Strategies for optimising early detection and obstetric first response management of postpartum haemorrhage at caesarean birth: a modified Delphi-based international expert consensus.

OBJECTIVE: There are no globally agreed on strategies on early detection and first response management of postpartum haemorrhage (PPH) during and after caesarean birth. Our study aimed to develop an international expert's consensus on evidence-based approaches for early detection and obstetric first response management of PPH intraoperatively and postoperatively in caesarean birth. DESIGN: Systematic review and three-stage modified Delphi expert consensus. SETTING: International. POPULATION: Panel of 22 global experts in PPH with diverse backgrounds, and gender, professional and geographic balance. OUTCOME MEASURES: Agreement or disagreement on strategies for early detection and first response management of PPH at caesarean birth. RESULTS: Experts agreed that the same PPH definition should apply to both vaginal and caesarean birth. For the intraoperative phase, the experts agreed that early detection should be accomplished via quantitative blood loss measurement, complemented by monitoring the woman's haemodynamic status; and that first response should be triggered once the woman loses at least 500 mL of blood with continued bleeding or when she exhibits clinical signs of haemodynamic instability, whichever occurs first. For the first response, experts agreed on immediate administration of uterotonics and tranexamic acid, examination to determine aetiology and rapid initiation of cause-specific responses. In the postoperative phase, the experts agreed that caesarean birth-related PPH should be detected primarily via frequently monitoring the woman's haemodynamic status and clinical signs and symptoms of internal bleeding, supplemented by cumulative blood loss assessment performed quantitatively or by visual estimation. Postoperative first response was determined to require an individualised approach. CONCLUSION: These agreed on proposed approaches could help improve the detection of PPH in the intraoperative and postoperative phases of caesarean birth and the first response management of intraoperative PPH. Determining how best to implement these strategies is a critical next step.

Preventing postpartum hemorrhage: A network meta-analysis on routes of administration of uterotonics.

1. OBJECTIVE: To perform a network meta-analysis to specify the route of administration that maximises the effectiveness of each of the available prophylactic uterotonics without increasing the risk for side effects. 2. DATA SOURCES: Literature searches on 12th September 2022 included: CENTRAL, MEDLINE, Embase, CINAHL, ClinicalTrials.gov and the WHO International Clinical Trials Registry Platform. The reference lists of the retrieved study records were also searched. 3. STUDY ELIGIBILITY CRITERIA: Population: Randomized controlled trials involving women in the third stage of labour after a vaginal or caesarean delivery in hospital or community settings. INTERVENTIONS: Systemically administered prophylactic uterotonics of any route and dose for primary postpartum hemorrhage prevention. Comparison: Any other prophylactic uterotonic, or a different route or dose of a given uterotonic, or placebo, or no treatment. Outcomes (primary): postpartum hemorrhage ≥ 500 mL and ≥ 1000 mL. 4. STUDY APPRAISAL AND SYNTHESIS METHODS: Risk of bias and trustworthiness assessments were performed, according to Cochrane's guidance. Direct, indirect and network meta-analyses were conducted, and results were summarized either as risk ratio or mean difference with 95% confidence intervals for dichotomous and continuous outcomes, respectively. The certainty of generated evidence was assessed according to the GRADE approach. Cumulative probabilities were calculated and the surface under the cumulative ranking curve was used to create a ranking of the available drugs. 5. RESULTS: One hundred eighty-one studies involving 122,867 randomised women were included. Most studies were conducted in hospital settings in lower-middle income countries and involved women delivering vaginally. When compared with intramuscular oxytocin, carbetocin (RR 0.58, 95 % CI 0.40-0.84) and oxytocin (RR 0.75, 95 % CI 0.59-0.97) by an intravenous bolus, and intramuscular ergometrine plus oxytocin combination (RR 0.71, 95 % CI 0.56-0.91) are probably more effective in preventing primary postpartum hemorrhage. Intramuscularly administered oxytocin and carbetocin by an intravenous bolus have a favourable side effects profile. 6. CONCLUSIONS: Generated evidence was generally moderate and global inconsistency was low. Carbetocin and oxytocin by an intravenous bolus, and intramuscular ergometrine plus oxytocin combination are probably the top uterotonics for primary postpartum hemorrhage prevention. Large scale studies exploring different routes of administration for available prophylactic uterotonics, and women's views should be conducted.

A systematic review of behaviour change interventions to improve maternal health outcomes in sub-Saharan Africa.

The rate of decline in the global burden of avoidable maternal deaths has stagnated and remains an issue of concern in many sub-Saharan Africa countries. As per the most recent evidence, an average maternal mortality ratio (MMR) of 223 deaths per 100,000 live births has been estimated globally, with sub-Saharan Africa's average MMR at 536 per 100,000 live births-more than twice the global average. Despite the high MMR, there is variation in MMR between and within sub-Saharan Africa countries. Differences in the behaviour of those accessing and/or delivering maternal healthcare may explain variations in outcomes and provide a basis for quality improvement in health systems. There is a gap in describing the landscape of interventions aimed at modifying the behaviours of those accessing and delivering maternal healthcare for improving maternal health outcomes in sub-Saharan Africa. Our objective was to extract and synthesise the target behaviours, component behaviour change strategies and outcomes of behaviour change interventions for improving maternal health outcomes in sub-Saharan Africa. We followed the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) guidelines. Our protocol was published a priori on PROSPERO (registration number CRD42022315130). We searched ten electronic databases (PsycINFO, Cochrane Database of Systematic Reviews, International Bibliography of Social Sciences, EMBASE, MEDLINE, Scopus, CINAHL PLUS, African Index Medicus, African Journals Online, and Web of Science) and included randomised trials and quasi-experimental studies. We extracted target behaviours and specified the behavioural interventions using the Action, Actor, Context, Time, and Target (AACTT) framework. We categorised the behaviour change strategies using the intervention functions described in the Behaviour Change Wheel (BCW). We reviewed 52 articles (26 randomized trials and 26 quasi-experimental studies). They had a mixed risk of bias. Out of these, 41 studies (78.8%) targeted behaviour change of those accessing maternal healthcare services, while seven studies (13.5%) focused on those delivering maternal healthcare. Four studies (7.7%) targeted mixed stakeholder groups. The studies employed a range of behaviour change strategies, including education 37 (33.3%), persuasion 20 (18%), training 19 (17.1%), enablement 16 (14.4%), environmental restructuring 8 (7.2%), modelling 6 (5.4%) and incentivisation 5 (4.5%). No studies used restriction or coercion strategies. Education was the most common strategy for changing the behaviour of those accessing maternal healthcare, while training was the most common strategy in studies targeting the behaviour of those delivering maternal healthcare. Of the 52 studies, 40 reported effective interventions, 7 were ineffective, and 5 were equivocal. A meta-analysis was not feasible due to methodological and clinical heterogeneity across the studies. In conclusion, there is evidence of effective behaviour change interventions targeted at those accessing and/or delivering maternal healthcare in sub-Saharan Africa. However, more focus should be placed on behaviour change by those delivering maternal healthcare within the health facilities to fast-track the reduction of the huge burden of avoidable maternal deaths in sub-Saharan Africa.

The use of immunomodulation therapy in women with recurrent implantation failure undergoing assisted conception: A multicentre cohort study.

PROBLEM: Recurrent implantation failure (RIF) after multiple embryo transfers remains a vexing problem and immunomodulators have been used with conflicting results. This study aims to assess the effect of immunomodulation therapy on live birth rate (LBR) in women with RIF undergoing assisted reproduction treatment (ART). METHOD OF STUDY DESIGN: This is a retrospective cohort study in multicentre network of private assisted conception units in the UK. The study included women who had at least two failed attempts of embryo transfers at CARE fertility network in the period from 1997 to 2018. Women in the treatment group had immunomodulator drugs in the form of corticosteroids, low molecular weight heparin (LMWH), and intravenous intralipid (IVIL) infusions, either separately or in combination, after immunological testing, in addition to standard ART whilst women in the control group had only ART without immunomodulators. The primary outcome was LBR per cycle. Secondary outcomes included the rates of clinical pregnancy (CPR), cumulative live birth (CLBR), and miscarriage. RESULTS: A total of 27 163 ART cycles fulfilled the inclusion criteria, of which 5083 had immunomodulation treatment in addition to standard ART treatment, and 22 080 had standard ART treatment alone. Women in the treatment group were significantly older (mean age 38.5 vs. 37.1 years, p < .001), and had a higher number of previous failed ART cycles (mean 4.3 vs. 3.8, p < .01). There was a higher LBR in women who received immunomodulation therapy when compared with the control group (20.9% vs. 15.8%, odds ratio [OR] 1.4, 95% confidence interval [CI] 1.29-1.53, p < .001). Multivariate regression analysis showed that immunomodulation treatment was a significant independent predictor of live birth after adjusting for other confounders (adjusted OR [aOR] 1.33, 95% CI 1.15-1.54, p < .001). Survival analysis showed a higher CLBR in the treatment group (adjusted hazard ratio [aHR] 1.78, 95% CI 1.62-1.94, p < .001). CONCLUSION(S): This study provides evidence of a potential beneficial effect of immunomodulation therapy in women with RIF after immunological testing. There remains a need for high quality, adequately powered multicentre RCTs to robustly address the role of immunomodulation in women with RIF. There is also an urgent need for standardised screening tests for immune disorders that could preclude implantation.

Vaginal micronised progesterone for the prevention of hypertensive disorders of pregnancy: A systematic review and meta-analysis.

BACKGROUND: Treatment with vaginal progesterone reduces the risk of miscarriage and preterm birth in selected high-risk women. The hypothesis that vaginal progesterone can reduce the risk of hypertensive disorders of pregnancy (HDP) is unexplored. OBJECTIVES: To summarise the evidence on the effectiveness of vaginal progesterone to reduce the risk of HDP. SEARCH STRATEGY: We searched Embase (OVID), MEDLINE (OVID), PubMed, CENTRAL and clinicaltrials.gov from inception until 20 June 2023. SELECTION CRITERIA: We included placebo-controlled randomised trials (RCTs) of vaginal progesterone for the prevention or treatment of any pregnancy complications. DATA COLLECTION AND ANALYSIS: We extracted absolute event numbers for HDP and pre-eclampsia in women receiving vaginal progesterone or placebo, and meta-analysed the data with a random effects model. We appraised the certainty of the evidence using GRADE methodology. MAIN RESULTS: The quantitative synthesis included 11 RCTs, of which three initiated vaginal progesterone in the first trimester, and eight in the second or third trimesters. Vaginal progesterone started in the first trimester of pregnancy lowered the risk of any HDP (risk ratio [RR] 0.71, 95% confidence interval [CI] 0.53-0.93, 2 RCTs, n = 4431 women, I2 = 0%; moderate-certainty evidence) and pre-eclampsia (RR 0.61, 95% CI 0.41-0.92, 3 RCTs, n = 5267 women, I2 = 0%; moderate-certainty evidence) when compared with placebo. Vaginal progesterone started in the second or third trimesters was not associated with a reduction in HDP (RR 1.19, 95% CI 0.67-2.12, 3 RCTs, n = 1602 women, I2 = 9%; low-certainty evidence) or pre-eclampsia (RR 0.97, 95% CI 0.71-1.31, 5 RCTs, n = 4274 women, I2 = 0%; low-certainty evidence). CONCLUSIONS: Our systematic review found first-trimester initiated vaginal micronised progesterone may reduce the risk of HDP and pre-eclampsia.

A comparison of morphokinetic models and morphological selection for prioritizing euploid embryos: a multicentre cohort study.

STUDY QUESTION: Are morphokinetic models better at prioritizing a euploid embryo for transfer over morphological selection by an embryologist? SUMMARY ANSWER: Morphokinetic algorithms lead to an improved prioritization of euploid embryos when compared to embryologist selection. WHAT IS KNOWN ALREADY: PREFER (predicting euploidy for embryos in reproductive medicine) is a previously published morphokinetic model associated with live birth and miscarriage. The second model uses live birth as the target outcome (LB model). STUDY DESIGN, SIZE, DURATION: Data for this cohort study were obtained from 1958 biopsied blastocysts at nine IVF clinics across the UK from January 2021 to December 2022. PARTICIPANTS/MATERIALS, SETTING, METHODS: The ability of the PREFER and LB models to prioritize a euploid embryo was compared against arbitrary selection and the prediction of four embryologists using the timelapse video, blinded to the morphokinetic time stamp. The comparisons were made using calculated percentages and normalized discounted cumulative gain (NDCG), whereby an NDCG score of 1 would equate to all euploid embryos being ranked first. In arbitrary selection, the ploidy status was randomly assigned within each cycle and the NDGC calculated, and this was then repeated 100 times and the mean obtained. MAIN RESULTS AND THE ROLE OF CHANCE: Arbitrary embryo selection would rank a euploid embryo first 37% of the time, embryologist selection 39%, and the LB and PREFER ploidy morphokinetic models 46% and 47% of the time, respectively. The AUC for LB and PREFER model was 0.62 and 0.63, respectively. Morphological selection did not significantly improve the performance of both morphokinetic models when used in combination. There was a significant difference between the NDGC metric of the PREFER model versus embryologist selection at 0.96 and 0.87, respectively (t = 14.1, P < 0.001). Similarly, there was a significant difference between the LB model and embryologist selection with an NDGC metric of 0.95 and 0.87, respectively (t = 12.0, P < 0.001). All four embryologists ranked embryos similarly, with an intraclass coefficient of 0.91 (95% CI 0.82-0.95, P < 0.001). LIMITATIONS, REASONS FOR CAUTION: Aside from the retrospective study design, limitations include allowing the embryologist to watch the time lapse video, potentially providing more information than a truly static morphological assessment. Furthermore, the embryologists at the participating centres were familiar with the significant variables in time lapse, which could bias the results. WIDER IMPLICATIONS OF THE FINDINGS: The present study shows that the use of morphokinetic models, namely PREFER and LB, translates into improved euploid embryo selection. STUDY FUNDING/COMPETING INTEREST(S): This study received no specific grant funding from any funding agency in the public, commercial or not-for-profit sectors. Dr Alison Campbell is minor share holder of Care Fertility. All other authors have no conflicts of interest to declare. Time lapse is a technology for which patients are charged extra at participating centres. TRIAL REGISTRATION NUMBER: N/A.

COVID-19 in pregnant women: a systematic review and meta-analysis on the risk and prevalence of pregnancy loss.

BACKGROUND: Pregnant women infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) are more likely to experience preterm birth and their neonates are more likely to be stillborn or admitted to a neonatal unit. The World Health Organization declared in May 2023 an end to the coronavirus disease 2019 (COVID-19) pandemic as a global health emergency. However, pregnant women are still becoming infected with SARS-CoV-2 and there is limited information available regarding the effect of SARS-CoV-2 infection in early pregnancy on pregnancy outcomes. OBJECTIVE AND RATIONALE: We conducted this systematic review to determine the prevalence of early pregnancy loss in women with SARS-Cov-2 infection and compare the risk to pregnant women without SARS-CoV-2 infection. SEARCH METHODS: Our systematic review is based on a prospectively registered protocol. The search of PregCov19 consortium was supplemented with an extra electronic search specifically on pregnancy loss in pregnant women infected with SARS-CoV-2 up to 10 March 2023 in PubMed, Google Scholar, and LitCovid. We included retrospective and prospective studies of pregnant women with SARS-CoV-2 infection, provided that they contained information on pregnancy losses in the first and/or second trimester. Primary outcome was miscarriage defined as a pregnancy loss before 20 weeks of gestation, however, studies that reported loss up to 22 or 24 weeks were also included. Additionally, we report on studies that defined the pregnancy loss to occur at the first and/or second trimester of pregnancy without specifying gestational age, and for second trimester miscarriage only when the study presented stillbirths and/or foetal losses separately from miscarriages. Data were stratified into first and second trimester. Secondary outcomes were ectopic pregnancy (any extra-uterine pregnancy), and termination of pregnancy. At least three researchers independently extracted the data and assessed study quality. We calculated odds ratios (OR) and risk differences (RDs) with corresponding 95% CI and pooled the data using random effects meta-analysis. To estimate risk prevalence, we performed meta-analysis on proportions. Heterogeneity was assessed by I2. OUTCOMES: We included 120 studies comprising a total of 168 444 pregnant women with SARS-CoV-2 infection; of which 18 233 women were in their first or second trimester of pregnancy. Evidence level was considered to be of low to moderate certainty, mostly owing to selection bias. We did not find evidence of an association between SARS-CoV-2 infection and miscarriage (OR 1.10, 95% CI 0.81-1.48; I2 = 0.0%; RD 0.0012, 95% CI -0.0103 to 0.0127; I2 = 0%; 9 studies, 4439 women). Miscarriage occurred in 9.9% (95% CI 6.2-14.0%; I2 = 68%; 46 studies, 1797 women) of the women with SARS CoV-2 infection in their first trimester and in 1.2% (95% CI 0.3-2.4%; I2 = 34%; 33 studies; 3159 women) in the second trimester. The proportion of ectopic pregnancies in women with SARS-CoV-2 infection was 1.4% (95% CI 0.02-4.2%; I2 = 66%; 14 studies, 950 women). Termination of pregnancy occurred in 0.6% of the women (95% CI 0.01-1.6%; I2 = 79%; 39 studies; 1166 women). WIDER IMPLICATIONS: Our study found no indication that SARS-CoV-2 infection in the first or second trimester increases the risk of miscarriages. To provide better risk estimates, well-designed studies are needed that include pregnant women with and without SARS-CoV-2 infection at conception and early pregnancy and consider the association of clinical manifestation and severity of SARS-CoV-2 infection with pregnancy loss, as well as potential confounding factors such as previous pregnancy loss. For clinical practice, pregnant women should still be advised to take precautions to avoid risk of SARS-CoV-2 exposure and receive SARS-CoV-2 vaccination.

Perceptions and experiences of the prevention, detection, and management of postpartum haemorrhage: a qualitative evidence synthesis.

BACKGROUND: Postpartum haemorrhage (PPH), defined as blood loss of 500 mL or more after childbirth, is the leading cause of maternal mortality worldwide. It is possible to prevent complications of PPH with timely and appropriate detection and management. However, implementing the best methods of PPH prevention, detection and management can be challenging, particularly in low- and middle-income countries. OBJECTIVES: Our overall objective was to explore the perceptions and experiences of women, community members, lay health workers, and skilled healthcare providers who have experience with PPH or with preventing, detecting, and managing PPH, in community or health facility settings. SEARCH METHODS: We searched MEDLINE, CINAHL, Scopus, and grey literature on 13 November 2022 with no language restrictions. We then performed reference checking and forward citation searching of the included studies. SELECTION CRITERIA: We included qualitative studies and mixed-methods studies with an identifiable qualitative component. We included studies that explored perceptions and experiences of PPH prevention, detection, and management among women, community members, traditional birth attendants, healthcare providers, and managers. DATA COLLECTION AND ANALYSIS: We used three-stage maximum variation sampling to ensure diversity in terms of relevance of the study to the review objectives, richness of data, and coverage of critical contextual elements: setting (region, country income level), perspective (type of participant), and topic (prevention, detection, management). We extracted data using a data extraction form designed for this review. We used thematic synthesis to analyse and synthesise the evidence, and we used the GRADE-CERQual (Confidence in the Evidence from Reviews of Qualitative research) approach to assess our confidence in each finding. To identify factors that may influence intervention implementation, we mapped each review finding to the Theoretical Domains Framework (TDF) and the Capability, Motivation, and Opportunity model of Behaviour change (COM-B). We used the Behaviour Change Wheel to explore implications for practice. MAIN RESULTS: We included 67 studies and sampled 43 studies for our analysis. Most were from low- or middle-income countries (33 studies), and most included the perspectives of women and health workers. We downgraded our confidence in several findings from high confidence to moderate, low, or very-low confidence, mainly due to concerns about how the studies were conducted (methodological limitations) or concerns about missing important perspectives from some types of participants or in some settings (relevance). In many communities, bleeding during and after childbirth is considered "normal" and necessary to expel "impurities" and restore and cleanse the woman's body after pregnancy and birth (moderate confidence). In some communities, people have misconceptions about causes of PPH or believe that PPH is caused by supernatural powers or evil spirits that punish women for ignoring or disobeying social rules or for past mistakes (high confidence). For women who give birth at home or in the community, female family members or traditional birth attendants are the first to recognise excess bleeding after birth (high confidence). Family members typically take the decision of whether and when to seek care if PPH is suspected, and these family members are often influenced by trusted traditional birth attendants or community midwives (high confidence). If PPH is identified for women birthing at home or in the community, decision-making about the subsequent referral and care pathway can be multifaceted and complex (high confidence). First responders to PPH are not always skilled or trained healthcare providers (high confidence). In health facilities, midwives may consider it easy to implement visual estimation of blood loss with a kidney dish or under-pad, but difficult to accurately interpret the amount of blood loss (very low confidence). Quantifying (rather than estimating) blood loss may be a complex and contentious change of practice for health workers (low confidence). Women who gave birth in health facilities and experienced PPH described it as painful, embarrassing, and traumatic. Partners or other family members also found the experience stressful. While some women were dissatisfied with their level of involvement in decision-making for PPH management, others felt health workers were best placed to make decisions (moderate confidence). Inconsistent availability of resources (drugs, medical supplies, blood) causes delays in the timely management of PPH (high confidence). There is limited availability of misoprostol in the community owing to stockouts, poor supply systems, and the difficulty of navigating misoprostol procurement for community health workers (moderate confidence). Health workers described working on the maternity ward as stressful and intense due to short staffing, long shifts, and the unpredictability of emergencies. Exhausted and overwhelmed staff may be unable to appropriately monitor all women, particularly when multiple women are giving birth simultaneously or on the floor of the health facility; this could lead to delays in detecting PPH (moderate confidence). Inadequate staffing, high turnover of skilled health workers, and appointment of lower-level cadres of health workers are key challenges to the provision of quality PPH care (high confidence). Through team-based simulation training, health workers of different cadres (doctors, midwives, lay health workers) can develop a shared mental model to help them work quickly, efficiently, and amicably as a team when managing women with PPH (moderate confidence). AUTHORS' CONCLUSIONS: Our findings highlight how improving PPH prevention, detection, and management is underpinned by a complex system of interacting roles and behaviours (community, women, health workers of different types and with different experiences). Multiple individual, sociocultural, and environmental factors influence the decisions and behaviours of women, families, communities, health workers, and managers. It is crucial to consider the broader health and social systems when designing and implementing PPH interventions to change or influence these behaviours. We have developed a set of prompts that may help programme managers, policymakers, researchers, and other key stakeholders to identify and address factors that affect implementation and scale-up of interventions to improve PPH prevention, detection, and management.

Interventions to prevent miscarriage.

The physical and psychological impact of miscarriage can be devastating. There are many lifestyle and therapeutic interventions that may prevent a miscarriage. In this review, we have outlined the key areas for health optimization to prevent pregnancy loss, drawing on the most up-to-date evidence available. The 3 key areas identified are lifestyle optimization in women, lifestyle optimization in men, and therapeutic interventions. The evidence demonstrates that the treatments to consider are first-trimester progesterone administration, levothyroxine in women with subclinical hypothyroidism, and the combination of aspirin and heparin in women with antiphospholipid antibodies.

Genetic causes of sporadic and recurrent miscarriage.

Approximately 80% of miscarriages happen within the first 12 weeks of gestation. More than half of early losses result from genetic defects, usually presenting as abnormal chromosome numbers or gene rearrangements in the embryo. However, the impact of genetics on pregnancy loss goes well beyond embryonic aneuploidy. For example, the use of big data has recently led to the discovery of specific gene mutations that may be implicated in sporadic and recurrent miscarriages. Further, emerging data suggest that genetic factors play a role in conditions for which there is a causative association with recurrent pregnancy loss. Here, we summarize the evidence on the genetics of miscarriage and provide an overview of the diagnosis and prevention of genetic causes associated with sporadic and recurrent pregnancy loss.

Early recognition and management of maternal sepsis in Pakistan: a feasibility study of the implementation of FAST-M intervention.

OBJECTIVE: Maternal sepsis is the third leading cause of maternal mortality globally. WHO and collaborators developed a care bundle called FAST-M (Fluids, Antibiotics, Source identification and treatment, Transfer and Monitoring) for early identification and management of maternal sepsis in low-resource settings. This study aimed to determine feasibility of FAST-M intervention in a low-resource setting in Pakistan. The FAST-M intervention consists of maternal sepsis screening tools, treatment bundle and implementation programme. DESIGN AND SETTING: A feasibility study with before and after design was conducted in women with suspected maternal sepsis admitted at the Liaquat University of Medical and Health Sciences hospital Hyderabad. The study outcomes were compared between baseline and intervention phases. In the baseline phase (2 months), the existing sepsis care practices were recorded, followed by a training programme for healthcare providers on the application of FAST-M tools. These tools were implemented in the intervention phase (4 months) to assess any change in clinical practices compared with the baseline phase. RESULTS: During the FAST-M implementation, 439 women were included in the study. 242/439 were suspected maternal infection cases, and 138/242 were women with suspected maternal sepsis. The FAST-M bundle was implemented in women with suspected maternal sepsis. Following the FAST-M intervention, significant changes were observed. Improvements were seen in the monitoring of oxygen saturation measurements (25.5% vs 100%; difference: 74%; 95% CI: 68.4% to 80.5%; p<0.01), fetal heart rate assessment (58% vs 100%; difference: 42.0%; 95% CI: 33.7% to 50.3%; p≤0.01) and measurement of urine output (76.5% vs 100%; difference: 23.5%; 95% CI: 17.6% to 29.4%; p<0.01). Women with suspected maternal sepsis received all components of the treatment bundle within 1 hour of sepsis recognition (0% vs 70.5%; difference: 70.5%; 95% CI: 60.4% to 80.6%; p<0.01). CONCLUSION: Implementation of the FAST-M intervention was considered feasible and enhanced early identification and management of maternal sepsis at the study site. TRIAL REGISTRATION NUMBER: ISRCTN17105658.

Heparin for women with recurrent miscarriage and inherited thrombophilia (ALIFE2): an international open-label, randomised controlled trial.

BACKGROUND: Anticoagulant therapy might reduce the number of miscarriages and adverse pregnancy outcomes in women with recurrent pregnancy loss and inherited thrombophilia. We aimed to assess use of low-molecular-weight heparin (LMWH) versus standard care in this population. METHODS: The ALIFE2 trial was an international open-label, randomised controlled trial undertaken in hospitals in the UK (n=26), the Netherlands (n=10), the USA (n=2), Belgium (n=1), and Slovenia (n=1). Women aged 18-42 years who had two or more pregnancy losses and confirmed inherited thrombophilia, and who were trying to conceive or were already pregnant (≤7 weeks' gestation), were eligible for inclusion. Women were randomly assigned (1:1) to use low-dose LMWH or not (alongside standard care in both groups) once they had a positive urine pregnancy test. LMWH was started at or before 7 weeks' gestation and continued until the end of pregnancy. The primary outcome measure was livebirth rate, assessed in all women with available data. Safety outcomes included bleeding episodes, thrombocytopenia, and skin reactions, and were assessed in all randomly assigned women who reported a safety event. The trial was registered within the Dutch Trial Register (NTR3361) and EudraCT (UK: 2015-002357-35). FINDINGS: Between Aug 1, 2012, and Jan 30, 2021, 10 625 women were assessed for eligibility, 428 were registered, and 326 conceived and were randomly assigned (164 to LMWH and 162 to standard care). 116 (72%) of 162 women with primary outcome data in the LMWH group and 112 (71%) of 158 in the standard care group had livebirths (adjusted odds ratio 1·08, 95% CI 0·65 to 1·78; absolute risk difference, 0·7%, 95% CI -9·2% to 10·6%). 39 (24%) of 164 women in the LMWH group and 37 (23%) of 162 women in the standard care group reported adverse events. INTERPRETATION: LMWH did not result in higher livebirth rates in women who had two or more pregnancy losses and confirmed inherited thrombophilia. We do not advise use of LMWH in women with recurrent pregnancy loss and inherited thrombophilia, and we advise against screening for inherited thrombophilia in women with recurrent pregnancy loss. FUNDING: National Institute for Health and Care Research and the Netherlands Organization for Health Research and Development.

Association between a morphokinetic ploidy prediction model risk score and miscarriage and live birth: a multicentre cohort study.

OBJECTIVE: To determine whether the aneuploidy risk score from a morphokinetic ploidy prediction model, Predicting Euploidy for Embryos in Reproductive Medicine (PREFER), is associated with miscarriage and live birth outcomes. DESIGN: Multicentre cohort study. SETTING: Nine in vitro fertilization clinics in the United Kingdom. PATIENTS: Data were obtained from the treatment of patients from 2016-2019. A total of 3587 fresh single embryo transfers were included; preimplantation genetic testing for aneuploidy) cycles were excluded. INTERVENTION: PREFER is a model developed using 8,147 biopsied blastocyst specimens to predict ploidy status using morphokinetic and clinical biodata. A second model using only morphokinetic (MK) predictors was developed, P PREFER-MK. The models will categorize embryos into the following three risk score categories for aneuploidy: "high risk," "medium risk," and "low risk." MAIN OUTCOME MEASURES: The primary outcomes are miscarriage and live birth. Secondary outcomes include biochemical clinical pregnancy per single embryo transfer. RESULTS: When applying PREFER, the miscarriage rates were 12%, 14%, and 22% in the "low risk," "moderate risk," and "high risk" categories, respectively. Those embryos deemed "high risk" had a significantly higher egg provider age compared with "low risk," and there was little variation in risk categories in patients of the same age. The trend in miscarriage rate was not seen when using PREFER-MK; however, there was an association with live birth, increasing from 38%-49% and 50% in the "high risk," "moderate risk," and "low risk" groups, respectively. An adjusted logistic regression analysis demonstrated that PREFER-MK was not associated with miscarriage when comparing "high risk" to "moderate risk" embryos (odds ratio [OR], 0.87; 95% confidence interval [CI], 0.63-1.63) or "high risk" to "low risk" embryos (OR, 1.07; 95% CI, 0.79-1.46). An embryo deemed "low risk" by PREFER-MK was significantly more likely to result in a live birth than those embryos graded "high risk" (OR, 1.95; 95% CI, 1.65-2.25). CONCLUSION: The PREFER model's risk scores were significantly associated with live births and miscarriages. Importantly, this study also found that this model applied too much weight to clinical factors, such that it could no longer rank a patient's embryos effectively. Therefore, a model including only MKs would be preferred; this was similarly associated with live birth but not miscarriage.

A re-analysis of 150 women's health trials to investigate how the Bayesian approach may offer a solution to the misinterpretation of statistical findings.

OBJECTIVE: To investigate whether a Bayesian interpretation might help prevent misinterpretation of statistical findings and support authors to differentiate evidence of no effect from statistical uncertainty. DESIGN: A Bayesian re-analysis to determine posterior probabilities of clinically important effects (e.g., a large effect is set at a 4 percentage point difference and a trivial effect to be within a 0.5 percentage point difference). Posterior probabilities greater than 95% are considered as strong statistical evidence, and less than 95% as inconclusive. SAMPLE: 150 major women's health trials with binary outcomes. MAIN OUTCOME MEASURES: Posterior probabilities of large, moderate, small and trivial effects. RESULTS: Under frequentist methods, 48 (32%) were statistically significant (p-value ≤ 0.05) and 102 (68%) statistically non-significant. The frequentist and Bayesian point estimates and confidence intervals showed strong concordance. Of the statistically non-significant trials (n = 102), the Bayesian approach classified the majority (94, 92%) as inconclusive, neither able to confirm or refute effectiveness. A small number of statistically non-significant findings (8, 8%) were classified as having strong statistical evidence of an effect. CONCLUSIONS: Whilst almost all trials report confidence intervals, in practice most statistical findings are interpreted on the basis of statistical significance, mostly concluding evidence of no effect. Findings here suggest the majority are likely uncertain. A Bayesian approach could help differentiate evidence of no effect from statistical uncertainty.

Randomized Trial of Early Detection and Treatment of Postpartum Hemorrhage.

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.).

The association between dietary patterns and risk of miscarriage: a systematic review and meta-analysis.

IMPORTANCE: The evidence on the association between diet and miscarriage risk is scant and conflicting. OBJECTIVE: To summarize the evidence on the association between periconceptual diet and miscarriage risk in healthy women of reproductive age. DATA SOURCES: Electronic databases were searched from inception to August 2022 without restriction of regions, publication types, or languages. STUDY SELECTION AND SYNTHESIS: Experimental or observational studies were considered for inclusion. The population was healthy women of reproductive age. Exposure was periconception diet. Study quality was assessed using the modified Newcastle-Ottawa Scale. Summary effect sizes (odds ratio [OR] with 95% confidence interval [CI]) were calculated for each food category. MAIN OUTCOMES: Miscarriage rate (as defined by primary studies). RESULTS: We included 20 studies (11 cohort and 9 case-control), of which 6 presented data suitable for meta-analysis (2 cohort and 4 case-control, n = 13,183 women). Our primary analyses suggest a reduction in miscarriage odds with high intake of the following food groups: fruit (OR, 0.39; 95% CI, 0.33-0.46), vegetables (OR, 0.59; 95% CI, 0.46-0.76), fruit and vegetables (OR, 0.63; 95% CI, 0.50-0.81), seafood (OR, 0.81; 95% CI, 0.71-0.92), dairy products (OR, 0.63; 95% CI, 0.54-0.73), eggs (OR, 0.81; 95% CI, 0.72-0.90), and cereal (grains) (OR, 0.67; 95% CI, 0.52-0.87). The evidence was uncertain for meat, red meat, white meat, fat and oil, and sugar substitutes. We did not find evidence of an association between adherence to predefined dietary patterns and miscarriage risk. However, a whole diet containing healthy foods as perceived by the trialists, or with a high Dietary Antioxidant Index score (OR, 0.43; 95% CI, 0.20-0.91) may be associated with a reduction in miscarriage risk. In contrast, a diet rich in processed food was demonstrated to be associated with increased miscarriage risk (OR, 1.97; 95% CI, 1.36-3.34). CONCLUSION AND RELEVANCE: A diet abundant in fruit, vegetables, seafood, dairy, eggs, and grain may be associated with lower miscarriage odds. Further interventional studies are required to accurately assess the effectiveness of periconception dietary modifications on miscarriage risk. PROSPERO REGISTRATION: CRD42020218133.

Evaluation of the FAST-M maternal sepsis intervention in Pakistan: A qualitative exploratory study.

INTRODUCTION: The World Health Organization and partners developed and evaluated a maternity-specific sepsis care bundle called 'FAST-M' for low-resource settings. However, this bundle has not yet been studied in Asia. Our study sought to evaluate the perceptions of healthcare providers about the implementation of the FAST-M intervention in Pakistan. MATERIALS AND METHODS: The study was conducted at a public sector hospital in Hyderabad. We conducted three focus group discussions with healthcare providers including doctors, nurses, and healthcare administrators (n = 22) who implemented the FAST-M intervention. The Consolidated Framework for Implementation Research was used as a guiding framework for data collection and analysis. The data were analyzed using a thematic analysis approach and deductive methods. RESULTS: Five overarching themes emerged: (I) FAST-M intervention and its significance including HCPs believing in the advantages of using the intervention to improve clinical practices; (II) Influence of outer and inner settings including non-availability of resources in the facility for sepsis care; (III) HCPs perceptions about sustainability, which were positive (IV) Integration into the clinical setting including HCPs views on the existing gaps, for example, shortage of HCPs and communication gaps, and their recommendations to improve these; and (V) Outcomes of the intervention including improved clinical processes and outcomes using the FAST-M intervention. Significant improvement in patient monitoring and FAST-M bundle completion within an hour of diagnosis of sepsis was reported by the HCPs. CONCLUSIONS: The healthcare providers' views were positive about the intervention, its outcomes, and long-term sustainability. The qualitative data provided findings on the acceptability of the overall implementation processes to support subsequent scaling up of the intervention.

A core outcome set for trials in miscarriage management and prevention: An international consensus development study.

OBJECTIVE: To develop core outcome sets (COS) for miscarriage management and prevention. DESIGN: Modified Delphi survey combined with a consensus development meeting. SETTING: International. POPULATION: Stakeholder groups included healthcare providers, international experts, researchers, charities and couples with lived experience of miscarriage from 15 countries: 129 stakeholders for miscarriage management and 437 for miscarriage prevention. METHODS: Modified Delphi method and modified nominal group technique. RESULTS: The final COS for miscarriage management comprises six outcomes: efficacy of treatment, heavy vaginal bleeding, pelvic infection, maternal death, treatment or procedure-related complications, and patient satisfaction. The final COS for miscarriage prevention comprises 12 outcomes: pregnancy loss <24 weeks' gestation, live birth, gestation at birth, pre-term birth, congenital abnormalities, fetal growth restriction, maternal (antenatal) complications, compliance with intervention, patient satisfaction, maternal hospitalisation, neonatal or infant hospitalisation, and neonatal or infant death. Other outcomes identified as important were mental health-related outcomes, future fertility and health economic outcomes. CONCLUSIONS: This study has developed two core outcome sets, through robust methodology, that should be implemented across future randomised trials and systematic reviews in miscarriage management and prevention. This work will help to standardise outcome selection, collection and reporting, and improve the quality and safety of future studies in miscarriage.