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

Nutrition, microbiota, and endotoxin-related diseases in dairy cows Nutrição, microbiota e doenças relacionadas à endotoxina em vacas leiteiras

In this review article we present an overall summary of the role that high-grain/low forage diets have on rumen composition of microbiota and how changes in the diet affect the release of bacterial cell wall components that are toxic to the host. One of these toxic compounds is lipopolysaccharide or endotoxin, a component of the outer membrane of all Gram-negative bacteria. Moreover, data are provided that support the concept that endotoxin translocates into the blood circulation and show that rumen endotoxin is associated with multiple perturbations of blood variables related to carbohydrate, lipid, and mineral metabolism. In addition, endotoxin induces a general, nonspecific immune response known as acute phase response. We also pinpoint the fact that high-grain diets are associated with distinct clusters of plasma metabolites and immune variables suggesting that changing cereal grain to forage ratio in the diet is very important for the health of dairy cattle. Furthermore, we provide information that support the concept that endotoxin is involved in multiple metabolic diseases such as fatty liver, milk fever, laminitis, retained placenta, displaced abomasum, and downer cow syndrome. More research is warranted to clarify the mechanisms by which nutrition, microbiota, and endotoxin contribute to development of metabolic diseases in dairy cattle. It is concluded that besides the aforementioned causal agents other compounds generated in the gastrointestinal tract such as lipoteichoic acid or methylated amines might be involved in the etiology of several metabolic diseases.Neste artigo de revisão é apresentado um resumo total do papel que a dieta de alto teor de grãos e baixo teor de forragem tem sobre a composição da microbiota do rúmen e como as mudanças na dieta afetam a liberação de componentes da parede celular bacteriana tóxicos ao hospedeiro. Um destes compostos tóxicos é um lipopolisacarídeo ou endotoxina, um componente da membrana exterior de todas bactérias gram-negativas. Também são fornecidos dados que apoiam a idéia de que a endotoxina se transloca na circulação sanguínea e que estas endotoxinas ruminais estão associadas a múltiplas perturbações das variáveis sanguíneas relacionadas a carboidratos, lipídios e metabolismo mineral. Além disso, endotoxina induz resposta imune geral e não específica, denominada resposta aguda de fase. Destaca-se também o fato de que dietas de alto teor de grão estão associadas a grupos distintos de metabolitos do plasma e variáveis imunes, sugerindo que a mudança na proporção entre grãos de cereal e forragem na dieta é muito importante para a saúde do gado leiteiro. Fornecemos também informações que apoiam o conceito de que a endotoxina está envolvida em múltiplas doenças metabólicas, como fígado gorduroso, febre do leite, laminitis, placenta retida, abomasum deslocado e síndrome downer cow. Maior número de pesquisas é necessário para esclarecer os mecanismos pelo qual nutrição, microbiota e endotoxina contribuem para o desenvolvimento de doenças metabólicas. Concluímos que, além dos agentes causais acima mencionados, outros compostos gerados na área de gastrointestinal, como ácido de lipoteicóico ou aminas metiladas, podem estar envolvidos na etiologia de doenças metabólicas

Repeated oronasal exposure to lipopolysaccharide induced mucosal IgA responses in periparturient dairy cows.

This study investigated the effects of repeated oronasal treatment with lipopolysaccharide (LPS) on the humoral immune responses in saliva, vaginal mucus, and the plasma markers of the acute phase response in periparturient dairy cows. One hundred pregnant Holstein cows were administered either 3 increasing doses of LPS (n = 50) as follows: 1) 0.01 µg/kg body weight (BW) on d -28, 2) 0.05 µg/kg BW on d -25, and -21, and 3) 0.1 µg/kg BW on d -18, and -14, or sterile saline solution (controls; n = 50) oronasally for 3 consecutive wk starting at 28 d before parturition. Intensive sampling was conducted on thirty cows (n = 15/group). Multiple saliva, vaginal mucus and blood samples were collected around parturition and analyzed for total immunoglobulin-(Ig)A, plasma serum amyloid A (SAA), lipopolysaccharide-binding protein (LBP), anti-LPS IgA, IgG, IgM, tumour necrosis factor(TNF)-α, and interleukin(IL)-1. Results regarding total secretory IgA (sIgA) antibodies showed greater concentrations in the saliva and an overall tendency for higher total sIgA in the vaginal mucus of the LPS-treated cows. Treatment had no effect on plasma sIgA, IgG, IgM anti-LPS antibodies, haptoglobin, SAA, LBP, TNF-α, and IL-1. Treatments by time interactions were observed for SAA and IL-1 with lowered concentrations of both variables in the plasma of LPS-treated cows after parturition. Overall, repeated oronasal LPS treatment clearly enhanced total sIgA antibodies in the saliva, stimulated their production in vaginal mucus shortly before calving, and lowered plasma IL-1 around parturition, but showed limited effects on markers of the acute phase response in the plasma in dairy cows around parturition

Fetomaternal Outcome in Women with COVID-19 in a COVID Designated Hospital in Lahore, Pakistan

Background and Objective: The pandemic caused by Coronavirus disease-2019 (COVID-19) is notably becoming similar to severe acute respiratory syndrome (SARS) and Middle East respiratory syndrome viruses (MERS) for causing poor feto-maternal outcome. There is not much data available about COVID-19 during pregnancy in Pakistan therefore the objective of this study is to determine maternal and fetal outcome in pregnant women affected with COVID-19 and to find out frequency of vertical transmission. Methods: This descriptive case series was conducted from 1st April 2020 to 10th May 2020 at Department of Obstetrics and Gynecology, COVID ward, Sir Ganga Ram Hospital, Lahore. A total of 20 women were included in the study that were found positive for viral RNA by Real-Time Reverse TranscriptionPolymerase Chain Reaction (rRT-PCR) of nasopharyngeal specimens. Demographics, duration of gestation, fetomaternal outcome and vertical transmission were noted in the respected proformas. The data was analyzed using Statistical Package for Social Sciences version 20. Results: The mean age of these gravid females was 29.3 &plusmn; 4.17 years. The mean gravidity was 2.60 &plusmn; 1.14 and mean gestational age was 29 &plusmn; 9.53 weeks. Among 20 patients, 4(20%) were primigravida, 5(25%) females were gravida 2 and remaining 11(55%) cases were gravida 3 and 4. The most common presenting complaints were fever followed by dry cough, myalgia and shortness of breath. Nine patients were delivered by lower segment cesarean section in which fetal distress was observed in 5(55.6%) newborns and 1(10%) newborn was preterm. Among all newborns, 02 developed respiratory distress syndrome and were admitted in pediatric intensive care unit. All pharyngeal swabs of newborns were negative at 12 and 24 hours of life. Conclusion: COVID-19 in pregnant females is not different than in general population. The fetomaternal outcome is usually good and there is no evidence of vertical transmission in any newborn.</p

Concentrations of plasma haptoglobin in periparturient Holstein cows primed oronasally with LPS (▪) or saline (⋄).

<p>Cows in the LPS group were administered orally and nasally 2(0.15 M of NaCl), respectively, containing 3 increasing doses of LPS from <i>E. coli</i> 0111:B4 as follows: 1) 0.01 µg/kg body weight (BW) on d −28, 2) 0.05 µg/kg BW on d −25, and −21, and 3) 0.1 µg/kg BW on d −18, and −14, whereas control cows received 2 mL oral and 1 mL nasal sterile saline solution. (LSM ± SEM; n = 15; Trt  =  effect of treatment; Time  =  effect of sampling day, Trt×time  =  effect of treatment by sampling day; *indicates treatment differences at specific time points at <i>P</i><0.05).</p

Concentrations of plasma serum amyloid A (a), and lipopolysaccharide binding protein (b), in periparturient Holstein cows primed oronasally with LPS (▪) or saline (⋄).

<p>Cows in the LPS group were administered orally and nasally 2(0.15 M of NaCl), respectively, containing 3 increasing doses of LPS from <i>E. coli</i> 0111:B4 as follows: 1) 0.01 µg/kg body weight (BW) on d −28, 2) 0.05 µg/kg BW on d −25, and −21, and 3) 0.1 µg/kg BW on d −18, and −14, whereas control cows received 2 mL oral and 1 mL nasal sterile saline solution. (LSM ± SEM; n = 15; Trt  =  effect of treatment; Time  =  effect of sampling day, Trt×time  =  effect of treatment by sampling day; * indicates treatment differences at specific time points at <i>P</i><0.05).</p

Concentrations of plasma immunoglobulin(Ig)-A (a), IgG (b), and IgM (c) in periparturient Holstein cows primed oronasally with LPS (▪) or saline (⋄).

<p>Cows in the LPS group were administered orally and nasally 2(0.15 M of NaCl), respectively, containing 3 increasing doses of LPS from <i>E. coli</i> 0111:B4 as follows: 1) 0.01 µg/kg body weight (BW) on d −28, 2) 0.05 µg/kg BW on d −25, and −21, and 3) 0.1 µg/kg BW on d −18, and −14, whereas control cows received 2 mL oral and 1 mL nasal sterile saline solution. (LSM ± SEM; n = 15; Trt  =  effect of treatment; Time  =  effect of sampling day, Trt×time  =  effect of treatment by sampling day).</p

Concentrations of total salivary (a) or vaginal (b) immunoglobulin(Ig) A in periparturient Holstein cows primed oronasally with LPS (▪) or saline (⋄).

<p>Cows in the LPS group were administered orally and nasally 2(0.15 M of NaCl), respectively, containing 3 increasing doses of LPS from <i>E. coli</i> 0111:B4 as follows: 1) 0.01 µg/kg body weight (BW) on d −28, 2) 0.05 µg/kg BW on d −25, and −21, and 3) 0.1 µg/kg BW on d −18, and −14, whereas control cows received 2 mL oral and 1 mL nasal sterile saline solution. (LSM ± SEM; n = 15; Trt  =  effect of treatment; Time  =  effect of sampling day, Trt×time  =  effect of treatment by sampling day; *indicates treatment differences at specific time points at <i>P</i><0.05).</p