mL) plus MOTIVE (uterine Massage, Oxytocics, Tranexamic acid, IntraVenous fluids, and Examination and Escalation of care) treatment bundle; 2-option trigger PPH diagnosis with calibrated drape (1. clinical concern, or 2. blood loss ≥ 500 mL) plus MOTIVE treatment bundle; calibrated drape-based diagnosis plus usual care for treatment; gravimetric method-based diagnosis plus usual care for treatment; MaternaWell tray-based diagnosis plus usual care for treatment. SYNTHESIS OF RESULTS:3-option trigger PPH diagnosis plus MOTIVE bundle versus visual estimation-based diagnosis plus usual care (direct evidence; 1 study, 170,956 participants) reduces PPH ≥ 500 mL (RR 0.48, 95% CI 0.39 to 0.58; high-certainty evidence), and PPH ≥ 1000 mL (RR 0.34, 95% CI 0.26 to 0.44; high-certainty). Moderate-certainty evidence suggests it probably makes little or no difference to the need for blood transfusion (RR 0.82, 95% CI 0.62 to 1.08) or additional uterotonics (RR 1.19, 95% CI 0.94 to 1.50), and maternal death (RR 0.73, 95% CI 0.36 to 1.48). 2-option trigger PPH diagnosis plus MOTIVE bundle versus visual estimation-based diagnosis plus usual care (direct evidence; 1 study, 39,176 participants) reduces PPH ≥ 500 mL (RR 0.73, 95% CI 0.60 to 0.89; high-certainty). It probably makes little or no difference to PPH ≥ 1000 mL (RR 0.88, 95% CI 0.69 to 1.12; moderate-certainty), and the need for blood transfusion (RR 1.06, 95% CI 0.55 to 2.04; moderate-certainty), and may make little or no difference to maternal death (RR 1.01, 95% CI 0.00 to 4.0 × 107; low-certainty). High-certainty evidence suggests it increases the need for additional uterotonics (RR 3.54, 95% CI 2.27 to 5.52). 3-option trigger PPH diagnosis plus MOTIVE bundle versus 2-option trigger PPH diagnosis plus MOTIVE bundle (indirect evidence) reduces PPH ≥ 500 mL (RR 0.65, 95% CI 0.49 to 0.86; high-certainty), PPH ≥ 1000 mL (RR 0.38, 95% CI 0.27 to 0.55; high-certainty), and the need for additional uterotonics (RR 0.34, 95% CI 0.20 to 0.55; high-certainty). It probably makes little or no difference to the need for blood transfusion (RR 0.78, 95% CI 0.38 to 1.59; moderate-certainty), and may make little or no difference to maternal death (RR 0.72, 95% CI 0.00 to 2.9 × 107; low-certainty). Calibrated drape-based diagnosis plus usual care (in a European setting (E)) versus visual estimation-based diagnosis plus usual care (E) (direct evidence; 1 study, 25,381 participants) probably makes little or no difference to the need for blood transfusion (RR 0.83, 95% CI 0.57 to 1.21; moderate-certainty). Gravimetric method-based diagnosis plus usual care versus calibrated drape-based diagnosis plus usual care (direct evidence; 1 study, 1195 participants) reduces PPH ≥ 500 mL (RR 0.54, 95% CI 0.32 to 0.90; high-certainty), and may make little or no difference to need for blood transfusion (RR 1.00, 95% CI 0.06 to 15.94; low-certainty). MaternaWell tray-based diagnosis plus usual care versus calibrated drape-based diagnosis plus usual care (direct evidence; 1 study, 63 participants) may make little or no difference to PPH ≥ 500 mL (RR 0.61, 95% CI 0.11 to 3.38; low-certainty), and PPH ≥ 1000 mL (RR 0.30, 95% CI 0.01 to 7.19; low-certainty). Gravimetric method-based diagnosis plus usual care versus MaternaWell tray-based diagnosis plus usual care (indirect evidence) may make little or no difference to PPH ≥ 500 mL (RR 0.89, 95% CI 0.15 to 5.35; low-certainty). No data were available for other critical and important outcomes. AUTHORS' CONCLUSIONS:Both 3-option trigger PPH diagnosis plus MOTIVE bundle and 2-option trigger PPH diagnosis plus MOTIVE bundle were more effective than visual estimation-based diagnosis plus usual care (direct evidence). 3-option trigger PPH diagnosis plus MOTIVE bundle was more effective than 2-option trigger PPH diagnosis plus MOTIVE bundle (indirect evidence). As the treatment strategy (MOTIVE bundle) is the same in these combinations, the increased effectiveness is likely due to the 3-option trigger PPH diagnosis, which adds blood loss of ≥ 300 mL to < 500 mL in the drape plus abnormal clinical observations as a PPH diagnostic trigger. None of the comparisons demonstrated differences in blood transfusion or maternal mortality outcomes. Future research should assess the effectiveness of combination diagnostic and treatment strategies in non-hospital settings, and for women having a caesarean birth. Studies should provide more data on side effects, and maternal experience of care. FUNDING:Gates Foundation REGISTRATION: PROSPERO (CRD42024600189).

BACKGROUND:Postpartum haemorrhage (excessive bleeding after birth) is a leading cause of maternal mortality and morbidity worldwide. However, there is no global consensus on which clinical markers best define excessive bleeding or reliably predict adverse maternal outcomes. The aim of this study was to assess the prognostic accuracy of clinical markers of postpartum bleeding in predicting maternal mortality or severe morbidity. METHODS:In this individual participant data meta-analysis, eligible datasets were identified through a global call for data issued by WHO and systematic searches of PubMed, MEDLINE, Embase, the Cochrane Library, and WHO trial registries (from database inception to Nov 6, 2024). Studies were eligible if they included at least 200 participants with objectively measured blood loss or other clinical markers of haemodynamic instability, and reported at least one clinical outcome of interest. Individual participant data were requested for all eligible studies. For each dataset, we computed the prognostic accuracy of each clinical marker to predict a composite outcome of maternal mortality or severe morbidity (blood transfusion, surgical interventions, or admission to intensive care unit). Five clinical markers were assessed: measured blood loss, pulse rate, systolic blood pressure, diastolic blood pressure, and shock index. Results were meta-analysed through two-level mixed-effects logistic regression models, with a bivariate normal model used to generate summary accuracy estimates. Clinical marker and threshold selections were informed by a WHO expert consensus process, which placed emphasis on maximising prognostic sensitivity (preferably >80%) over prognostic specificity (preferably ≥50%). This meta-analysis was registered on PROSPERO (CRD420251034918). FINDINGS:We identified 33 potentially eligible datasets and successfully obtained and analysed full data for 12 datasets, comprising 312 151 women. At the conventional threshold of 500 mL, measured blood loss had a summary prognostic sensitivity of 75·7% (95% CI 60·3-86·4) and specificity of 81·4% (95% CI 70·7-88·8) for predicting the composite outcome. The preferred sensitivity threshold was reached at 300 mL (83·9% [95% CI 72·8-91·1]), although at the expense of reduced specificity (54·8% [95% CI 38·0-70·5]). Prognostic performance improved with a decision rule that combined the use of either blood loss thresholds less than 500 mL (≥300 mL to ≥450 mL) and any abnormal haemodynamic sign (pulse rate >100 beats per min, systolic blood pressure <100 mm Hg, diastolic blood pressure <60 mm Hg, or shock index >1·0) or 500 mL or more of blood loss, with sensitivities ranging from 86·9% to 87·9% and specificities from 66·6% to 76·1%. INTERPRETATION:Measured blood loss below the conventional threshold, combined with abnormal haemodynamic signs, accurately predicts women at risk of death or life-threatening complications from postpartum bleeding and could support earlier postpartum haemorrhage diagnosis and treatment. FUNDING:The Gates Foundation and UNDP/UNFPA/UNICEF/WHO/World Bank Special Programme of Research, Development and Research Training in Human Reproduction.

OBJECTIVES:To characterize the trajectory of health-related quality of life, both overall utility and individual EuroQol 5-Dimension 5-Level (EQ-5D-5L) dimensions, over 12 months after miscarriage and assess whether this trajectory varies significantly for women with 2 or ≥3 miscarriages, compared with those with a single miscarriage within a new tiered Graded Model of Care. METHODS:Of the 203 women prospectively recruited into a cohort study at Birmingham Women's and Children's, the completion rate for the EQ-5D-5L questionnaire across 4 time points (baseline and follow-ups at 3, 6, and 12 months) was 71%. We used 2-way fixed-effects regression to estimate the effects of a subsequent miscarriage on the EQ-5D index and on optimal functioning outcomes in each health dimension. RESULTS:The mean baseline utility was 0.845; women with at least 3 miscarriages started lower (0.830). Relative to 1-loss trajectories, the recurrent miscarriage group showed additional decrements of -0.11 (95% CI -0.187 to -0.038) at 3 months and -0.12 (95% CI -0.198 to -0.036) at 6 months-exceeding the minimal clinically important difference. Deficits consistently arose from anxiety/depression. Women with 2 miscarriages exhibited a comparable mental health gap (≈30 percentage-point reduction in optimal anxiety/depression at 3 and 6 months). By 12 months, group differences were no longer significant. CONCLUSIONS:The health-related quality-of-life burden of miscarriage compounds with successive miscarriages. Recurrent loss leaves women ≥0.12 utility points worse off for up to 6 months, and a second miscarriage triggers substantial mental health impairment. Stratified care pathways offering earlier, intensified psychological and clinical support for women with at least 2 miscarriages are warranted.

BACKGROUND:A threshold of 500 mL or more of blood loss within 24 h of childbirth has conventionally been used to initiate postpartum haemorrhage (PPH) treatment. We assessed the cost-effectiveness of initiating PPH treatment at lower blood loss thresholds, alone and in combination with any abnormal haemodynamic marker (pulse, systolic and diastolic blood pressure, or shock index), compared with the conventional 500 mL or more threshold. METHODS:We developed a decision-tree model to assess the cost per disability-adjusted life-year (DALY) averted from a health-care provider perspective when the WHO PPH first-response treatment bundle was initiated using alternative criteria. Prognostic sensitivity and specificity of scenarios for identifying women at high risk of a composite outcome of maternal mortality or severe morbidity (blood transfusion, surgical intervention to stop bleeding, or intensive care admission) had been estimated using a WHO individual participant data meta-analysis of 12 datasets, comprising 312 151 women. Direct medical costs (2024 US$) were derived from a health economic study embedded within a randomised trial in Kenya, Nigeria, South Africa, and Tanzania. FINDINGS:Treatment initiation based on lower blood loss thresholds could avert additional composite outcomes. Use of lower blood loss thresholds in combination with any abnormal haemodynamic marker was more cost-effective than using blood loss alone. Combining blood loss thresholds (stepwise from ≥450 mL to ≥300 mL) with any abnormal haemodynamic marker could avert 15-27% of composite outcomes, increase costs by 9-29% per woman, and have a cost of US$271-504 per DALY averted, compared with using 500 mL blood loss threshold alone. Scenarios were particularly cost-effective for vaginal births, and cost-saving for populations with a composite outcome incidence ≥9%. INTERPRETATION:Expanding the conventional criteria for initiating PPH treatment to include lower blood loss thresholds in combination with any abnormal haemodynamic marker is cost-effective in improving maternal health outcomes, and cost-saving for obstetric populations with high incidence of PPH mortality and severe morbidity. Further research is needed in women undergoing caesarean birth. FUNDING:The Gates Foundation and the UNDP, UNFPA, UNICEF, WHO, and World Bank Special Programme of Research, Development, and Research Training in Human Reproduction, a cosponsored programme executed by WHO.

OBJECTIVE:To examine the variability in causes of maternal deaths in African countries using the World Health Organization (WHO) International Classification of Diseases Maternal Mortality (ICD-MM) framework and the contributing factors using the three delays framework. DESIGN:Secondary data analysis. SETTING:African countries. SAMPLE:National maternal death review reports. METHODS:A framework analysis of data extracted from maternal death review reports utilising the ICD-MM and three delays analytical frameworks. MAIN OUTCOME MEASURES:Proportions of the causes of maternal death and contributing factors. RESULTS:Twenty-two reports published between 2009 and 2022 were included, comprising 18,321 maternal deaths. The mean proportions were: 73% direct, 20% indirect, 8% unspecified, and 1% coincidental. The causes of death consisted of: 6% abortion-related; 16% hypertensive disorders; 33% obstetric haemorrhage; 9% infection; 10% other direct complications; 3% complications of management; 20% non-obstetric complications; 8% unknown; and 1% coincidental. All three delays contributed to maternal deaths. The third delay: receiving adequate care, was the most common in all countries except Ethiopia, where the first delay: deciding to seek care, dominated. On average, the first, second, and third delays contributed to 26%, 15%, and 61% of deaths, respectively. CONCLUSION:A renewed focus on the quality of care within health facilities, alongside addressing pre-facility contributing factors, could re-ignite progress in reducing the burden of preventable maternal deaths.

RATIONALE:Postpartum haemorrhage (PPH) is the leading cause of maternal mortality worldwide. Prophylactic uterotonic agents can prevent PPH. The current World Health Organization (WHO) recommendation for preventing PPH is 10 IU (international units) of intramuscular or intravenous oxytocin. Several uterotonics prevent PPH, but there remains uncertainty about the most effective agent with the fewest side effects. This is an update of a review first published in April 2018, and incorporates trustworthiness screening of eligible trials. OBJECTIVES:To identify the most effective uterotonic agent(s) to prevent PPH with the fewest side effects, and generate a ranking according to their effectiveness and side effect profile. SEARCH METHODS:On 5 February 2024, we searched CENTRAL, MEDLINE, Embase and CINAHL in collaboration with the Cochrane Information Specialist. ELIGIBILITY CRITERIA:All randomised controlled trials (RCTs) or cluster-RCTs that compared the effectiveness and side effects of uterotonic agents with other uterotonic agents, placebo or no treatment for preventing PPH were eligible for inclusion. We screened eligible trials for trustworthiness. We included randomised trials published only as abstracts if we could retrieve sufficient information; we excluded quasi-randomised trials. OUTCOMES:Primary outcomes were PPH ≥ 500 mL and PPH ≥ 1000 mL. Secondary outcomes included use of additional uterotonics, blood transfusion, vomiting, hypertension, and fever. RISK OF BIAS:We used RoB 1 to assess risk of bias. SYNTHESIS METHODS:At least three review authors independently assessed trials for inclusion, trustworthiness, risk of bias, and certainty of evidence using GRADE. We estimated the relative effects and rankings for the primary and secondary outcomes. We reported primary outcomes for prespecified subgroups, stratified by mode of birth (caesarean versus vaginal), setting (hospital versus community), prior risk of PPH (high versus low), dose of misoprostol (≥ 600 μg versus < 600 μg), and regimen of oxytocin (bolus versus bolus plus infusion versus infusion only). We performed pairwise meta-analyses and network meta-analysis to determine the relative effects and rankings of all available agents. INCLUDED STUDIES:The network meta-analysis included 122 trials (121,931 women), involving seven uterotonic agents and placebo or no treatment, conducted across 48 high-, middle- and low-income countries. Most were in a hospital setting (115/122, 94%), with women having a vaginal birth (87/122, 71%). SYNTHESIS OF RESULTS:Relative effects from the network meta-analysis suggested that all agents, except injectable prostaglandins, for which data were limited, were effective for preventing PPH ≥ 500 mL compared with placebo or no treatment. The two highest-ranked agents were ergometrine plus oxytocin and misoprostol plus oxytocin. Compared with oxytocin, ergometrine plus oxytocin reduces PPH ≥ 500 mL (risk ratio (RR) 0.76, 95% confidence interval (CI) 0.64 to 0.90, high-certainty evidence), and misoprostol plus oxytocin probably reduces PPH ≥ 500 mL (RR 0.70, 95% CI 0.57 to 0.87; moderate-certainty evidence). Carbetocin (high-), injectable prostaglandins (moderate-) and ergometrine (low-certainty evidence) have similar effects compared with oxytocin. The evidence for misoprostol is very low certainty. All agents, except ergometrine and injectable prostaglandins, for which data were limited, were effective for preventing PPH ≥ 1000 mL compared with placebo or no treatment. Ergometrine plus oxytocin, and misoprostol plus oxytocin were the highest-ranked agents. Compared with oxytocin, carbetocin and injectable prostaglandins (both moderate-certainty evidence), and misoprostol plus oxytocin (low-certainty evidence) make little or no difference to PPH ≥ 1000 mL. Misoprostol may be less effective in preventing PPH ≥ 1000 mL compared with oxytocin (RR 1.24, 95% CI 1.06 to 1.46; low-certainty evidence). The certainty of evidence for ergometrine and ergometrine plus oxytocin was very low. Compared with oxytocin, misoprostol plus oxytocin probably reduces the use of additional uterotonics (RR 0.55, 95% CI 0.42 to 0.72, moderate-certainty evidence), and carbetocin (RR 0.74, 95% CI 0.59 to 0.94; low-certainty evidence), and ergometrine plus oxytocin may reduce the use of additional uterotonics (RR 0.68, 95% CI 0.56 to 0.83; low-certainty evidence). Misoprostol (low-certainty evidence) makes little or no difference to this outcome. Misoprostol plus oxytocin probably reduces the risk of needing a blood transfusion (RR 0.40, 95% CI 0.28 to 0.58; moderate-certainty-evidence), and ergometrine plus oxytocin may reduce the risk of blood transfusion compared with oxytocin (RR 0.73, 95% CI 0.56 to 0.96, low-certainty evidence). Carbetocin (moderate-certainty evidence) and misoprostol (low-certainty evidence) probably make little or no difference to this outcome compared with oxytocin. All uterotonic agents, except for carbetocin, were associated with increased risks of side effects compared with oxytocin. Misoprostol may increase the likelihood of nausea, vomiting and fever, and probably increases the risk of diarrhoea. Injectable prostaglandins may increase the likelihood of diarrhoea. Ergometrine probably increases the likelihood of nausea and vomiting, and may increase the likelihood of hypertension, headache, and diarrhoea. Ergometrine plus oxytocin may increase the likelihood of nausea, vomiting, and diarrhoea. Misoprostol plus oxytocin probably increases the likelihood of nausea, vomiting and diarrhoea, and may increase the likelihood of fever. Analyses of the prespecified subgroups did not reveal important subgroup differences. Evidence for outcomes not presented above but reported in the summary of findings tables was very low certainty. AUTHORS' CONCLUSIONS:Most agents are effective for preventing PPH when compared with placebo or no treatment. Ergometrine plus oxytocin, and misoprostol plus oxytocin may be more effective than the current standard oxytocin. All agents, except for carbetocin, are associated with an increased risk of some side effects compared with oxytocin. FUNDING:Supported by UNDP/UNFPA/UNICEF/WHO/World Bank Special Programme of Research, Development and Research Training in Human Reproduction (HRP), a cosponsored programme executed by the WHO (Award No. HQHRP2220228-22.1-74309). REGISTRATION:Cochrane Library; Registration number: CD011689 and protocol [and previous versions] available via DOI: 10.1002/14651858.CD011689 [DOI: 10.1002/14651858.CD011689.pub3 and DOI: 10.1002/14651858.CD011689.pub2].

Background:Recurrent miscarriage is a debilitating disorder associated with considerable physical and psychological morbidity. An estimated 50% of first trimester miscarriages remain unexplained. The aim of this study was to provide a personalised framework to guide the expectations of women experiencing recurrent miscarriage, with the ultimate goal of transforming clinical practice. Methods:We used real-world data from a UK longitudinal study of 1201 couples attending National Health Service (NHS) miscarriage clinics, with a history of previous miscarriages, comprising medical and obstetric history, results of investigations and pregnancy and neonatal outcome. We developed, parametrised, and validated predictive models for the probability that the next pregnancy is viable and for the time to next pregnancy. Time to next pregnancy separates couples into two groups, a group with subfertility, i.e., delay in conception, and a group with no significant delay in conception. We used Bayesian inference for the latter model.Trial registration number: The prospective data collections were pre-registered ISRCTN17732518; https://doi.org/10.1186/ISRCTN17732518. Findings:Predictive models of the time to pregnancy, the probability of the couple being subfertility and the probability of having a viable pregnancy can be parametrised from longitudinal study data. We identified several predictors for such models. In the viable pregnancy model, increased maternal age, higher Body Mass Index (BMI), having Polycystic Ovaries Syndrome (PCOS) and the number of previous miscarriages were associated with reduced odds of viable pregnancy. In contrast, having had previous live births increased the odds of a viable pregnancy. Model validation against a second external dataset gave an Area Under Curve (AUC) of 0.65 (95% Confidence Interval (CI): 0.55, 0.76). Of the 942 women referred to our recurrent miscarriage clinics and followed up over a period of 3 years, 10.7% (101) did not conceive during this time, indicating a potential subfertility problem. In the time to pregnancy model, increased maternal age, higher BMI, and smoking were associated with reduced likelihood of conception. Conversely, taking folic acid supplements and having a history of previous conceptions were associated with increased fertility. In our cohort, 53.4% (577 out of 1080 women) reported a pregnancy within 12 months. Additionally, 22.8% (277 out of 996 women who were followed up over a 2-year period) experienced a first pregnancy event in the second year. The area under the curve (AUC) for predicting pregnancy within 12 months was 0.60 (95% CI: 0.50-0.70) in an external validation using a second dataset. Interpretation:The pregnancy journey can be predicted on a personalised basis by integrating the validated models. We provide a framework for evidence-based management of women with miscarriage, comprising informed decision-making, including optimal referral to fertility services, and a tailored insight into fertility outcomes, thereby guiding expectations and providing psychological support. Funding:Tommy's National Centre for Miscarriage Research.

BACKGROUND:An understanding of the causes of postpartum haemorrhage is needed to provide appropriate treatment and services. Knowledge of the risk factors for postpartum haemorrhage can help address modifiable risk factors. We did a systematic review and meta-analysis to identify and quantify the various causes and risk factors for postpartum haemorrhage. METHODS:In this systematic review and meta-analysis, we did a systematic literature search in MEDLINE, Embase, Web of Science, Cochrane Library, and Google Scholar for cohort studies of postpartum haemorrhage from Jan 1, 1960, to Nov 30, 2024 without language restrictions. At least two authors independently undertook study selection, data extraction, and quality assessment. Population-based cohort studies available in English were eligible. Rates of postpartum haemorrhage causes as well as crude and adjusted odds ratios (ORs) for risk factors were pooled using a random-effects model. Risk factors were classified as having weak, moderate, or strong association based on the pooled ORs: weak (OR >1 to 1·5), moderate (OR >1·5 to 2), and strong (OR >2). This study is registered with PROSPERO, CRD42023479686. FINDINGS:We synthesised data from 327 studies, including 847 413 451 women with no restriction on age, race, or ethnicity. Most studies were of high methodological quality. The pooled rates of the five commonly reported causes of postpartum haemorrhage were uterine atony (70·6% [95% CI 63·9-77·3]; n=834 707 women, 14 studies), genital tract trauma (16·9% [9·3-24·6]; n=18 449 women, six studies), retained placenta (16·4% [12·3-20·5]; n=235 021 women, nine studies), abnormal placentation (3·9% [0·1-7·6]; n=29 638 women, two studies), and coagulopathy (2·7% [0·8-4·5]; n=236 261, nine studies). The pooled rate of women with multiple postpartum haemorrhage causes was 7·8% (95% CI 4·7-10·8; n=666, two studies). Risk factors with a strong association with postpartum haemorrhage included anaemia, previous postpartum haemorrhage, caesarean birth, female genital mutilation, sepsis, no antenatal care, multiple pregnancy, placenta praevia, assisted reproductive technology use, macrosomia with a birthweight of more than 4500 g, and shoulder dystocia. Risk factors with moderate association with postpartum haemorrhage included BMI ≥30 kg/m2, COVID-19 infection, gestational diabetes, polyhydramnios, pre-eclampsia, and antepartum haemorrhage. Risk factors with weak association with postpartum haemorrhage included Black and Asian ethnicity, BMI 25-29·9 kg/m2, asthma, thrombocytopenia, uterine fibroids, antidepressant use, induction of labour, instrumental birth, and premature rupture of membranes. INTERPRETATION:The finding that uterine atony is the commonest cause of postpartum haemorrhage supports the WHO recommendation for all women giving birth to be given prophylactic uterotonics. Knowledge of risk factors with a strong association with postpartum haemorrhage can help to identify women at high risk of postpartum haemorrhage who could benefit from enhanced prophylaxis and treatment. The importance of multiple concurrent causes of postpartum haemorrhage supports the use of treatment bundles. FUNDING:Gates Foundation.

OBJECTIVE:To establish the effect of uterine surgery on miscarriage rates. Some surgical procedures risk compromising endometrial function and lead to reproductive dysfunction. There is no long-term data to demonstrate the effect of uterine surgery on miscarriage rates. Surgical management of miscarriage and cesarean section are commonly chosen management options. The effect of these on future fertility prospects should be established. DESIGN:A prospective multicenter cohort study. SUBJECTS:A total of 1,473 women with recurrent miscarriage. EXPOSURE:We evaluated the association between the surgical management of miscarriage and cesarean section and subsequent miscarriage risk. MAIN OUTCOME MEASURES:Miscarriage in first pregnancy after recruitment. Effect sizes were calculated as risk ratios (RRs) with 95% confidence intervals (CIs) using Poisson regression. This followed adjustments for known confounders. RESULTS:In women with two or more miscarriages at baseline, the RR of miscarriage after cesarean section was 1.31; 95% CI, 1.03-1.66. The risk after any history of surgical management of miscarriage was not increased. However, subgroup analysis showed a 47% increase in miscarriage risk in women with a history of three or more surgically managed miscarriages compared with women who had only expectant and/or medical management (RR, 1.5; 95% CI, 1.11-1.79). In women with three or more miscarriages at baseline, the increase in miscarriage risk was 50% with any history of cesarean section compared with no history of cesarean (RR, 1.5; 95% CI, 1.15-1.96). CONCLUSION:Within a cohort of women with two or more previous miscarriages, exposure to cesarean section increases the risk of future miscarriage. Women who have had three or more surgically managed miscarriages are also at a higher risk of subsequent miscarriage.

Accurately predicting oocyte yield is key to individualizing gonadotrophin dosing in assisted reproduction, where excessive responses carry significant risks and inadequate responses may compromise treatment success. Machine learning models are being developed to support this. This review evaluates the accuracy and clinical readiness of such models for predicting oocyte yield at transvaginal oocyte retrieval. A literature search of OVID MEDLINE, OVID EMBASE and the Cochrane Database identified nine relevant studies, eight retrospective and one prospective cohort, and encompassing 62,354 cycles. Study quality was assessed using the TRIPOD checklist and risk of bias was assessed with PROBAST. Accuracy was variably reported; the most frequent measure was mean absolute error, ranging from 0.62 to 4.13. A meta-analysis was not possible due to heterogeneity. Neural network models generally performed best. None of the studies were externally validated, limiting the generalizability. Most lacked transparency around data pre-processing, including handling missing data and variable transformation, reducing reproducibility. Although several models demonstrated promising internal performance, they remain at high risk of bias. Clinicians should be cautious in applying these models to practice until independently validated. Overall, machine learning-based prediction of oocyte yield remains in the early phase, and future development should prioritize external validation and transparent reporting.

OBJECTIVE:This study aimed to explore the effects of preconception and first-trimester metformin use on pregnancy outcomes in women with polycystic ovary syndrome. DATA SOURCES:MEDLINE, Embase, and the Cochrane Central Register of Controlled Trials were searched from database inception to August 1, 2024. STUDY ELIGIBILITY CRITERIA:Randomized controlled trials of metformin started before conception and continued at least until a positive pregnancy test compared with either placebo or no treatment in women with polycystic ovary syndrome were included. METHODS:A systematic review and meta-analysis was conducted. Pooled odds ratios with 95% confidence intervals were calculated for the following key outcomes: miscarriage (primary) and clinical pregnancy and live birth (secondary). The studies were assessed for quality using the Cochrane risk-of-bias tool for randomized trials (RoB 2) and the Grading of Recommendations, Assessment, Development, and Evaluation approach. Indirect comparisons were performed for all key outcomes on the timing of metformin treatment using the Bucher technique. RESULTS:A total of 12 trustworthy studies (involving 1708 women) were included in the meta-analysis, all of which were graded low to moderate quality. Women who received preconception metformin that was continued throughout the first trimester of pregnancy showed higher clinical pregnancy rates (odds ratio, 1.57 [95% confidence interval, 1.11-2.23]), a possible reduction in miscarriage (odds ratio, 0.64 [95% confidence interval, 0.32-1.25]), and possible increase in live birth (odds ratio, 1.24 [95% confidence interval, 0.59-2.61]) than women who received either a placebo or no treatment. Women who stopped metformin once pregnant not only had an increase in clinical pregnancy rate (odds ratio, 1.35 [95% confidence interval, 1.01-1.80]) but also had an indication of an increase in miscarriage rate (odds ratio, 1.46 [95% confidence interval, 0.73-2.90]) compared with those who received a placebo or no treatment. Indirect comparisons between metformin continued through the first trimester of pregnancy and metformin stopped once pregnant consistently demonstrated a trend favoring the continuation of metformin: clinical pregnancy odds ratio of 1.16 (95% confidence interval, 0.74-1.83), miscarriage odds ratio of 0.44 (95% confidence interval, 0.17-1.16), and live birth odds ratio of 1.14 (95% confidence interval, 0.41-3.13). CONCLUSION:Continuing metformin treatment throughout the first trimester of pregnancy may reduce the risk of miscarriage and increase live birth rates in women with polycystic ovary syndrome. Continuation of metformin seems to have greater clinical benefit than discontinuation of metformin after a positive pregnancy test. There is a need for further high-quality research.

BACKGROUND:The definition of primary postpartum haemorrhage as blood loss of 500 mL or more within 24 h after vaginal birth underemphasises the early postpartum hours due to limited data on the timing of postpartum haemorrhage diagnosis. Understanding postpartum haemorrhage diagnosis timing and diagnostic methods is important for guiding diagnostic and therapeutic strategies. The E-MOTIVE trial evaluated early postpartum haemorrhage diagnosis and a bundled treatment approach, which resulted in a 60% relative reduction in adverse outcomes from bleeding compared with usual care. We aimed to compare timing from vaginal birth to postpartum haemorrhage diagnosis and the diagnostic methods used among four African countries implementing the intervention from the E-MOTIVE trial. METHODS:Nested within the E-MOTIVE trial (NCT04341662), we conducted direct observations of health-care workers providing clinical care to postpartum women at 39 hospitals implementing the E-MOTIVE intervention across Nigeria, Kenya, Tanzania, and South Africa. One to two weeks of continuous observations were conducted from vaginal birth up to 2 h, between June 27, and Dec 18, 2022. Health-care workers were trained to use clinical judgement (ie, heavy vaginal blood loss, large blood clots expelled, or constant trickle) and various objective blood loss thresholds to diagnose postpartum haemorrhage. The objective blood loss thresholds used in Nigeria, Kenya, and Tanzania were 300 mL or more with at least one abnormal clinical sign (ie, pulse, blood pressure, uterine tone, and vaginal blood flow) or 500 mL or more. The objective blood loss threshold in South Africa was 500 mL or more. We descriptively analysed and compared timing from vaginal birth to postpartum haemorrhage diagnosis and diagnostic methods used between countries. FINDINGS:Of 2578 women, 295 postpartum haemorrhages were diagnosed. The median time from vaginal birth to postpartum haemorrhage diagnosis was 15 min in Nigeria and Tanzania, 17 min in Kenya, and 30 min in South Africa. Diagnosis within 30 min ranged from 58% in South Africa to 86% in Tanzania. By 60 min, 96% to 100% of postpartum haemorrhages were diagnosed across all countries. All postpartum haemorrhages that required an intervention were diagnosed within 90 min. Nigeria, Kenya, and Tanzania commonly used blood loss of 300 mL or more combined with at least one abnormal clinical sign (47%, 65%, and 68%, respectively) while South Africa relied on a definition of 500 mL or more (81%) as the dominant diagnostic strategy. INTERPRETATION:In countries where an objective blood loss threshold of 300 mL or more with at least one abnormal clinical sign was used, women received earlier interventions for postpartum bleeding, with a median time to diagnosis of 15-17 min. This was notably faster than in the country that predominantly used a 500 mL or more threshold, where the median time to diagnosis was 30 min. Regardless of whether the threshold was 300 mL or more with abnormal clinical signs or 500 mL or more alone, all postpartum haemorrhages were diagnosed within 90 min of vaginal birth. FUNDING:Bill & Melinda Gates Foundation and Ammalife.

Introduction Maternal mortality in sub-Saharan Africa remains high, with the rate of decline stagnated. Many countries conduct maternal reviews, which can help identify outliers. Outlier analysis could better inform the design and implementation of strategies to tackle the causes of preventable maternal deaths. Aim To examine the variability in causes of maternal deaths in African countries using the WHO International Classification of Diseases Maternal Mortality (ICD-MM) framework and the contributing factors using the three-delays framework. Methods An observational ecological study of national maternal death review reports from 23 African countries between 2009 and 2022. Results Twenty-three maternal death review reports, covering 19,319 deaths, were included. Direct causes were the most common (43-92%), with variability across ICD-MM groups and three-delay factors observed. Obstetric haemorrhage (ICD-MM Group 3) was the leading cause in 17 reports, non-obstetric complications (Group 7) in five, pregnancy with abortive outcomes (Group 1) in one, and hypertensive disorders (Group 2) in one, with varying magnitudes across countries. Most reports (94%) identified the third delay (delay in receiving adequate care) as the primary contributor, while one report cited the first delay (delay in decision to seek care). The magnitude of each delay varied by country: The first delay contributed 0-34% of the audited maternal deaths; the second delay, 5-44%; and the third delay, 32-100%. Conclusion Efforts to further reduce the burden of preventable maternal deaths in sub-Saharan Africa should prioritise addressing the third delay, i.e. the delay in receiving adequate care within health facilities.