Opportunities and challenges in assessing climate change vulnerability through genomics.

By investigating how past selection has affected allele frequencies across space, genomic tools are providing new insights into adaptive evolutionary processes. Now researchers are considering how this genomic information can be used to predict the future vulnerability of species under climate change. Genomic vulnerability assessments show promise, but challenges remain.

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.).

Conservation genetics as a management tool: The five best-supported paradigms to assist the management of threatened species.

About 50 y ago, Crow and Kimura [An Introduction to Population Genetics Theory (1970)] and Ohta and Kimura [Genet. Res. 22, 201-204 (1973)] laid the foundations of conservation genetics by predicting the relationship between population size and genetic marker diversity. This work sparked an enormous research effort investigating the importance of population dynamics, in particular small population size, for population mean performance, population viability, and evolutionary potential. In light of a recent perspective [J. C. Teixeira, C. D. Huber, Proc. Natl. Acad. Sci. U.S.A. 118, 10 (2021)] that challenges some fundamental assumptions in conservation genetics, it is timely to summarize what the field has achieved, what robust patterns have emerged, and worthwhile future research directions. We consider theory and methodological breakthroughs that have helped management, and we outline some fundamental and applied challenges for conservation genetics.

Oral misoprostol alone, compared with oral misoprostol followed by oxytocin, in women induced for hypertension of pregnancy: A multicentre randomised trial.

OBJECTIVE: To assess whether, in those requiring continuing uterine stimulation after cervical ripening with oral misoprostol and membrane rupture, augmentation with low-dose oral misoprostol is superior to intravenous oxytocin. DESIGN: Open-label, superiority randomised trial. SETTING: Government hospitals in India. POPULATION: Women who were induced for hypertensive disease in pregnancy and had undergone cervical ripening with oral misoprostol, but required continuing stimulation after artificial membrane rupture. METHODS: Participants received misoprostol (25 micrograms, orally, 2-hourly) or titrated oxytocin through an infusion pump. All women had one-to-one care; fetal monitoring was conducted using a mixture of intermittent and continuous electronic fetal monitoring. MAIN OUTCOME MEASURES: Caesarean birth. RESULTS: A total of 520 women were randomised and the baseline characteristics were comparable between the groups. The caesarean section rate was not reduced with the use of misoprostol (misoprostol, 84/260, 32.3%, vs oxytocin, 71/260, 27.3%; aOR 1.23; 95% CI 0.81-1.85; P = 0.33). The interval from randomisation to birth was somewhat longer with misoprostol (225 min, 207-244 min, vs 194 min, 179-210 min; aOR 1.137; 95% CI 1.023-1.264; P = 0.017). There were no cases of hyperstimulation in either arm. The rates of fetal heart rate abnormalities and maternal side effects were similar. Fewer babies in the misoprostol arm were admitted to the special care unit (10 vs 21 in the oxytocin group; aOR 0.463; 95% CI 0.203-1.058; P = 0.068) and there were no neonatal deaths in the misoprostol group, compared with three neonatal deaths in the oxytocin arm. Women's acceptability ratings were high in both study groups. CONCLUSIONS: Following cervical preparation with oral misoprostol and membrane rupture, the use of continuing oral misoprostol for augmentation did not significantly reduce caesarean rates, compared with the use of oxytocin. There were no hyperstimulation or significant adverse events in either arm of the trial.

Heterogeneous patterns of heterozygosity loss in isolated populations of the threatened eastern barred bandicoot (Perameles gunnii).

Identifying and analysing isolated populations is critical for conservation. Isolation can make populations vulnerable to local extinction due to increased genetic drift and inbreeding, both of which should leave imprints of decreased genome-wide heterozygosity. While decreases in heterozygosity among populations are frequently investigated, fewer studies have analysed how heterozygosity varies among individuals, including whether heterozygosity varies geographically along lines of discrete population structure or with continuous patterns analogous to isolation by distance. Here we explore geographical patterns of differentiation and individual heterozygosity in the threatened eastern barred bandicoot (Perameles gunnii) in Tasmania, Australia, using genomic data from 85 samples collected between 2008 and 2011. Our analyses identified two isolated demes undergoing significant genetic drift, and several areas of fine-scale differentiation across Tasmania. We observed discrete genetic structures across geographical barriers and continuous patterns of isolation by distance, with little evidence of recent or historical migration. Using a recently developed analytical pipeline for estimating autosomal heterozygosity, we found individual heterozygosities varied within demes by up to a factor of two, and demes with low-heterozygosity individuals also still contained those with high heterozygosity. Spatial interpolation of heterozygosity scores clarified these patterns and identified the isolated Tasman Peninsula as a location where low-heterozygosity individuals were more common than elsewhere. Our results provide novel insights into the relationship between isolation-driven genetic structure and local heterozygosity patterns. These may help improve translocation efforts, by identifying populations in need of assistance, and by providing an individualised metric for identifying source animals for translocation.

Introducing the participant-generated experience and satisfaction (PaGES) index: a novel, longitudinal mixed-methods evaluation tool.

BACKGROUND: Patient-Reported Outcomes or Experience Measures (PROMS / PREMS) are routinely used in clinical studies to assess participants' views and experiences of trial interventions and related quality of life. Purely quantitative approaches lack the necessary detail and flexibility to understand the real-world impact of study interventions on participants, according to their own priorities. Conversely, purely qualitative assessments are time consuming and usually restricted to a small, possibly unrepresentative, sub-sample. This paper, which reports a pilot study within a randomised controlled trial of induction of labour, reports the feasibility, and acceptability of the Participant-Generated Experience and Satisfaction (PaGES) Index, a new mixed qualitative / quantitative PREM tool. METHODS: The single-sheet PaGES Index was completed by hypertensive pregnant women in two hospitals in Nagpur, India before and after taking part in the 'Misoprostol or Oxytocin for Labour Induction' (MOLI) randomised controlled trial. Participants recorded aspects of the impending birth they considered most important, and then ranked them. After the birth, participants completed the PaGES Index again, this time also scoring their satisfaction with each item. Forms were completed on paper in the local language or in English, supported by Research Assistants. Following translation (when needed), responses were uploaded to a REDCap database, coded in Excel and analysed thematically. A formal qualitative evaluation (qMOLI) was also conducted to obtain stakeholder perspectives of the PaGES Index and the wider trial. Semi-structured interviews were conducted with participants, and focus groups with researchers and clinicians. Data were managed using NVivo 12 software and analysed using the framework approach. RESULTS: Participants and researchers found the PaGES Index easy to complete and administer; mothers valued the opportunity to speak about their experience. Qualitative analysis of the initial 68 PaGES Index responses identified areas of commonality and difference among participants and also when comparing antenatal and postnatal responses. Theme citations and associated comments scores were fairly stable before and after the birth. The qMOLI phase, comprising 53 one-to-one interviews with participants and eight focus groups involving 83 researchers and clinicians, provided support that the PaGES Index was an acceptable and even helpful means of capturing participant perspectives. CONCLUSIONS: Subjective participant experiences are an important aspect of clinical trials. The PaGES Index was found to be a feasible and acceptable measure that unites qualitative research's explanatory power with the comparative power of quantitative designs. It also offers the opportunity to conduct a before-and-after evaluation, allowing researchers to examine the expectations and actual experiences of all clinical trial participants, not just a small sub-sample. This study also shows that, with appropriate research assistant input, the PaGES Index can be used in different languages by participants with varying literacy levels. TRIAL REGISTRATION: Clinical Trials.gov (21/11/2018) (NCT03749902).

Maternal and umbilical cord blood lactate for predicting perinatal death: a secondary analysis of data from a randomized controlled trial.

BACKGROUND: In high resource settings, lactate and pH levels measured from fetal scalp and umbilical cord blood are widely used as predictors of perinatal mortality. However, the same is not true in low resource settings, where much of perinatal mortality occurs. The scalability of this practice has been hindered by difficulty in collecting fetal scalp and umbilical blood sample. Little is known about the use of alternatives such as maternal blood, which is easier and safer to obtain. Therefore, we aimed to compare maternal and umbilical cord blood lactate levels for predicting perinatal deaths. METHODS: This was secondary analysis of data from a randomized controlled trial assessing the effect of sodium bicarbonate on maternal and perinatal outcomes among women with obstructed labour at Mbale regional referral hospital in Eastern Uganda. Lactate concentration in maternal capillary, myometrial, umbilical venous and arterial blood was measured at the bedside using a lactate Pro 2 device (Akray, Japan Shiga) upon diagnosis of obstructed labour. We constructed Receiver Operating Characteristic curves to compare the predictive ability of maternal and umbilical cord lactate and the optimal cutoffs calculated basing on the maximal Youden and Liu indices. RESULTS: Perinatal mortality risk was: 102.2 deaths per 1,000 live births: 95% CI (78.1-130.6). The areas under the ROC curves were 0.86 for umbilical arterial lactate, 0.71 for umbilical venous lactate, and 0.65 for myometrial lactate, 0.59 for maternal lactate baseline, and 0.65 at1hr after administration of bicarbonate. The optimal cutoffs for predicting perinatal death were 15 0.85 mmol/L for umbilical arterial lactate, 10.15mmol/L for umbilical venous lactate, 8.75mmol/L for myometrial lactate, and 3.95mmol/L for maternal lactate at recruitment and 7.35mmol/L after 1 h. CONCLUSION: Maternal lactate was a poor predictor of perinatal death, but umbilical artery lactate has a high predictive value. There is need for future studies on the utility of amniotic fluid in predicting intrapartum perinatal deaths.

Disparities in Timing of Alveolar Bone Grafting and Dental Reconstruction in Patients With Clefts.

This study sought to identify disparities in the timing of alveolar bone grafting (ABG) surgery and the replacement strategy for missing maxillary lateral incisors for patients with clefts.A retrospective record review identified patients who underwent ABG. Multivariable regression analyzed the independent contribution of each variable.This institutional study was performed at the University of California, San Francisco.Patients who presented under age 12 and underwent secondary ABG between 2012 and 2020 (n = 160).The age at secondary ABG and the recommended dental replacement treatment for each patient, either dental implantation or canine substitution.The average age at ABG was 10.8 ± 2.1 years, 106 (66.3%) patients were not White, and 80 (50.0%) had private insurance. Independent predictors of older age at ABG included an income below $ 50 000 as estimated from ZIP code (ß = 15.0 months, 95% CI, 5.7-24.3, P = .002) and identifying as a race other than White (ß = 10.1 months, 95% CI, 2.1-18.0, P = .01). After ABG, patients were more likely to undergo dental implantation over canine substitution if they were female (odds ratio [OR] = 4.3, 95% CI, 1.3-17.1, P = .02) or had private insurance (OR = 12.5, 95% CI, 2.2-143.2, P = .01).Patients who were low-income or not White experienced delays in ABG, whereas dental implantation was more likely to be recommended for patients with private insurance. Understanding the sources of disparities in dental reconstruction of cleft deformities may reveal opportunities to improve equity.

A Randomized Trial of Prophylactic Antibiotics for Miscarriage Surgery.

BACKGROUND: Surgical intervention is needed in some cases of spontaneous abortion to remove retained products of conception. Antibiotic prophylaxis may reduce the risk of pelvic infection, which is an important complication of this surgery, particularly in low-resource countries. METHODS: We conducted a double-blind, placebo-controlled, randomized trial investigating whether antibiotic prophylaxis before surgery to complete a spontaneous abortion would reduce pelvic infection among women and adolescents in low-resource countries. We randomly assigned patients to a single preoperative dose of 400 mg of oral doxycycline and 400 mg of oral metronidazole or identical placebos. The primary outcome was pelvic infection within 14 days after surgery. Pelvic infection was defined by the presence of two or more of four clinical features (purulent vaginal discharge, pyrexia, uterine tenderness, and leukocytosis) or by the presence of one of these features and the clinically identified need to administer antibiotics. The definition of pelvic infection was changed before the unblinding of the data; the original strict definition was two or more of the clinical features, without reference to the administration of antibiotics. RESULTS: We enrolled 3412 patients in Malawi, Pakistan, Tanzania, and Uganda. A total of 1705 patients were assigned to receive antibiotics and 1707 to receive placebo. The risk of pelvic infection was 4.1% (68 of 1676 pregnancies) in the antibiotics group and 5.3% (90 of 1684 pregnancies) in the placebo group (risk ratio, 0.77; 95% confidence interval [CI], 0.56 to 1.04; P = 0.09). Pelvic infection according to original strict criteria was diagnosed in 1.5% (26 of 1700 pregnancies) and 2.6% (44 of 1704 pregnancies), respectively (risk ratio, 0.60; 95% CI, 0.37 to 0.96). There were no significant between-group differences in adverse events. CONCLUSIONS: Antibiotic prophylaxis before miscarriage surgery did not result in a significantly lower risk of pelvic infection, as defined by pragmatic broad criteria, than placebo. (Funded by the Medical Research Council and others; AIMS Current Controlled Trials number, ISRCTN97143849.).

Understanding and managing the interactive impacts of growth in urban land use and climate change on freshwater biota: A case study using the platypus (Ornithorhynchus anatinus).

Globally, urban expansion and climate change interact to threaten stream ecosystems and are accelerating the loss of aquatic biodiversity. Waterway managers urgently need tools to understand the potential combined impacts of urbanization and climate change and to identify effective mitigating management interventions for protecting freshwater biota. We address this challenge using the semi-aquatic mammal the platypus (Ornithorhynchus anatinus) as a focal species. We developed high-resolution environmental spatial data for stream networks and spatially explicit habitat suitability models (HSMs) to explore the impact of threats and to identify the combination of management actions most likely to maintain or improve habitat suitability over the next 50 years in greater Melbourne, Australia. We developed and evaluated platypus HSMs (males-and-females and females-only) including validation using an independent environmental DNA data set. Platypus occurred more commonly in larger, cooler streams with greater catchment-weighted discharge, following periods of greater stream flow. They were positively associated with near-stream forest cover and negatively associated with annual air temperature and urban stormwater runoff. Extensive reductions in suitable platypus habitat are predicted to occur under urbanization and climate change scenarios, with the greatest threat expected from reduced streamflows. This emphasizes the importance of maintaining flow regimes as part of conserving platypus in the region; however, substantial additional benefit is predicted by concurrent riparian revegetation and urban stormwater management efforts (that also have the potential to contribute to the streamflow objectives). Provision of adequate streamflows in a future with increasing water demands and water security requirements will likely require creative integrated water management solutions. Our high-resolution stream network and HSMs have allowed predictions of potential range-shifts due to urban expansion and climate change impacts at management-relevant scales and at the whole-of-landscape scale. This has enabled systematic strategic planning, priority action planning and target setting in strategic policy development.

Evaluating misoprostol and mechanical methods for induction of labour: Scientific Impact Paper No. 68 April 2022.

Increasingly, births around the world are started artificially using medications or other methods. This process is known as induction of labour. As it becomes more common, methods are needed to meet the different clinical needs and birth preferences of women. Induction of labour typically includes a combination of the medication dinoprostone inserted into the vagina, artificial rupture of membranes ('releasing the waters'), and synthetic oxytocin (hormone given via a drip). This paper reviews some of the methods less commonly used for induction in the UK, namely a drug called misoprostol, which can be given orally or vaginally, and 'mechanical' methods, where labour is started by stretching the cervix (neck of the womb), most commonly with a soft silicone tube with a balloon near the tip, filled with water. Low-dose oral misoprostol tablets are now commercially available in the UK. Other methods for labour induction are not reviewed in detail in this paper. The evidence suggests mechanical induction of labour (using a balloon catheter) and misoprostol are both at least as safe and effective as using the standard drug, dinoprostone. There is evidence to suggest a balloon catheter may reduce the chance of serious negative outcomes for babies when compared with dinoprostone, and that giving low-dose oral misoprostol results in fewer caesarean births. Where possible and after informed consent, the method of induction of labour should be personalised to suit the individual woman, her clinical condition, and the setting in which she is giving birth. Local contexts and resources also need to be taken into account. To date, research into women's perspectives and experiences of induction of labour have been significantly lacking.

A molecular method for biomonitoring of an exotic plant-pest: Leafmining for environmental DNA.

Understanding how invasive species respond to novel environments is limited by a lack of sensitivity and throughput in conventional biomonitoring methods. Arthropods in particular are often difficult to monitor due to their small size, rapid lifecycles, and/or visual similarities with co-occurring species. This is true for the agromyzid leafminer fly, Liriomyza sativae, a global pest of vegetable and nursery industries that has recently established in Australia. A robust method based on environmental DNA (eDNA) was developed exploiting traces of DNA left inside "empty" leaf mines, which are straightforward to collect and persist longer in the environment than the fly. This extends the window of possible diagnosis to at least 28 days after a leaf mine becomes empty. The test allowed for visually indistinguishable leafmining damage caused by L. sativae to be genetically differentiated from that of other flies. Field application resulted in the identification of new local plant hosts for L. sativae, including widely distributed weeds and common garden crops, which has important implications for the pest's ability to spread. Moreover, the test confirmed the presence of a previously unknown population of L. sativae on an island in the Torres Strait. The developed eDNA method is likely to become an important tool for L. sativae and other leafmining species of biosecurity significance, which, historically, have been difficult to detect, diagnose and monitor. More generally, eDNA is emerging as a highly sensitive and labour-efficient surveillance tool for difficult to survey species to improve outcomes for agricultural industries, global health, and the environment.

Multispecies models reveal that eDNA metabarcoding is more sensitive than backpack electrofishing for conducting fish surveys in freshwater streams.

Environmental DNA (eDNA) sampling can provide accurate, cost-effective, landscape-level data on species distributions. Previous studies have compared the sensitivity of eDNA sampling to traditional sampling methods for single species, but similar comparative studies on multispecies eDNA metabarcoding are rare. Using hierarchical site occupancy detection models, we examined whether key choices associated with eDNA metabarcoding (primer selection, low-abundance read filtering and the number of positive water samples used to classify a species as present at a site) affect the sensitivity of metabarcoding, relative to backpack electrofishing for fish in freshwater streams. Under all scenarios (teleostei and vertebrate primers; 0%, 0.1% and 1% read filtering thresholds; one or two positive samples required to classify species as present), we found that eDNA metabarcoding is, on average, more sensitive than electrofishing. Combining vertebrate and teleostei markers resulted in higher detection probabilities relative to the use of either marker in isolation. Increasing the threshold used to filter low-abundance reads decreased species detection probabilities but did not change our overall finding that eDNA metabarcoding was more sensitive than electrofishing. Using a threshold of two positive water samples (out of five) to classify a species as present typically had negligible effects on detection probabilities compared to using one positive water sample. Our findings demonstrate that eDNA metabarcoding is generally more sensitive than electrofishing for conducting fish surveys in freshwater streams, and that this outcome is not sensitive to methodological decisions associated with metabarcoding.

Umbilical vein injection for management of retained placenta.

BACKGROUND: Retained placenta is a common complication of pregnancy affecting 1% to 6% of all births. If a retained placenta is left untreated, spontaneous delivery of the placenta may occur, but there is a high risk of bleeding and infection. Manual removal of the placenta (MROP) in an operating theatre under anaesthetic is the usual treatment, but is invasive and may have complications. An effective non-surgical alternative for retained placenta would potentially reduce the physical and psychological trauma of the procedure, and costs. It could also be lifesaving by providing a therapy for settings without easy access to modern operating theatres or anaesthetics. Injection of uterotonics into the uterus via the umbilical vein and placenta is an attractive low-cost option for this. This is an update of a review last published in 2011. OBJECTIVES: To assess the use of umbilical vein injection (UVI) of saline solution with or without uterotonics compared to either expectant management or with an alternative solution or other uterotonic agent for retained placenta. SEARCH METHODS: For this update, we searched Cochrane Pregnancy and Childbirth's Trials Register, ClinicalTrials.gov, the WHO International Clinical Trials Registry Platform (14 June 2020), and reference lists of retrieved studies. SELECTION CRITERIA: Randomised controlled trials (RCTs) comparing UVI of saline or other fluids (with or without uterotonics), either with expectant management or with an alternative solution or other uterotonic agent, in the management of retained placenta. We considered quasi-randomised, cluster-randomised, and trials reported only in abstract form. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed trials for inclusion and risk of bias, extracted data, and checked them for accuracy. We assessed the certainty of the evidence using the GRADE approach. We calculated pooled risk ratios (RRs) and mean differences (MDs) with 95% confidence intervals (CIs), and presented results using 'Summary of findings' tables. MAIN RESULTS: We included 24 trials (n = 2348). All included trials were RCTs, one was quasi-randomised, and none were cluster-randomised. Risk of bias was variable across the included studies. We assessed certainty of evidence for four comparisons: saline versus expectant management, oxytocin versus expectant management, oxytocin versus saline, and oxytocin versus plasma expander. Evidence was moderate to very-low certainty and downgraded for risk of bias of included studies, imprecision, and inconsistency of effect estimates. Saline solution versus expectant management There is probably little or no difference in the incidence of MROP between saline and expectant management (RR 0.93, 95% CI 0.80 to 1.10; 5 studies, n = 445; moderate-certainty evidence). Evidence for the following remaining primary outcomes was very-low certainty: severe postpartum haemorrhage 1000 mL or greater, blood transfusion, and infection. There were no events reported for maternal mortality or postpartum anaemia (24 to 48 hours postnatal). No studies reported addition of therapeutic uterotonics. Oxytocin solution versus expectant management UVI of oxytocin solution might slightly reduce in the need for manual removal compared with expectant management (mean RR 0.73, 95% CI 0.56 to 0.95; 7 studies, n = 546; low-certainty evidence). There may be little to no difference between the incidence of blood transfusion between groups (RR 0.81, 95% CI 0.47 to 1.38; 4 studies, n = 339; low-certainty evidence). There were no maternal deaths reported (2 studies, n = 93). Evidence for severe postpartum haemorrhage of 1000 mL or greater, additional uterotonics, and infection was very-low certainty. There were no events for postpartum anaemia (24 to 48 hours postnatal). Oxytocin solution versus saline solution UVI of oxytocin solution may reduce the use of MROP compared with saline solution, but there was high heterogeneity (RR 0.82, 95% CI 0.69 to 0.97; 14 studies, n = 1370; I² = 54%; low-certainty evidence). There were no differences between subgroups according to risk of bias or oxytocin dose for the outcome MROP. There may be little to no difference between groups in severe postpartum haemorrhage of 1000 mL or greater, blood transfusion, use of additional therapeutic uterotonics, and antibiotic use. There were no events for postpartum anaemia (24 to 48 hours postnatal) (very low-certainty evidence) and there was only one event for maternal mortality (low-certainty evidence). Oxytocin solution versus plasma expander One small study reported UVI of oxytocin compared with plasma expander (n = 109). The evidence was very unclear about any effect on MROP or blood transfusion between the two groups (very low-certainty evidence). No other primary outcomes were reported. For other comparisons there were little to no differences for most outcomes examined. However, there was some evidence to suggest that there may be a reduction in MROP with prostaglandins in comparison to oxytocin (4 studies, n = 173) and ergometrine (1 study, n = 52), although further large-scale studies are needed to confirm these findings. AUTHORS' CONCLUSIONS: UVI of oxytocin solution is an inexpensive and simple intervention that can be performed when placental delivery is delayed. This review identified low-certainty evidence that oxytocin solution may slightly reduce the need for manual removal. However, there are little or no differences for other outcomes. Small studies examining injection of prostaglandin (such as dissolved misoprostol) into the umbilical vein show promise and deserve to be studied further.

Low-dose oral misoprostol for induction of labour.

BACKGROUND: Misoprostol given orally is a commonly used labour induction method. Our Cochrane Review is restricted to studies with low-dose misoprostol (initially ≤ 50 µg), as higher doses pose unacceptably high risks of uterine hyperstimulation. OBJECTIVES: To assess the efficacy and safety of low-dose oral misoprostol for labour induction in women with a viable fetus in the third trimester of pregnancy. SEARCH METHODS: We searched Cochrane Pregnancy and Childbirth's Trials Register, ClinicalTrials.gov,  the WHO International Clinical Trials Registry Platform (14 February 2021) and reference lists of retrieved studies. SELECTION CRITERIA: Randomised trials comparing low-dose oral misoprostol (initial dose ≤ 50 µg) versus placebo, vaginal dinoprostone, vaginal misoprostol, oxytocin, or mechanical methods; or comparing oral misoprostol protocols (one- to two-hourly versus four- to six-hourly; 20 µg to 25 µg versus 50 µg; or 20 µg hourly titrated versus 25 µg two-hourly static). DATA COLLECTION AND ANALYSIS: Using Covidence, two review authors independently screened reports, extracted trial data, and performed quality assessments. Our primary outcomes were vaginal birth within 24 hours, caesarean section, and hyperstimulation with foetal heart changes. MAIN RESULTS: We included 61 trials involving 20,026 women. GRADE assessments ranged from moderate- to very low-certainty evidence, with downgrading decisions based on imprecision, inconsistency, and study limitations. Oral misoprostol versus placebo/no treatment (four trials; 594 women) Oral misoprostol may make little to no difference in the rate of caesarean section (risk ratio (RR) 0.81, 95% confidence interval (CI) 0.59 to 1.11; 4 trials; 594 women; moderate-certainty evidence), while its effect on uterine hyperstimulation with foetal heart rate changes is uncertain (RR 5.15, 95% CI 0.25 to 105.31; 3 trials; 495 women; very low-certainty evidence). Vaginal births within 24 hours was not reported. In all trials, oxytocin could be commenced after 12 to 24 hours and all women had pre-labour ruptured membranes. Oral misoprostol versus vaginal dinoprostone (13 trials; 9676 women) Oral misoprostol probably results in fewer caesarean sections (RR 0.84, 95% CI 0.78 to 0.90; 13 trials, 9676 women; moderate-certainty evidence). Subgroup analysis indicated that 10 µg to 25 µg (RR 0.80, 95% CI 0.74 to 0.87; 9 trials; 8652 women) may differ from 50 µg (RR 1.10, 95% CI 0.91 to 1.34; 4 trials; 1024 women) for caesarean section. Oral misoprostol may decrease vaginal births within 24 hours (RR 0.93, 95% CI 0.87 to 1.00; 10 trials; 8983 women; low-certainty evidence) and hyperstimulation with foetal heart rate changes (RR 0.49, 95% CI 0.40 to 0.59; 11 trials; 9084 women; low-certainty evidence). Oral misoprostol versus vaginal misoprostol (33 trials; 6110 women) Oral use may result in fewer vaginal births within 24 hours (average RR 0.81, 95% CI 0.68 to 0.95; 16 trials, 3451 women; low-certainty evidence), and less hyperstimulation with foetal heart rate changes (RR 0.69, 95% CI 0.53 to 0.92, 25 trials, 4857 women, low-certainty evidence), with subgroup analysis suggesting that 10 µg to 25 µg orally (RR 0.28, 95% CI 0.14 to 0.57; 6 trials, 957 women) may be superior to 50 µg orally (RR 0.82, 95% CI 0.61 to 1.11; 19 trials; 3900 women). Oral misoprostol probably does not increase caesarean sections overall (average RR 1.00, 95% CI 0.86 to 1.16; 32 trials; 5914 women; low-certainty evidence) but likely results in fewer caesareans for foetal distress (RR 0.74, 95% CI 0.55 to 0.99; 24 trials, 4775 women). Oral misoprostol versus intravenous oxytocin (6 trials; 737 women, 200 with ruptured membranes) Misoprostol may make little or no difference to vaginal births within 24 hours (RR 1.12, 95% CI 0.95 to 1.33; 3 trials; 466 women; low-certainty evidence), but probably results in fewer caesarean sections (RR 0.67, 95% CI 0.50 to 0.90; 6 trials; 737 women; moderate-certainty evidence). The effect on hyperstimulation with foetal heart rate changes is uncertain (RR 0.66, 95% CI 0.19 to 2.26; 3 trials, 331 women; very low-certainty evidence). Oral misoprostol versus mechanical methods (6 trials; 2993 women) Six trials compared oral misoprostol to transcervical Foley catheter. Misoprostol may increase vaginal birth within 24 hours (RR 1.32, 95% CI 0.98 to 1.79; 4 trials; 1044 women; low-certainty evidence), and probably reduces the risk of caesarean section (RR 0.84, 95% CI 0.75 to 0.95; 6 trials; 2993 women; moderate-certainty evidence). There may be little or no difference in hyperstimulation with foetal heart rate changes (RR 1.31, 95% CI 0.78 to 2.21; 4 trials; 2828 women; low-certainty evidence). Oral misoprostol one- to two-hourly versus four- to six-hourly (1 trial; 64 women) The evidence on hourly titration was very uncertain due to the low numbers reported. Oral misoprostol 20 µg hourly titrated versus 25 µg two-hourly static (2 trials; 296 women) The difference in regimen may have little or no effect on the rate of vaginal births in 24 hours (RR 0.97, 95% CI 0.80 to 1.16; low-certainty evidence). The evidence is of very low certainty for all other reported outcomes. AUTHORS' CONCLUSIONS: Low-dose oral misoprostol is probably associated with fewer caesarean sections (and therefore more vaginal births) than vaginal dinoprostone, and lower rates of hyperstimulation with foetal heart rate changes. However, time to birth may be increased, as seen by a reduced number of vaginal births within 24 hours. Compared to transcervical Foley catheter, low-dose oral misoprostol is associated with fewer caesarean sections, but equivalent rates of hyperstimulation. Low-dose misoprostol given orally rather than vaginally is probably associated with similar rates of vaginal birth, although rates may be lower within the first 24 hours. However, there is likely less hyperstimulation with foetal heart changes, and fewer caesarean sections performed due to foetal distress. The best available evidence suggests that low-dose oral misoprostol probably has many benefits over other methods for labour induction. This review supports the use of low-dose oral misoprostol for induction of labour, and demonstrates the lower risks of hyperstimulation than when misoprostol is given vaginally. More trials are needed to establish the optimum oral misoprostol regimen, but these findings suggest that a starting dose of 25 µg may offer a good balance of efficacy and safety.

Do stress and anxiety in early pregnancy affect the progress of labor: Evidence from the Wirral Child Health and Development Study.

INTRODUCTION: Despite widespread belief that anxiety causes longer labor, evidence of association is inconsistent. Data gathered as part of a prospective epidemiological longitudinal study were used to investigate associations between antenatal anxiety and pregnancy-specific stress, and labor progression was assessed by duration and use of augmentation. MATERIAL AND METHODS: Pregnant primiparous women completed measures for anxiety and pregnancy-specific stress at 20 weeks' gestation (n = 1145). Birth outcome data were extracted from medical records. Regression analyses and a path analysis assessed associations between antenatal anxiety and pregnancy-specific stress, and indices of labor progression (labor duration and augmentation). RESULTS: Anxiety/pregnancy-specific stress were not directly associated with duration of stage 1 labor (HIGH/LOW anxiety: mean difference = 13.94 minutes, SD = 20.66, 95% CI -26.60 to 54.49, P < .50)/(HIGH/LOW pregnancy-specific stress: mean difference = 12.05 minutes, SD = 16.09, 95% CI -19.52 to 43.63, P < .45). However, anxiety/pregnancy-specific stress were associated with epidural use (HIGH/LOW anxiety: 39% vs 31%, P < .042; HIGH/LOW pregnancy-specific stress: 38% vs 29%, P < .001), which was itself associated with longer labor (mean difference: 158.79 minutes, SD = 16.76, 95% CI 125.89-191.68, P < .001). Anxiety and pregnancy-specific stress were associated with increased likelihood of augmentation but these associations were nonsignificant after accounting for epidural, which was itself highly associated with augmentation. However, path analysis indicated an indirect effect linking pregnancy-specific stress, but not general anxiety, to labor duration and augmentation: elevated pregnancy-specific stress led to greater use of epidural, which was linked to both increased rates of augmentation, and increased labor duration. CONCLUSIONS: Contrary to general belief, general anxiety and specific pregnancy stress were not directly linked to longer duration of stage one labor. However specific pregnancy stress was associated with epidural use, which in turn was significantly associated with risk of augmentation, and longer stage one labor. Identification of pregnancy-specific stress could help to identify women for whom psychological interventions could improve birth experience.

Oral Misoprostol alone versus oral misoprostol followed by oxytocin for labour induction in women with hypertension in pregnancy (MOLI): protocol for a randomised controlled trial.

BACKGROUND: Every year approximately 30,000 women die from hypertensive disease in pregnancy. Magnesium sulphate and anti-hypertensives reduce morbidity, but delivery is the only cure. Low dose oral misoprostol, a prostaglandin E1 analogue, is a highly effective method for labour induction. Usually, once active labour has commenced, the misoprostol is replaced with an intravenous oxytocin infusion if ongoing stimulation is required. However, some studies have shown that oral misoprostol can be continued into active labour, a simpler and potentially more acceptable protocol for women. To date, these two protocols have never been directly compared. METHODS: This pragmatic, open-label, randomised trial will compare a misoprostol alone labour induction protocol with the standard misoprostol plus oxytocin protocol in three Indian hospitals. The study will recruit 520 pregnant women being induced for hypertensive disease in pregnancy and requiring augmentation after membrane rupture. Participants will be randomised to receive either further oral misoprostol 25mcg every 2 h, or titrated intravenous oxytocin. The primary outcome will be caesarean birth. Secondary outcomes will assess the efficacy of the induction process, maternal and fetal/neonatal complications and patient acceptability. This protocol (version 1.04) adheres to the SPIRIT checklist. A cost-effectiveness analysis, situational analysis and formal qualitative assessment of women's experience are also planned. DISCUSSION: Avoiding oxytocin and continuing low dose misoprostol into active labour may have a number of benefits for both women and the health care system. Misoprostol is heat stable, oral medication and thus easy to store, transport and administer; qualities particularly desirable in low resource settings. An oral medication protocol requires less equipment (e.g. electronic infusion pumps) and may free up health care providers to assist with other aspects of the woman's care. The simplicity of the protocol may also help to reduce human errors associated with the delivery of intravenous infusions. Finally, women may prefer to be mobile during labour and not restricted by an intravenous infusion. There is a need, therefore, to assess whether augmentation using oral misoprostol is superior clinically and economically to the standard protocol of intravenous oxytocin. TRIAL REGISTRATION: Clinical Trials.gov, NCT03749902 , registered on 21st Nov 2018.

Training and expertise in undertaking assisted vaginal delivery (AVD): a mixed methods systematic review of practitioners views and experiences.

BACKGROUND: During childbirth, complications may arise which necessitate an expedited delivery of the fetus. One option is instrumental assistance (forceps or a vacuum-cup), which, if used with skill and sensitivity, can improve maternal/neonatal outcomes. This review aimed to understand the core competencies and expertise required for skilled use in AVD in conjunction with reviewing potential barriers and facilitators to gaining competency and expertise, from the point of view of maternity care practitioners, funders and policy makers. METHODS: A mixed methods systematic review was undertaken in five databases. Inclusion criteria were primary studies reporting views, opinions, perspectives and experiences of the target group in relation to the expertise, training, behaviours and competencies required for optimal AVD, barriers and facilitators to achieving practitioner competencies, and to the implementation of appropriate training. Quality appraisal was carried out on included studies. A mixed-methods convergent synthesis was carried out, and the findings were subjected to GRADE-CERQual assessment of confidence. RESULTS: 31 papers, reporting on 27 studies and published 1985-2020 were included. Studies included qualitative designs (3), mixed methods (3), and quantitative surveys (21). The majority (23) were from high-income countries, two from upper-middle income countries, one from a lower-income country: one survey included 111 low-middle countries. Confidence in the 10 statements of findings was mostly low, with one exception (moderate confidence). The review found that AVD competency comprises of inter-related skill sets including non-technical skills (e.g. behaviours), general clinical skills; and specific technical skills associated with particular instrument use. We found that practitioners needed and welcomed additional specific training, where a combination of teaching methods were used, to gain skills and confidence in this field. Clinical mentorship, and observing others confidently using the full range of instruments, was also required, and valued, to develop competency and expertise in AVD. However, concerns regarding poor outcomes and litigation were also raised. CONCLUSION: Access to specific AVD training, using a combination of teaching methods. Complements, but does not replace, close clinical mentorship from experts who are positive about AVD, and opportunities to practice emerging AVD skills with supportive supervision. Further research is required to ascertain effective modalities for wider training, education, and supportive supervision for optimal AVD use.

During the late stages of childbirth, complications can occur which require rapid birth of the baby. This can be facilitated with instruments (usually forceps or a suction cup) or by surgery (caesarean section). In some circumstances, instrumental birth (also termed assisted vaginal delivery, AVD) may be a better option than caesarean section. AVD requires practitioners to develop skills, competence and expertise in the procedure. Our aim for this review was to examine practitioners', funders' and policy makers' views about competence and expertise in AVD, how they can best gain this, the barriers and facilitators to implementing training packages, and their views, opinions and perspectives of their training. We included 27 studies (published 1985­2020), mostly from high-income countries. We had moderate confidence on one findings statement, with the rest assessed with low confidence. We found that practitioners valued extra training in AVD, observing others using the different instruments, and opportunities for clinical supervision, mentorship to gain experience, competence and expertise. We also found that, from the practitioners' perspective, competence encompasses a number of inter-related skill sets; non-technical skills (e.g. effective communication with the labouring woman), broad clinical skills (e.g. capacity to assess the whole clinical picture) and technical instrumental skills (e.g. correct application of a vacuum cup to the fetal head, or capacity to turn the baby so it is in the right position). Practitioners also identified a number of barriers and facilitators that supported (or did not support) their training needs and development.

Heterogeneous genetic invasions of three insecticide resistance mutations in Indo-Pacific populations of Aedes aegypti (L.).

Nations throughout the Indo-Pacific region use pyrethroid insecticides to control Aedes aegypti, the mosquito vector of dengue, often without knowledge of pyrethroid resistance status of the pest or origin of resistance. Two mutations (V1016G + F1534C) in the sodium channel gene (Vssc) of Ae. aegypti modify ion channel function and cause target-site resistance to pyrethroid insecticides, with a third mutation (S989P) having a potential additive effect. Of 27 possible genotypes involving these mutations, some allelic combinations are never seen whereas others predominate. Here, five allelic combinations common in Ae. aegypti from the Indo-Pacific region are described and their geographical distributions investigated using genome-wide SNP markers. We tested the hypothesis that resistance allele combinations evolved de novo in populations versus the alternative that dispersal of Ae. aegypti between populations facilitated genetic invasions of allele combinations. We used latent factor mixed-models to detect SNPs throughout the genome that showed structuring in line with resistance allele combinations and compared variation at SNPs within the Vssc gene with genome-wide variation. Mixed-models detected an array of SNPs linked to resistance allele combinations, all located within or in close proximity to the Vssc gene. Variation at SNPs within the Vssc gene was structured by resistance profile, whereas genome-wide SNPs were structured by population. These results demonstrate that alleles near to resistance mutations have been transferred between populations via linked selection. This indicates that genetic invasions have contributed to the widespread occurrence of Vssc allele combinations in Ae. aegypti in the Indo-Pacific region, pointing to undocumented mosquito invasions between countries.

Mechanical and surgical interventions for treating primary postpartum haemorrhage.

BACKGROUND: Primary postpartum haemorrhage (PPH) is commonly defined as bleeding from the genital tract of 500 mL or more within 24 hours of birth. It is one of the most common causes of maternal mortality worldwide and causes significant physical and psychological morbidity. An earlier Cochrane Review considering any treatments for the management of primary PPH, has been split into separate reviews. This review considers treatment with mechanical and surgical interventions. OBJECTIVES: To determine the effectiveness and safety of mechanical and surgical interventions used for the treatment of primary PPH. SEARCH METHODS: We searched Cochrane Pregnancy and Childbirth's Trials Register, ClinicalTrials.gov, the WHO International Clinical Trials Registry Platform (ICTRP) (26 July 2019) and reference lists of retrieved studies. SELECTION CRITERIA: Randomised controlled trials (RCTs) of mechanical/surgical methods for the treatment of primary PPH compared with standard care or another mechanical/surgical method. Interventions could include uterine packing, intrauterine balloon insertion, artery ligation/embolism, or uterine compression (either with sutures or manually). We included studies reported in abstract form if there was sufficient information to permit risk of bias assessment. Trials using a cluster-RCT design were eligible for inclusion, but quasi-RCTs or cross-over studies were not. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed studies for inclusion and risk of bias, independently extracted data and checked data for accuracy. We used GRADE to assess the certainty of the evidence. MAIN RESULTS: We included nine small trials (944 women) conducted in Pakistan, Turkey, Thailand, Egypt (four trials), Saudi Arabia, Benin and Mali. Overall, included trials were at an unclear risk of bias. Due to substantial differences between the studies, it was not possible to combine any trials in meta-analysis. Many of this review's important outcomes were not reported. GRADE assessments ranged from very low to low, with the majority of outcome results rated as very low certainty. Downgrading decisions were mainly based on study design limitations and imprecision; one study was also downgraded for indirectness. External uterine compression versus normal care (1 trial, 64 women) Very low-certainty evidence means that we are unclear about the effect on blood transfusion (risk ratio (RR) 2.33, 95% confidence interval (CI) 0.66 to 8.23). Uterine arterial embolisation versus surgical devascularisation plus B-Lynch (1 trial, 23 women) The available evidence for hysterectomy to control bleeding (RR 0.73, 95% CI 0.15 to 3.57) is unclear due to very low-certainty evidence. The available evidence for intervention side effects is also unclear because the evidence was very low certainty (RR 1.09; 95% CI 0.08 to 15.41). Intrauterine Tamponade Studies included various methods of intrauterine tamponade: the commercial Bakri balloon, a fluid-filled condom-loaded latex catheter ('condom catheter'), an air-filled latex balloon-loaded catheter ('latex balloon catheter'), or traditional packing with gauze. Balloon tamponade versus normal care (2 trials, 356 women) One study(116 women) used the condom catheter. This study found that it may increase blood loss of 1000 mL or more (RR 1.52, 95% CI 1.15 to 2.00; 113 women), very low-certainty evidence. For other outcomes the results are unclear and graded as very low-certainty evidence: mortality due to bleeding (RR 6.21, 95% CI 0.77 to 49.98); hysterectomy to control bleeding (RR 4.14, 95% CI 0.48 to 35.93); total blood transfusion (RR 1.49, 95% CI 0.88 to 2.51); and side effects. A second study of 240 women used the latex balloon catheter together with cervical cerclage. Very low-certainty evidence means we are unclear about the effect on hysterectomy (RR 0.14, 95% CI 0.01 to 2.74) and additional surgical interventions to control bleeding (RR 0.20, 95% CI 0.01 to 4.12). Bakri balloon tamponade versus haemostatic square suturing of the uterus (1 trial, 13 women) In this small trial there was no mortality due to bleeding, serious maternal morbidity or side effects of the intervention, and the results are unclear for blood transfusion (RR 0.57, 95% CI 0.14 to 2.36; very low certainty). Bakri balloon tamponade may reduce mean 'intraoperative' blood loss (mean difference (MD) -426 mL, 95% CI -631.28 to -220.72), very low-certainty evidence. Comparison of intrauterine tamponade methods (3 trials, 328 women) One study (66 women) compared the Bakri balloon and the condom catheter, but it was uncertain whether the Bakri balloon reduces the risk of hysterectomy to control bleeding due to very low-certainty evidence (RR 0.50, 95% CI 0.05 to 5.25). Very low-certainty evidence also means we are unclear about the results for the risk of blood transfusion (RR 0.97, 95% CI 0.88 to 1.06). A second study (50 women) compared Bakri balloon, with and without a traction stitch. Very low-certainty evidence means we are unclear about the results for hysterectomy to control bleeding (RR 0.20, 95% CI 0.01 to 3.97). A third study (212 women) compared the condom catheter to gauze packing and found that it may reduce fever (RR 0.47, 95% CI 0.38 to 0.59), but again the evidence was very low certainty. Modified B-Lynch compression suture versus standard B-Lynch compression suture (1 trial, 160 women) Low-certainty evidence suggests that a modified B-Lynch compression suture may reduce the risk of hysterectomy to control bleeding (RR 0.33, 95% CI 0.11 to 0.99) and postoperative blood loss (MD -244.00 mL, 95% CI -295.25 to -192.75). AUTHORS' CONCLUSIONS: There is currently insufficient evidence from RCTs to determine the relative effectiveness and safety of mechanical and surgical interventions for treating primary PPH. High-quality randomised trials are urgently needed, and new emergency consent pathways should facilitate recruitment. The finding that intrauterine tamponade may increase total blood loss > 1000 mL suggests that introducing condom-balloon tamponade into low-resource settings on its own without multi-system quality improvement does not reduce PPH deaths or morbidity. The suggestion that modified B-Lynch suture may be superior to the original requires further research before the revised technique is adopted. In high-resource settings, uterine artery embolisation has become popular as the equipment and skills become more widely available. However, there is little randomised trial evidence regarding efficacy and this requires further research. We urge new trial authors to adopt PPH core outcomes to facilitate consistency between primary studies and subsequent meta-analysis.