Effect of early tranexamic acid administration on mortality, hysterectomy, and other morbidities in women with post-partum haemorrhage (WOMAN): an international, randomised, double-blind, placebo-controlled trial

Background Post-partum haemorrhage is the leading cause of maternal death worldwide. Early administration of tranexamic acid reduces deaths due to bleeding in trauma patients. We aimed to assess the effects of early administration of tranexamic acid on death, hysterectomy, and other relevant outcomes in women with post-partum haemorrhage. Methods In this randomised, double-blind, placebo-controlled trial, we recruited women aged 16 years and older with a clinical diagnosis of post-partum haemorrhage after a vaginal birth or caesarean section from 193 hospitals in 21 countries. We randomly assigned women to receive either 1 g intravenous tranexamic acid or matching placebo in addition to usual care. If bleeding continued after 30 min, or stopped and restarted within 24 h of the first dose, a second dose of 1 g of tranexamic acid or placebo could be given. Patients were assigned by selection of a numbered treatment pack from a box containing eight numbered packs that were identical apart from the pack number. Participants, care givers, and those assessing outcomes were masked to allocation. We originally planned to enrol 15 000 women with a composite primary endpoint of death from all-causes or hysterectomy within 42 days of giving birth. However, during the trial it became apparent that the decision to conduct a hysterectomy was often made at the same time as randomisation. Although tranexamic acid could influence the risk of death in these cases, it could not affect the risk of hysterectomy. We therefore increased the sample size from 15 000 to 20 000 women in order to estimate the effect of tranexamic acid on the risk of death from post-partum haemorrhage. All analyses were done on an intention-to-treat basis. This trial is registered with ISRCTN76912190 (Dec 8, 2008); ClinicalTrials.gov, number NCT00872469; and PACTR201007000192283. Findings Between March, 2010, and April, 2016, 20 060 women were enrolled and randomly assigned to receive tranexamic acid (n=10 051) or placebo (n=10 009), of whom 10 036 and 9985, respectively, were included in the analysis. Death due to bleeding was significantly reduced in women given tranexamic acid (155 [1·5%] of 10 036 patients vs 191 [1·9%] of 9985 in the placebo group, risk ratio [RR] 0·81, 95% CI 0·65–1·00; p=0·045), especially in women given treatment within 3 h of giving birth (89 [1·2%] in the tranexamic acid group vs 127 [1·7%] in the placebo group, RR 0·69, 95% CI 0·52–0·91; p=0·008). All other causes of death did not differ significantly by group. Hysterectomy was not reduced with tranexamic acid (358 [3·6%] patients in the tranexamic acid group vs 351 [3·5%] in the placebo group, RR 1·02, 95% CI 0·88–1·07; p=0·84). The composite primary endpoint of death from all causes or hysterectomy was not reduced with tranexamic acid (534 [5·3%] deaths or hysterectomies in the tranexamic acid group vs 546 [5·5%] in the placebo group, RR 0·97, 95% CI 0·87-1·09; p=0·65). Adverse events (including thromboembolic events) did not differ significantly in the tranexamic acid versus placebo group. Interpretation Tranexamic acid reduces death due to bleeding in women with post-partum haemorrhage with no adverse effects. When used as a treatment for postpartum haemorrhage, tranexamic acid should be given as soon as possible after bleeding onset. Funding London School of Hygiene & Tropical Medicine, Pfizer, UK Department of Health, Wellcome Trust, and Bill & Melinda Gates Foundation

Safety and Efficacy of Febuxostat Treatment in Subjects with Gout and Severe Allopurinol Adverse Reactions

Objective.Allopurinol, a purine base analog inhibitor of xanthine oxidase (XO) activity, remains the standard for pharmacologic urate-lowering management of gout. Allopurinol is efficacious and safe in most patients, but intolerance is estimated to occur in up to 10% of treated patients. Severe or life-threatening allopurinol adverse reactions (AE) occur much less frequently, and include severe cutaneous allopurinol reactions, vasculitis, and/or a multisystem allopurinol hypersensitivity syndrome. During clinical development of febuxostat (FEB), a recently approved non-purine analog inhibitor of XO, subjects with severe allopurinol intolerance were excluded from randomized double-blind FEB/allopurinol comparative trials.Methods.In this retrospective study, safety and urate-lowering efficacy of FEB was assessed in 13 successively encountered gout patients with prior documented severe allopurinol reactions.Results.FEB was well tolerated in 12 of 13 patients, each of whom remains on treatment. One patient previously hospitalized with documented exfoliative erythroderma during allopurinol treatment, developed biopsy-confirmed cutaneous leukocytoclastic vasculitis. None of the other 12 patients treated with FEB showed rash, worsening hepatic function, blood cytopenia or eosinophilia.Conclusion.In 12 of our 13 gout patients with previously documented severe allopurinol AE, FEB treatment was safe. However, the development of a hypersensitivity type cutaneous vasculitis (likely but not definitively FEB-related) early in treatment mandates caution, careful dose escalation, and close monitoring when FEB urate-lowering therapy of allopurinol-intolerant patients is considered.</jats:sec

Uterine Rupture: an audit to analyze management options, maternal &amp; fetal outcome

Study Design: An analysis of 14 cases of ruptured uterus was done during January 2003 to December 2003 in Obstetrics &amp; Gynae Department of Lahore General Hospital, Lahore. Objective: The purpose of this Audit was to analyse the different management options, maternal and fetal outcome in uterine rupture. Material and Methods: Total no of births in 2003 was 4840. Total number of ruptured uterus found to be 14 (2.9%/1000) deliveries. Among these incomplete rupture were 3 (21.4%) and complete rupture were 11 (78.4%). Regarding the common sites of uterine rupture lower uterine segment interior surface = 11 (78.4%). Lower uterine segment posterior surface = 2 (14.2%) and upper uterine segment rupture was = 1 (7.14%). The most common cause of uterine rupture was found to be multiparity and injudicious use of oxytocin by TBA in 5 cases. (35.7%) and previous uterine surgery in 5 cases (35.7%). 2 cases (14.21) were due to cephalopelvic disproportion due to hydrocephalus and 2 (14.2%) cases were of malpresentation (transverse lie) mostly handled at home by TBAs. Hysterectomy, total or sub total was done in 7 cases (50%). Repair of uterus was done in 5 cases (35.7%), in 2-cases (14.2%). Bladder repair alongwith uterine repair was done. In two cases (14.2%) of scar dehiscence, repeat cesarean section was done. The maternal mortality was found to be zero, while intrauterine death were 10(71.4%) and alive babies were 4 (28.5%) high perinatal mortality of 71% were found. Conclusion: Ruptured uterus is avoidable catastrophe by proper education, training of patients and TBA`s and by providing effective family planning services, transportation, diagnostic facilities and by reducing the unnecessary caesarean section.</jats:p