Prevention of postpartum haemorrhage: Economic evaluation of the novel butterfly device in a UK setting.

OBJECTIVES: To explore the cost-effectiveness of a novel PPH device as compared with usual care. DESIGN: A decision analytical model was used to explore the cost-effectiveness of the PPH Butterfly device compared with usual care. This was part of a United Kingdom, UK, clinical trial ISRCTN15452399 using a matched historical cohort who had standard PPH management without the use of the PPH Butterfly device. The economic evaluation was conducted from a UK National Health Service (NHS) perspective. SETTING: Liverpool Women's Hospital, UK. PARTICIPANTS: 57 women with 113 matched controls. INTERVENTION: The PPH Butterfly is a novel device that has been invented and developed in the UK to facilitate bimanual compression of the uterus in the treatment of PPH. MAIN OUTCOME MEASURES: Main outcome measures included healthcare costs, blood loss, and maternal morbidity events. RESULTS: Mean treatment costs in the Butterfly cohort were £3,459.66 as compared with standard care £3,223.93. Treatment with the Butterfly device resulted in decreased total blood loss in comparison with standard care. The Butterfly device had an incremental cost-effectiveness ratio of £3,795.78 per PPH progression avoided (defined as ≤ 1000 ml additional blood loss from device insertion point). If the NHS is prepared to pay £8,500 per PPH progression avoided, then the Butterfly device is cost-effective with a probability of 87 percent. In the PPH Butterfly treatment arm there were 9% fewer cases of massive obstetric haemorrhage (severe PPH of more than 2000mls or more than 4 units of blood transfusion required) recorded as compared with the standard care historical cohort. As a low-cost device, the PPH Butterfly device is cost-effective but can be cost-saving to the NHS. CONCLUSION: The PPH pathway can result in high-cost resource use such as blood transfusion or high dependence unit hospital stays. The Butterfly device is a relative low-cost device in a UK NHS setting with a high probability of being cost-effective. The National Institute for Health and Care Excellence (NICE) can use this evidence in considering the adoption of innovative technologies such as the Butterfly device in the NHS. Extrapolation on an international scale to lower and middle-income countries could prevent mortality associated with PPH.

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.

World Health Organization Recommendation for Using Uterine Balloon Tamponade to Treat Postpartum Hemorrhage.

The World Health Organization (WHO) recently published a new recommendation on the use of the uterine balloon tamponade for the treatment of postpartum hemorrhage. The recommendation that uterine balloon tamponade should be used only where there is already access to other postpartum hemorrhage treatments (including immediate recourse to surgery) has proved controversial. It is especially problematic for those working in low-level health care facilities in under-resourced settings, where there are already programs that have introduced low-cost uterine balloon tamponade devices for use, even in settings where recourse to surgical interventions is not possible. However, there are now two separate randomized trials that both unexpectedly show unfavorable outcomes in these settings when a condom catheter uterine balloon tamponade device was introduced. Considering the balance of potential benefits and these safety concerns, the WHO postpartum hemorrhage guideline panel therefore recommends that uterine balloon tamponade should be used only in contexts where other supportive postpartum hemorrhage interventions are available if needed.

The golden hour for postpartum hemorrhage: Results from a prospective cohort study.

OBJECTIVE: To evaluate the predictive capacity of vital signs for the diagnosis of postpartum hemorrhage (PPH). METHODS: A prospective cohort study performed at the University of Campinas, Brazil, between February 2015 and March 2016 with women who delivered vaginally. Vital signs and postpartum bleeding were collected over 24 h. Exploratory data analysis was performed plus receiver operating characteristic curve analysis where the areas under the curve was used to determine the best cutoff points for sensitivity, specificity, likelihood ratio, and diagnostic odds ratio. RESULTS: For the 270 women recruited, mean blood loss after 120 min was 427.49 ± 335.57 ml, while 84 (31.1%) and 22 (8.1%) women had blood loss ≥500 and ≥1000 ml, respectively. Heart rate cutoff point of 105 bpm measured between 21-40 min after birth identified blood loss ≥1000 ml with 90% specificity. A shock index (SI) of 0.965 at 41-60 min after birth identified blood loss ≥500 and ≥1000 ml within 2 h with approximately 95% specificity. CONCLUSION: Shock index and heart rate measured after birth showed high specificity with low sensitivity to identify PPH. In clinical practice, "The rule of 1s" should receive special attention: SI ≥1, or heart rate >100 bpm, or estimated blood loss ≥1 L.

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.

Pattern of Peri-Operative Antibiotic Use among Surgical Patients in a Regional Referral and Teaching Hospital in Uganda.

Background: Prolonged surgical antimicrobial prophylaxis (SAP) to prevent surgical site infection (SSI) is generally discouraged after completion of surgery. However, little is known about the pattern of peri-operative antibiotic use in resource-limited settings. We aimed to describe its use at a typical government hospital in Uganda. Methods: A study was originally conducted in a rural Ugandan regional referral and teaching hospital in 2014 and 2015 to improve hand hygiene practice and measure its impact on health-care-associated infections including SSI (WardGel study). This is a secondary analysis of the data from the WardGel study to assess the frequency of peri-operative antibiotic use among surgical patients. Results: Of 3,627 patients enrolled into the original study, 960 (26.5%) underwent surgery at the hospital and 907 patients (94.5%) received antibiotic agents during hospitalization. Of these, 880 patients (97.0%, of 907 patients) received antibiotic agents on the day of surgery. A combination of ceftriaxone and metronidazole was the most common regimen (609/907 patients, 67.1%). Thirty-six of 907 patients (4.0%) started and completed their antibiotic agents on the day of surgery. The mean length of antibiotic use during hospitalization was 3.5 days (standard deviation, 3.3). After adjusting for covariates, linear regression analysis showed an extra 1.9 days of antibiotic use post-operatively (95% confidence interval = 1.7-2.3). During the total 4,960 inpatient-days for those having surgery, there were 6,503 days of therapy (DOTs) of antibiotic agents and 1,649 antibiotic-free days (AFDs). Conclusions: Most patients received prolonged antibiotic therapy after surgery. Antimicrobial stewardship for SAP can play a major role in combating antimicrobial resistance in resource-limited settings.

Antibiotic prophylaxis in the surgical management of miscarriage in low-income countries: a cost-effectiveness analysis of the AIMS trial.

BACKGROUND: There is ongoing debate on the clinical benefits of antibiotic prophylaxis for reducing pelvic infection after miscarriage surgery. We aimed to study the cost-effectiveness of antibiotic prophylaxis in the surgical management of miscarriage in low-income countries. METHODS: We did an incremental cost-effectiveness analysis using data from 3412 women recruited to the AIMS trial, a randomised, double-blind, placebo-controlled trial designed to evaluate the effectiveness of antibiotic prophylaxis in the surgical management of miscarriage in Malawi, Pakistan, Tanzania, and Uganda. Economic evaluation was done from a health-care-provider perspective on the basis of the outcome of cost per pelvic infection avoided within 2 weeks of surgery. Pelvic infection was broadly defined by the presence of clinical features or the clinically identified need to administer antibiotics. We used non-parametric bootstrapping and multilevel random effects models to estimate incremental mean costs and outcomes. Decision uncertainty was shown via cost-effectiveness acceptability frontiers. The AIMS trial is registered with the ISRCTN registry, number ISRCTN97143849. FINDINGS: Between June 2, 2014, and April 26, 2017, 3412 women were assigned to receive either antibiotic prophylaxis (1705 [50%] of 3412) or placebo (1707 [50%] of 3412) in the AIMS trial. 158 (5%) of 3412 women developed pelvic infection within 2 weeks of surgery, of whom 68 (43%) were in the antibiotic prophylaxis group and 90 (57%) in the placebo group. There is 97-98% probability that antibiotic prophylaxis is a cost-effective intervention at expected thresholds of willingness-to-pay per additional pelvic infection avoided. In terms of post-surgery antibiotics, the antibiotic prophylaxis group was US$0·27 (95% CI -0·49 to -0·05) less expensive per woman than the placebo group. A secondary analysis, a sensitivity analysis, and all subgroup analyses supported these findings. Antibiotic prophylaxis, if implemented routinely before miscarriage surgery, could translate to an annual total cost saving of up to $1·4 million across the four participating countries and up to $8·5 million across the two regions of sub-Saharan Africa and south Asia. INTERPRETATION: Antibiotic prophylaxis is more effective and less expensive than no antibiotic prophylaxis. Policy makers in various settings should be confident that antibiotic prophylaxis in miscarriage surgery is cost-effective. FUNDING: UK Medical Research Council, Wellcome Trust, and the UK Department for International Development.

Use of histograms to assess the efficacy of uterotonic treatment for post-partum haemorrhage: A feasibility study.

Post-partum haemorrhage (PPH) is a major pathological condition leading to mortality of women worldwide. Its initial treatment has largely been focused on uterotonics. This paper examines the use of histograms to assess the efficacy of uterotonic treatment for PPH. Previous examinations of large datasets in which women were treated at 700 ml of measured blood loss according to strict protocols have shown a quantifiable peak in the histogram at 700-800 ml following treatment. It is not clear whether this is commonly seen in other studies. The main aim was therefore to assess whether post-treatment peaks are routinely seen in postpartum blood loss histograms and whether the peaks are seen only in treated women. Four datasets of more than 1000 women with measured blood loss were identified and the original data examined. The secondary peak was not only seen in histograms attributed to treatment, but also many of the histograms where women had not received uterotonic treatment. Many women received treatment despite having blood loss of less than 500 ml, and many women who stopped bleeding with final blood losses of more than 500 ml did not receive any uterotonics. The routine use of histogram analysis to assess the efficiency of uterotonic therapy is not recommended. The paper also provides further insights into clinical practice, with clinicians frequently using uterotonic therapies even when the volume of the blood loss is low. This demonstrates how uterotonic use in practice is often not linked to the standard 500 ml definition of post-partum haemorrhage.

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.).

Prophylactic antibiotics to reduce pelvic infection in women having miscarriage surgery - The AIMS (Antibiotics in Miscarriage Surgery) trial: study protocol for a randomized controlled trial.

BACKGROUND: The estimated annual global burden of miscarriage is 33 million out of 210 million pregnancies. Many women undergoing miscarriage have surgery to remove pregnancy tissues, resulting in miscarriage surgery being one of the most common operations performed in hospitals in low-income countries. Infection is a serious consequence and can result in serious illness and death. In low-income settings, the infection rate following miscarriage surgery has been reported to be high. Good quality evidence on the use of prophylactic antibiotics for surgical miscarriage management is not available. Given that miscarriage surgery is common, and infective complications are frequent and serious, prophylactic antibiotics may offer a simple and affordable intervention to improve outcomes. METHODS: Eligible patients will be approached once the diagnosis of miscarriage has been made according to local practice. Once informed consent has been given, participants will be randomly allocated using a secure internet facility (1:1 ratio) to a single dose of oral doxycycline (400 mg) and metronidazole (400 mg) or placebo. Allocation will be concealed to both the patient and the healthcare providers. A total of 3400 women will be randomised, 1700 in each arm. The medication will be given approximately 2 hours before surgery, which will be provided according to local practice. The primary outcome is pelvic infection 2 weeks after surgery. Women will be invited to the hospital for a clinical assessment at 2 weeks. Secondary outcomes include overall antibiotic use, individual components of the primary outcome, death, hospital admission, unplanned consultations, blood transfusion, vomiting, diarrhoea, adverse events, anaphylaxis and allergy, duration of clinical symptoms, and days before return to usual activities. An economic evaluation will be performed to determine if prophylactic antibiotics are cost-effective. DISCUSSION: This trial will assess whether a single dose of doxycycline (400 mg) and metronidazole (400 mg) taken orally 2 hours before miscarriage surgery can reduce the incidence of pelvic infection in women up to 2 weeks after miscarriage surgery. TRIAL REGISTRATION: Registered with the ISRCTN (international standard randomised controlled trial number) registry: ISRCTN 97143849 . (Registered on April 17, 2013).

Misoprostol-induced fever and genetic polymorphisms in drug transporters SLCO1B1 and ABCC4 in women of Latin American and European ancestry.

AIM: Misoprostol, a prostaglandin analogue used for the treatment of postpartum hemorrhage and termination of pregnancy, can cause high fevers. Genetic susceptibility may play a role in misoprostol-induced fever. SUBJECTS & METHODS: Body temperature of women treated with misoprostol for termination of pregnancy in the UK (n = 107) and for postpartum hemorrhage in Ecuador (n = 50) was measured. Genotyping for 33 single nucleotide polymorphisms in 15 candidate genes was performed. Additionally, we investigated the transport of radiolabeled misoprostol acid across biological membranes in vitro. RESULTS: The ABCC4 single nucleotide polymorphism rs11568658 was associated with misoprostol-induced fever. Misoprostol acid was transported across a blood-brain barrier model by MRP4 and SLCO1B1. CONCLUSION: Genetic variability in ABCC4 may contribute to misoprostol-induced fever in pregnant women. Original submitted 21 January 2015; Revision submitted 24 April 2015.

Bleeding and outcome in acute coronary syndrome: insights from continuous electrocardiogram monitoring in the Integrilin and Enoxaparin Randomized Assessment of Acute Coronary Syndrome Treatment (INTERACT) Trial.

BACKGROUND: Bleeding is associated with adverse outcome in acute coronary syndromes. However, the precise pathophysiologic mechanisms have not been elucidated. We sought to determine the relationship between bleeding and myocardial ischemia detected by concurrent continuous electrocardiogram (ECG) monitoring and their independent long-term prognostic significance. METHODS: The INTERACT trial was a randomized controlled trial of enoxaparin versus unfractionated heparin in patients with high-risk non-ST-elevation acute coronary syndromes. Continuous ECG monitoring, performed after enrollment up to 96 hours, was analyzed by an automated algorithm and reviewed by a blinded cardiologist. We centrally adjudicated all bleeding and clinical events in a blinded fashion and calculated the Global Registry of Acute Coronary Events risk score (a validated predictor of mortality) for each patient. RESULTS: Of the 746 patients enrolled, 34 (4.6%) developed major bleeding within 96 hours. After a median follow-up of 2.4 years, patients with bleeding had a higher risk of death (28.4% vs 7.3%, P < .001) and death/myocardial infarction (38.0% vs 12.9%, P < .001) compared with those without bleeding. Overall, 619 patients survived the first 96 hours with complete data on continuous ECG monitoring. Bleeding was associated with the simultaneous presence of ST-segment shifts on continuous ECG monitoring (P = .03). After adjusting for Global Registry of Acute Coronary Events risk score and myocardial ischemia detected by continuous ECG monitoring, major bleeding remained an independent predictor of death (adjusted hazard ratio = 3.48, 95% confidence interval 1.51-8.03, P = .003) and death/myocardial infarction (adjusted hazard ratio = 2.85, 95% confidence interval 1.40-5.78, P = .004). CONCLUSIONS: Bleeding is a powerful independent predictor of poor long-term outcome, even after adjusting for other associated prognostic factors such as advanced age and renal dysfunction. Although bleeding is associated with concurrent myocardial ischemia, its adverse prognostic impact may be mediated by complex pathophysiologic mechanisms rather than myocardial ischemia alone. Our findings suggest that future investigations should focus on other biologically plausible mechanisms.