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Uterotonic agents for preventing postpartum haemorrhage: A network meta-analysis
Abstract
Background:
Postpartum haemorrhage (PPH) is the leading cause of maternal mortality worldwide. Prophylactic uterotonic agents can prevent PPH, and are routinely recommended. The current World Health Organization (WHO) recommendation for preventing PPH is 10 IU (international units) of intramuscular or intravenous oxytocin. There are several uterotonic agents for preventing PPH but there is still uncertainty about which agent is most effective with the least side effects. This is an update of a Cochrane Review which was first published in April 2018 and was updated to incorporate results from a recent large WHO trial.
Objectives:
To identify the most effective uterotonic agent(s) to prevent PPH with the least side effects, and generate a ranking according to their effectiveness and side-effect profile.
Search methods:
We searched the Cochrane Pregnancy and Childbirth's Trials Register, ClinicalTrials.gov, the World Health Organization (WHO) International Clinical Trials Registry Platform (ICTRP) (24 May 2018), and reference lists of retrieved studies.
Selection criteria:
All randomised controlled trials or cluster-randomised trials comparing the effectiveness and side effects of uterotonic agents with other uterotonic agents, placebo or no treatment for preventing PPH were eligible for inclusion. Quasi-randomised trials were excluded. Randomised trials published only as abstracts were eligible if sufficient information could be retrieved.
Data collection and analysis:
At least three review authors independently assessed trials for inclusion and risk of bias, extracted data and checked them for accuracy. We estimated the relative effects and rankings for preventing PPH ≥ 500 mL and PPH ≥ 1000 mL as primary outcomes. Secondary outcomes included blood loss and related outcomes, morbidity outcomes, maternal well-being and satisfaction and side effects. Primary outcomes were also reported for pre-specified subgroups, stratifying by mode of birth, prior risk of PPH, healthcare setting, dosage, regimen and route of administration. We performed pairwise meta-analyses and network meta-analysis to determine the relative effects and rankings of all available agents.
Main results:
The network meta-analysis included 196 trials (135,559 women) involving seven uterotonic agents and placebo or no treatment, conducted across 53 countries (including high-, middle- and low-income countries). Most trials were performed in a hospital setting (187/196, 95.4%) with women undergoing a vaginal birth (71.5%, 140/196).Relative effects from the network meta-analysis suggested that all agents were effective for preventing PPH ≥ 500 mL when compared with placebo or no treatment. The three highest ranked uterotonic agents for prevention of PPH ≥ 500 mL were ergometrine plus oxytocin combination, misoprostol plus oxytocin combination and carbetocin. There is evidence that ergometrine plus oxytocin (RR 0.70, 95% CI 0.59 to 0.84, moderate certainty), carbetocin (RR 0.72, 95% CI 0.56 to 0.93, moderate certainty) and misoprostol plus oxytocin (RR 0.70, 95% CI 0.58 to 0.86, low certainty) may reduce PPH ≥ 500 mL compared with oxytocin. Low-certainty evidence suggests that misoprostol, injectable prostaglandins, and ergometrine may make little or no difference to this outcome compared with oxytocin.All agents except ergometrine and injectable prostaglandins were effective for preventing PPH ≥ 1000 mL when compared with placebo or no treatment. High-certainty evidence suggests that ergometrine plus oxytocin (RR 0.83, 95% CI 0.66 to 1.03) and misoprostol plus oxytocin (RR 0.88, 95% CI 0.70 to 1.11) make little or no difference in the outcome of PPH ≥ 1000 mL compared with oxytocin. Low-certainty evidence suggests that ergometrine may make little or no difference to this outcome compared with oxytocin meanwhile the evidence on carbetocin was of very low certainty. High-certainty evidence suggests that misoprostol is less effective in preventing PPH ≥ 1000 mL when compared with oxytocin (RR 1.19, 95% CI 1.01 to 1.42). Despite the comparable relative treatment effects between all uterotonics (except misoprostol) and oxytocin, ergometrine plus oxytocin, misoprostol plus oxytocin combinations and carbetocin were the highest ranked agents for PPH ≥ 1000 mL.Misoprostol plus oxytocin reduces the use of additional uterotonics (RR 0.56, 95% CI 0.42 to 0.73, high certainty) and probably also reduces the risk of blood transfusion (RR 0.51, 95% CI 0.37 to 0.70, moderate certainty) when compared with oxytocin. Carbetocin, injectable prostaglandins and ergometrine plus oxytocin may also reduce the use of additional uterotonics but the certainty of the evidence is low. No meaningful differences could be detected between all agents for maternal deaths or severe morbidity as these outcomes were rare in the included randomised trials where they were reported.The two combination regimens were associated with important side effects. When compared with oxytocin, misoprostol plus oxytocin combination increases the likelihood of vomiting (RR 2.11, 95% CI 1.39 to 3.18, high certainty) and fever (RR 3.14, 95% CI 2.20 to 4.49, moderate certainty). Ergometrine plus oxytocin increases the likelihood of vomiting (RR 2.93, 95% CI 2.08 to 4.13, moderate certainty) and may make little or no difference to the risk of hypertension, however absolute effects varied considerably and the certainty of the evidence was low for this outcome.Subgroup analyses did not reveal important subgroup differences by mode of birth (caesarean versus vaginal birth), setting (hospital versus community), risk of PPH (high versus low risk for PPH), dose of misoprostol (≥ 600 mcg versus < 600 mcg) and regimen of oxytocin (bolus versus bolus plus infusion versus infusion only).
Authors' conclusions:
All agents were generally effective for preventing PPH when compared with placebo or no treatment. Ergometrine plus oxytocin combination, carbetocin, and misoprostol plus oxytocin combination may have some additional desirable effects compared with the current standard oxytocin. The two combination regimens, however, are associated with significant side effects. Carbetocin may be more effective than oxytocin for some outcomes without an increase in side effects.
... The studies by Greenaway (2019) 18 The six studies included in this review consist of three systematic reviews, 19-21 1 scoping literature review, 18 1 case-control study 22 and 1 expert consensus. 23 The studies by Wren (2017) 20 and Gallos et al. (2018) 23 included both an emergency, in-hospital component and an out-of-hospital component, increasing the inclusive breadth of the evidence, as supported by JBI. A summary of the characteristics of these studies can be observed in Table S1. ...
... A summary of the characteristics of these studies can be observed in Table S1. In regard to certainty of evidence, the articles by Pantoja et al. (2016), 19 Wren (2017) 20 and Gallos et al. (2018) 21 were considered high in terms of GRADE. 15 The three articles by Greenaway (2019), 18 Klemettilä were of low certainty 15 due to their study design. ...
... 19 With reference to the French College of Gynaecologists and Obstetrics PPH guideline's Grade A recommendations, 24 23 Greenaway (2019) 18 described significantly less blood loss (408 vs. 521 mL, 95% CI) (p < 0.001) with intravenous oxytocin infusion. Gallos et al. (2018) 21 reported that all uterotonic drugs are effective in preventing blood loss greater or equal to 500 mL, in comparison to no treatment. Gallos et al. (2018) 21 found that 122 in 1000 women given oxytocin following a vaginal birth would experience a PPH of ≥500 mL (RR 0.58, 95% CI). ...
Introduction
Primary postpartum haemorrhage causes approximately 25% of global maternal deaths and accounts for significant maternal morbidity. While high certainty evidence demonstrates that tranexamic acid reduces comparative blood loss in postpartum haemorrhage in hospital settings, limited data exist on the specific pharmacological management of this condition in out‐of‐hospital settings, and the implications for rural communities.
Objective
To determine the efficacy of oxytocin compared to tranexamic acid in women suffering postpartum haemorrhage in the out‐of‐hospital environment.
Design
A systematic review comparing evidence containing patients with postpartum haemorrhage in the out‐of‐hospital and/or rural setting, in which oxytocin/tranexamic acid were used. Outcome measures were comparative blood loss/haemorrhagic shock, the need for further interventions and maternal/neonatal morbidity/mortality.
Findings
No randomised control trials have been conducted in an out‐of‐hospital environment in relation to oxytocin/tranexamic acid. In this setting, there is no difference in outcome measures when using oxytocin compared to no intervention, or oxytocin compared to standard care. Data are lacking on the effect of tranexamic acid on the same outcome measures.
Discussion
Rural and out‐of‐hospital management of postpartum haemorrhage is limited by resource availability and practitioner availability, capacity and experience. In‐hospital evidence may lack transferability, therefore direct evidence on the efficacy of pharmacological management in these contexts is scant and requires redress.
Conclusion
There is no difference in blood loss, neonatal or maternal mortality or morbidity, or need for further interventions, when using oxytocin or TXA compared to no intervention, or compared to standard care, for PPH. Further studies are needed on the efficacy of these drugs, and alternate or co‐drug therapies, for PPH in the out‐of‐hospital environment and rural clinical practice.
... Due to the uterotonic effects, it has been recommended for the treatment and prevention of PPH by the International Federation of Obstetrics and Gynecology (FIGO) and WHO [3,4]. Although oxytocin is the gold standard drug for the prevention and treatment of PPH, the use of combined misoprostol and oxytocin significantly reduced the amount of blood loss after delivery compared to a higher dose of oxytocin alone [10,11]. Furthermore, misoprostol offers many advantages as it is heat-stable, cheaper and has variable routes of administration which makes it widely affordable and available, especially in low-resource countries, when compared to oxytocin [7]. ...
... Despite more than 60 years of use, there is a need for further research and refinement of the use of this agent [3]. There were very few studies in the literature in which a 2 IU bolus was administered [4]. Therefore, we aimed to determine the incidence of side effects of 2 IU bolus oxytocin in a larger patient population. ...
Uterotonics are essential in preventing postpartum hemorrhage (PPH), the leading direct cause of maternal death worldwide. However, uterotonics are often substandard in low- and middle-income countries, contributing to poor maternal health outcomes. This study examines the health and economic impact of substandard uterotonics in Ghana. A decision-tree model was built to simulate vaginal and cesarean section births across health facilities, uterotonic quality and utilization, PPH risk and diagnosis, and resulting health and economic outcomes. We utilized delivery data from Ghana’s maternal health survey, risks of health outcomes from a Cochrane review, and E-MOTIVE trial data for health outcomes related to oxytocin quality. We compared scenarios with and without substandard uterotonics, as well as scenarios altering uterotonic use and care-seeking behaviors. We found that substandard uterotonic use contributes to $18.8 million in economic burden annually, including $6.3 million and $4.8 million in out-of-pocket expenditures in public and private sectors, respectively. Annually, the National Health Insurance Scheme bears $1.6 million in costs due to substandard uterotonic use. Substandard uterotonics contribute to $6 million in long-term productivity losses from maternal mortality annually. Improving the quality of uterotonics could reduce 20,000 (11%) PPH cases, 5,000 (11%) severe PPH cases, and 100 (11%) deaths due to PPH annually in Ghana. Ensuring the quality of uterotonics would result in millions of dollars in cost savings and improve maternal health outcomes for the government and families in Ghana. Cost savings from improving uterotonic quality would provide financial protection and help Ghana advance toward Universal Health Coverage.
Objective
There are no globally agreed on strategies on early detection and first response management of postpartum haemorrhage (PPH) during and after caesarean birth. Our study aimed to develop an international expert’s consensus on evidence-based approaches for early detection and obstetric first response management of PPH intraoperatively and postoperatively in caesarean birth.
Design
Systematic review and three-stage modified Delphi expert consensus.
Setting
International.
Population
Panel of 22 global experts in PPH with diverse backgrounds, and gender, professional and geographic balance.
Outcome measures
Agreement or disagreement on strategies for early detection and first response management of PPH at caesarean birth.
Results
Experts agreed that the same PPH definition should apply to both vaginal and caesarean birth. For the intraoperative phase, the experts agreed that early detection should be accomplished via quantitative blood loss measurement, complemented by monitoring the woman’s haemodynamic status; and that first response should be triggered once the woman loses at least 500 mL of blood with continued bleeding or when she exhibits clinical signs of haemodynamic instability, whichever occurs first. For the first response, experts agreed on immediate administration of uterotonics and tranexamic acid, examination to determine aetiology and rapid initiation of cause-specific responses. In the postoperative phase, the experts agreed that caesarean birth-related PPH should be detected primarily via frequently monitoring the woman’s haemodynamic status and clinical signs and symptoms of internal bleeding, supplemented by cumulative blood loss assessment performed quantitatively or by visual estimation. Postoperative first response was determined to require an individualised approach.
Conclusion
These agreed on proposed approaches could help improve the detection of PPH in the intraoperative and postoperative phases of caesarean birth and the first response management of intraoperative PPH. Determining how best to implement these strategies is a critical next step.
Peripartum hemorrhage, which can occur during pregnancy, labor, or delivery, is an all-inclusive term for bleeding that can happen from 24+0 weeks of gestation to 12 weeks after birth. It is a serious obstetric emergency that affects the entire world and is linked to both mother and fetal morbidity and mortality. It continues to be difficult to treat and to be a significant financial burden. One to ten percentage of deliveries are being complicated by peripartum hemorrhage, and it is the sixth most common cause of maternal mortality in the UK between 2015 and 2017, accounting for 8% of all maternal deaths. Postpartum hemorrhage can be categorized into primary and secondary categories. The 4Ts (Tone, Trauma, Tissue, and Thrombin) are typically used to describe the etiopathogenesis of primary PPH. Over 70% of primary PPH cases had inadequate uterine contractions or uterine atony as a contributing factor. Clinical detection of bleeding severity necessitates alertness and a high degree of suspicion. It is a preventable cause of maternal death and improvements in pharmacology, anesthesia, blood transfusion/hematological support, and innovative surgical methods have dramatically reduced mortality. Rotational thrombelastometry (ROTEM) testing has recently been proven to be a quicker way to diagnose coagulopathy in those who are bleeding. Early resuscitation to prevent hypovolemic shock, to achieve hemodynamic stability, and other specialized strategies as well as identification and management therapy of the underlying cause(s) of the hemorrhage are crucial in controlling peripartum hemorrhage. It has been demonstrated that routine delivery room drills, simulations, and quick multidisciplinary team involvement further improve care even when major bleeding happens suddenly. Proper application of all these should make maternal mortality purely due to hemorrhage a rare event.
Afet Durumlarında Rejyonel Anestezi Yönetimi Kıvanç ÖNCÜ Antikoagulan İlac Kullanan Hastalarda Noroaksiyel, Periferal ve Derin Sinir Blokları için Guvenli Aralık Sedat SAYLAN Ali AKDOĞAN Preeklampsili Hastada Anestezi Yönetimi Ali AKDOĞAN Engin ERTÜRK Postpartum Hemoraji ve Anestezi Yönetimi Özge ŞIKTAŞ Ortopedi Hastalarında Cerrahi Sonrası Hızlandırılmış İyileşme (ERAS) Protokolleri Demet LAFLI TUNAY Bolum 6 Malign Hipertermi ve Anestezi Yönetimi Murat TÜMER Rokuronyum İnfuzyonu İle Sağlanan Noromuskuler Bloğun Sugammadeks İle Geri Dondurulmesinin Desfluran veya Propofol Anestezisinde Karşılaştırmalı Değerlendirilmesi Necmiye ŞENGEL Gözde İNAN Mustafa ARSLAN
Objective: we compare the effect of rectal misoprostol & oxytocin intraoperative bleeding & hemoglobin level & post operative bleeding.Study design: in this study 100 pregnant women candidate of elective cesarean section (CS) were randomally allocated in one of two group of patient receiving either 600mg of misoprostol, rectally other group receive intravenous oxytocin, after delivery of baby. Intraoperative bleeding, haemoglobing level before & 24hr after. Operation, Mean arterial Blood pressure, heart rate before & after the administration of the drugs.
Background
Postpartum hemorrhage is the most common cause of maternal death. Oxytocin is the standard therapy for the prevention of postpartum hemorrhage, but it requires cold storage, which is not available in many countries. In a large trial, we compared a novel formulation of heat-stable carbetocin with oxytocin.
Methods
We enrolled women across 23 sites in 10 countries in a randomized, double-blind, noninferiority trial comparing intramuscular injections of heat-stable carbetocin (at a dose of 100 μg) with oxytocin (at a dose of 10 IU) administered immediately after vaginal birth. Both drugs were kept in cold storage (2 to 8°C) to maintain double-blinding. There were two primary outcomes: the proportion of women with blood loss of at least 500 ml or the use of additional uterotonic agents, and the proportion of women with blood loss of at least 1000 ml. The noninferiority margins for the relative risks of these outcomes were 1.16 and 1.23, respectively.
Results
A total of 29,645 women underwent randomization. The frequency of blood loss of at least 500 ml or the use of additional uterotonic agents was 14.5% in the carbetocin group and 14.4% in the oxytocin group (relative risk, 1.01; 95% confidence interval [CI], 0.95 to 1.06), a finding that was consistent with noninferiority. The frequency of blood loss of at least 1000 ml was 1.51% in the carbetocin group and 1.45% in the oxytocin group (relative risk, 1.04; 95% CI, 0.87 to 1.25), with the confidence interval crossing the margin of noninferiority. The use of additional uterotonic agents, interventions to stop bleeding, and adverse effects did not differ significantly between the two groups.
Conclusions
Heat-stable carbetocin was noninferior to oxytocin for the prevention of blood loss of at least 500 ml or the use of additional uterotonic agents. Noninferiority was not shown for the outcome of blood loss of at least 1000 ml; low event rates for this outcome reduced the power of the trial. (Funded by Merck Sharpe & Dohme; CHAMPION Australian New Zealand Clinical Trials Registry number, ACTRN12614000870651; EudraCT number, 2014-004445-26; and Clinical Trials Registry–India number, CTRI/2016/05/006969.)
Purpose:
To compare the effectiveness of intravenous carbetocin to that of intravenous oxytocin for prevention of atonic postpartum hemorrhage (PPH) after vaginal delivery in high-risk singleton pregnancies.
Methods:
This triple-blind randomized controlled trial included singleton pregnant women who delivered at Siriraj Hospital between August 2016 and January 2017 and who were 20 years or older, had a gestational age of at least 34 weeks, had a vaginal delivery, and had at least one risk factor for atonic postpartum hemorrhage. Immediately after vaginal delivery, participants were randomly assigned to receive either 5 U of oxytocin or 100 mcg of carbetocin intravenously. Postpartum blood loss was measured objectively in mL using a postpartum drape with a calibrated bag.
Results:
A total of 174 and 176 participants constituted the oxytocin and carbetocin groups, respectively. The baseline characteristics were comparable between the groups. The carbetocin group had less postpartum blood loss (146.7 ± 90.4 vs. 195.1 ± 146.2 mL; p < 0.01), a lower incidence of atonic PPH (0 vs. 6.3%; p < 0.01), less usage of additional uterotonic drugs (9.1 vs. 27.6%; p < 0.01), and a lower incidence of postpartum anemia (Hb ≤ 10 g/dL) (9.1 vs. 18.4%; p < 0.05) than the oxytocin group. No significant differences regarding side effects were evident between the groups.
Conclusions:
Intravenous carbetocin is more effective than intravenous oxytocin for the prevention of atonic PPH among singleton pregnancies with at least one risk factor for PPH.
Clinical trial registration:
TCTR20160715004.
Introduction: Worldwide PPH remains one of the most common cause of maternal mortality and is largely preventable maternaldeaths mainly in low income countries. 80% of it occurs due to uterine atony and uterotonics can decrease the risk of uterine atony. Misoprostolhas powerful uterotonic effect because it is well absorbed and has potential to be used more widely than would be possible with injectableuterotonics alone. Objective: The objective of this study is to compare efficacy of misoprostol with ergometrine in cesarean delivery formanagement of PPH. Study Design: Randomized controlled trial. Duration of study: The duration of study was six months from 1/1/2010 to30th/6/2010. Setting: Department of Gynae and obstetrics, DHQ hospital, Faisalabad. Subjects and methods: All patients fulfilling inclusioncriteria were included in study and before cesarean section Hb was carried out and Patients were divided into two groups, GP , and GP . GP 1 2 1was given 800 ug MP per rectal just before starting cesarean Section and GP was given intravenous ergometrine at delivery of head or anterior 2shoulder. Blood loss was measured objectively after delivery of the baby with help of standard size kidney tray of 500cc and post operative Hbwas Carried out on 3rd post operative day. Results: 187 Patients were randomly allocated in GP and GP each. In GP , misoprostol was given 1 2 1800 μg per rectal just before starting cesarean section and 13 patients (7%) out of 187 have blood loss more than 500ml measured by standardsize kidney tray while in GP intravenous ergometrine was given at delivery of the head and in this group 25 patients (13.5%) out of 187 had 2blood loss more than 500ml, so misoprostol was found to be a better uterotonic than ergometrine for prevention of PPH. On the third postoperative day Hb was carried out and in GP 13 patients (7%) out of 187 had their Hb less than 9 g/dl while in GP 25 patients (13.5%) had Hb less 1 2than 9 g/d1. Conclusions: Mp is stable, cost effective and easily administrable drug and was found to be comparatively more powerfuluterotonic than ergometrine for preventing uterine atony.
The most common complication 0f the third stage of labour is postpartumhaemorrhage, which remains a leading cause of maternal mortality (25.0%), especially indeveloping countries. In developed countries, 3-5% of deliveries are complicated by postpartumhaemorrhage: in developing countries, it is 50 times more common .Third stage of labourwhich exceeds 30 minutes is associated with a significant risk of postpartum haemorrhage andpuerperal infection. The best preventive strategy for these complications is active managementof third stage of labour. Active management includes administration of oxytocin within oneminute of birth of baby. Objectives: To compare the mean blood loss after administration ofintra umbilical oxytocin versus intravenous oxytocin at anterior shoulder for active managementof third stage of labour. Study Design: Randomized controlled trial. Period: Six months from1-1-2013 to 30-06-2013. Setting: Department of Obstetrics and Gynaecology, Unit-III JinnahHospital Lahore. Methodology: 100 patients fulfilling selection criteria were included in thestudy from labour room. These patients were randomly divided into two groups by usinglottery method. Group-A, 50 patients were administered 10 units of oxytocin diluted in 20ml ofnormal saline intraumbilically and group-B, 50 patients were administered 5 units of oxytocinintravenous stat at anterior shoulder. Total blood loss was noted after complete delivery ofplacenta. Results: Mean age was 25.0±3.9 and 24.4±3.5 in group-A and B, respectively. Meangestational age was 38.20±0.96 weeks in group-A and 38.40±0.94 weeks in group-B. Meanblood loss in intraumbilical oxytocin group was 311.20±27.23 ml and in intravenous oxytocingroup mean blood loss was 373.60±66.47 ml. There was statistically significant differencebetween two groups (p<0.001). In group-A 15 patients (30.0%) and in group-B 20 patients(40.0%) were primigravida while remaining patients were multigravida. Conclusion: The usageof intraumbilical oxytocin in active management of third stage of labour is beneficial in reducingthe blood loss in third stage and thus helps in preventing postpartum haemorrhage.
