Effectiveness of uterine tamponade devices for refractory postpartum haemorrhage after vaginal birth: a systematic review
BJOG : an international journal of obstetrics and gynaecology. 2021
OBJECTIVES To evaluate uterine tamponade devices' effectiveness for atonic refractory postpartum haemorrhage (PPH) after vaginal birth and the effect of including them in institutional protocols. SEARCH STRATEGY PubMed, EMBASE, CINAHL, LILACS, POPLINE, from inception to January 2021. STUDY SELECTION randomised and non-randomised comparative studies. OUTCOMES composite outcome including surgical interventions (artery ligations, compressive sutures or hysterectomy) or maternal death, and hysterectomy. RESULTS all included studies were at high risk of bias. The certainty of the evidence was rated as very low to low. One randomised study measured the effect of the condom-catheter balloon compared to standard care and found unclear results for the composite outcome (RR 2.33, 95%CI 0.76-7.14) and hysterectomy (RR 4.14, 95%CI 0.48-35.93). Three comparative studies assessed the effect of including UBTs in institutional protocols. A stepped wedge cluster RCT suggested an increase in the composite outcome (RR 4.08, 95%CI 1.07-15.58) and unclear results for hysterectomy (RR 4.38, 95% CI 0.47-41.09) with the use of the condom-catheter or surgical glove balloon. One non-randomised study showed unclear effects on the composite outcome (RR 0.33, 95%CI 0.11-1.03) and hysterectomy (RR 0.49, 95%CI 0.04-5.38) after the inclusion of the Bakri balloon. The second non-randomised study found unclear effects on the composite outcome (RR 0.95, 95%CI 0.32-2.81) and hysterectomy (RR 1.84, 95%CI 0.44-7.69) after the inclusion of Ebb or Bakri balloon. CONCLUSIONS the effect of uterine tamponade devices for the management of atonic refractory PPH after vaginal delivery is unclear, as is the role of the type of device and the setting.
Suction Tube Uterine Tamponade' for treatment of refractory postpartum hemorrhage: Internal feasibility and acceptability pilot of a randomized clinical trial
International journal of gynaecology and obstetrics: the official organ of the International Federation of Gynaecology and Obstetrics. 2021
OBJECTIVE To assess feasibility and acceptability of a novel, low-cost 'Suction Tube Uterine Tamponade' (STUT) treatment for refractory postpartum hemorrhage (PPH). METHODS We allocated patients with refractory PPH by randomly ordered envelopes to STUT or routine uterine balloon tamponade (UBT, Ellavi free-flow system) in ten hospitals in South Africa. In the STUT group, a 24FG Levin stomach tube was inserted into the uterine cavity and vacuum created with a vacuum pump or manual vacuum aspiration syringe. RESULTS For this internal pilot study, 12 participants were allocated to STUT and 12 to UBT. Insertion failed in one of each group and was recorded as difficult in 3/10 STUT and 4/9 UBT insertions respectively (5 missing data). There were two laparotomies and one intensive care unit admission in the UBT group. Pain during STUT insertion was graded as none/mild in 9/10 and severe in 1/10. The experience of the STUT procedure was graded as fine in 4/11 and 'uncomfortable but acceptable' in 7/11. CONCLUSION STUT is feasible and acceptable, justifying continuation of our trial. These data will also inform a large World Health Organization trial to test effectiveness of uterine tamponade methods. The numbers are too small to support any clinical recommendation.
Uterotonic agents for first-line treatment of postpartum haemorrhage: a network meta-analysis
The Cochrane database of systematic reviews. 2020;11:Cd012754
BACKGROUND Postpartum haemorrhage (PPH), defined as a blood loss of 500 mL or more after birth, is the leading cause of maternal death worldwide. The World Health Organization (WHO) recommends that all women giving birth should receive a prophylactic uterotonic agent. Despite the routine administration of a uterotonic agent for prevention, PPH remains a common complication causing one-quarter of all maternal deaths globally. When prevention fails and PPH occurs, further administration of uterotonic agents as 'first-line' treatment is recommended. However, there is uncertainty about which uterotonic agent is best for the 'first-line' treatment of PPH. OBJECTIVES To identify the most effective uterotonic agent(s) with the least side-effects for PPH treatment, and generate a meaningful ranking among all available agents according to their relative effectiveness and side-effect profile. SEARCH METHODS We searched the Cochrane Pregnancy and Childbirth's Trials Register, ClinicalTrials.gov, the WHO International Clinical Trials Registry Platform (ICTRP) (5 May 2020), and the reference lists of all retrieved studies. SELECTION CRITERIA All randomised controlled trials or cluster-randomised trials comparing the effectiveness and safety of uterotonic agents with other uterotonic agents for the treatment of PPH were eligible for inclusion. DATA COLLECTION AND ANALYSIS Two review authors independently assessed all trials for inclusion, extracted data and assessed each trial for risk of bias. Our primary outcomes were additional blood loss of 500 mL or more after recruitment to the trial until cessation of active bleeding and the composite outcome of maternal death or severe morbidity. Secondary outcomes included blood loss-related outcomes, morbidity outcomes, and patient-reported outcomes. We performed pairwise meta-analyses and indirect comparisons, where possible, but due to the limited number of included studies, we were unable to conduct the planned network meta-analysis. We used the GRADE approach to assess the certainty of evidence. MAIN RESULTS Seven trials, involving 3738 women in 10 countries, were included in this review. All trials were conducted in hospital settings. Randomised women gave birth vaginally, except in one small trial, where women gave birth either vaginally or by caesarean section. Across the seven trials (14 trial arms) the following agents were used: six trial arms used oxytocin alone; four trial arms used misoprostol plus oxytocin; three trial arms used misoprostol; one trial arm used Syntometrine® (oxytocin and ergometrine fixed-dose combination) plus oxytocin infusion. Pairwise meta-analysis of two trials (1787 participants), suggests that misoprostol, as first-line treatment uterotonic agent, probably increases the risk of blood transfusion (risk ratio (RR) 1.47, 95% confidence interval (CI) 1.02 to 2.14, moderate-certainty) compared with oxytocin. Low-certainty evidence suggests that misoprostol administration may increase the incidence of additional blood loss of 1000 mL or more (RR 2.57, 95% CI 1.00 to 6.64). The data comparing misoprostol with oxytocin is imprecise, with a wide range of treatment effects for the additional blood loss of 500 mL or more (RR 1.66, 95% CI 0.69 to 4.02, low-certainty), maternal death or severe morbidity (RR 1.98, 95% CI 0.36 to 10.72, low-certainty, based on one study n = 809 participants, as the second study had zero events), and the use of additional uterotonics (RR 1.30, 95% CI 0.57 to 2.94, low-certainty). The risk of side-effects may be increased with the use of misoprostol compared with oxytocin: vomiting (2 trials, 1787 participants, RR 2.47, 95% CI 1.37 to 4.47, high-certainty) and fever (2 trials, 1787 participants, RR 3.43, 95% CI 0.65 to 18.18, low-certainty). According to pairwise meta-analysis of four trials (1881 participants) generating high-certainty evidence, misoprostol plus oxytocin makes little or no difference to the use of additional uterotonics (RR 0.99, 95% CI 0.94 to 1.05) and to blood transfusion (RR 0.95, 95% CI 0.77 to 1.17) compared with oxytocin. We cannot rule out an important benefit of using the misoprostol plus oxytocin combination over oxytocin alone, for additional blood loss of 500 mL or more (RR 0.84, 95% CI 0.66 to 1.06, moderate-certainty). We also cannot rule out important benefits or harms for additional blood loss of 1000 mL or more (RR 0.76, 95% CI 0.43 to 1.34, moderate-certainty, 3 trials, 1814 participants, one study reported zero events), and maternal mortality or severe morbidity (RR 1.09, 95% CI 0.35 to 3.39, moderate-certainty). Misoprostol plus oxytocin increases the incidence of fever (4 trials, 1866 participants, RR 3.07, 95% CI 2.62 to 3.61, high-certainty), and vomiting (2 trials, 1482 participants, RR 1.85, 95% CI 1.16 to 2.95, high-certainty) compared with oxytocin alone. For all outcomes of interest, the available evidence on the misoprostol versus Syntometrine® plus oxytocin combination was of very low-certainty and these effects remain unclear. Although network meta-analysis was not performed, we were able to compare the misoprostol plus oxytocin combination with misoprostol alone through the common comparator of oxytocin. This indirect comparison suggests that the misoprostol plus oxytocin combination probably reduces the risk of blood transfusion (RR 0.65, 95% CI 0.42 to 0.99, moderate-certainty) and may reduce the risk of additional blood loss of 1000 mL or more (RR 0.30, 95% CI 0.10 to 0.89, low-certainty) compared with misoprostol alone. The combination makes little or no difference to vomiting (RR 0.75, 95% CI 0.35 to 1.59, high-certainty) compared with misoprostol alone. Misoprostol plus oxytocin compared to misoprostol alone are compatible with a wide range of treatment effects for additional blood loss of 500 mL or more (RR 0.51, 95% CI 0.20 to 1.26, low-certainty), maternal mortality or severe morbidity (RR 0.55, 95% CI 0.07 to 4.24, low-certainty), use of additional uterotonics (RR 0.76, 95% CI 0.33 to 1.73, low-certainty), and fever (RR 0.90, 95% CI 0.17 to 4.77, low-certainty). AUTHORS' CONCLUSIONS The available evidence suggests that oxytocin used as first-line treatment of PPH probably is more effective than misoprostol with less side-effects. Adding misoprostol to the conventional treatment of oxytocin probably makes little or no difference to effectiveness outcomes, and is also associated with more side-effects. The evidence for most uterotonic agents used as first-line treatment of PPH is limited, with no evidence found for commonly used agents, such as injectable prostaglandins, ergometrine, and Syntometrine®.
Women with postpartum haemorrhage (PPH), (7 studies, n= 3,738).
Systematic review and network meta-analysis identifying the most effective uterotonic agent(s) for first-line PPH treatment with the least side-effects.
Oxytocin alone; misoprostol plus oxytocin; misoprostol alone; and Syntometrine® (oxytocin and ergometrine fixed-dose combination) plus oxytocin infusion.
Pairwise meta-analysis of two trials (n= 1,787), suggested that misoprostol, as first-line treatment uterotonic agent, probably increases the risk of blood transfusion compared with oxytocin. Low-certainty evidence suggested that misoprostol administration may increase the incidence of additional blood loss of 1,000 mL or more. The data comparing misoprostol with oxytocin was imprecise, with a wide range of treatment effects for the additional blood loss of 500 mL or more, maternal death or severe morbidity. The risk of side-effects may be increased with the use of misoprostol compared with oxytocin. According to pairwise meta-analysis of four trials (n= 1,881 participants) generating high-certainty evidence, misoprostol plus oxytocin made little or no difference to the use of additional uterotonics and to blood transfusion compared with oxytocin.
Maternal characteristics and causes associated with refractory postpartum haemorrhage after vaginal birth: a secondary analysis of the WHO CHAMPION trial data
BJOG : an international journal of obstetrics and gynaecology. 2019
OBJECTIVE To assess the maternal characteristics and causes associated with refractory postpartum haemorrhage (PPH). DESIGN Secondary analysis of the WHO CHAMPION trial data. SETTING 23 hospitals in 10 countries. POPULATION Women from the CHAMPION trial who received uterotonics as first line treatment of PPH. METHODS We assessed the association between socio-demographic, pregnancy and childbirth factors and refractory PPH, and compared the causes of PPH between women with refractory PPH, and women responsive to first-line PPH treatment. MAIN OUTCOME MEASURES Maternal characteristics; causes of PPH RESULTS Women with labour induced or augmented with uterotonics (aOR 1.35; 95% CI 1.07 - 1.72), with episiotomy or tears requiring suturing (aOR 1.82; 95% CI 1.34 - 2.48), and who had babies with birthweights ≥ 3500 g (aOR 1.33; 95% CI 1.04 - 1.69), showed significantly higher odds of refractory PPH compared to the reference categories in the multivariate analysis adjusted by center and trial arm. While atony was the sole PPH cause in 53.2% (116/218) of the women in the responsive PPH group, it accounted for only 31.5% (45/143) of the causes in the refractory PPH group. Conversely, tears were the sole cause in 12.8% (28/218) and 28% (40/143) of the responsive PPH and refractory PPH groups respectively. Placental problems were the sole cause in 11% and 5.6% in the responsive and refractory PPH groups respectively. CONCLUSION Women with refractory PPH showed a different pattern of maternal characteristics and PPH causes compared to those with first-line treatment responsive PPH.
Randomized feasibility study of suction-tube uterine tamponade for postpartum hemorrhage
International journal of gynaecology and obstetrics: the official organ of the International Federation of Gynaecology and Obstetrics. 2019
OBJECTIVE To identify an inexpensive catheter suitable for uterine suction tamponade (UST) for postpartum hemorrhage and assess its functionality. METHODS Randomized, single-center, double-blind feasibility study in East London, South Africa, among 45 women undergoing cesarean delivery between October and November 2018. A search of medical supply websites for catheters with predefined characteristics (inexpensive, flexible, wide-bore, circumferentially-arranged side apertures, rounded tip) identified the FG36 Levin stomach tube. During cesarean, the tube was placed in the uterus and connected transvaginally to a suction unit. Participants were randomized via a computer-generated random sequence to early (after uterine closure; n=24) or delayed (after skin closure; n=21) UST. RESULTS The tube functioned well with respect to stability in the uterus and aspirating blood from the uterine cavity without blockage. Blood loss was similar between the groups (mean difference, 7.3 mL; 95% confidence interval, -61 to 75; P=0.433), as were secondary outcomes. There were no complications. Absolute effectiveness was not tested because there was no non-suction group. CONCLUSION The FG36 Levin tube was found to be a suitable device for "suction-tube uterine tamponade". There was no difference in functionality between early and late UST. Future trials should assess the effectiveness of this approach for postpartum hemorrhage. This article is protected by copyright. All rights reserved.
Uterotonic Drugs for the Prevention of Postpartum Haemorrhage: A Cost-Effectiveness Analysis
PharmacoEconomics - open. 2018
OBJECTIVE The objective of this study was to estimate the relative cost effectiveness for the full range of uterotonic drugs available for preventing postpartum haemorrhage (PPH). METHODS A model-based economic evaluation was constructed using effectiveness data from a network meta-analysis, and supplemented by the literature. A UK National Health Service (NHS) perspective was adopted for the analysis, which is based on UK costs from published sources. The primary outcome measure is cost per case of PPH avoided (≥ 500 mL blood loss), with secondary outcome measures of cost per case of severe PPH avoided (≥ 1000 mL) and cost per major outcome (surgery) averted also being analysed. RESULTS Carbetocin is shown to be the most effective strategy. Excluding adverse events, 'ergometrine plus oxytocin' was shown to be the least costly strategy. The incremental cost-effectiveness ratio for prevention of PPH with carbetocin compared with prevention with 'ergometrine plus oxytocin' was pound1889 per case of PPH ≥ 500 mL avoided; pound30,013 per case of PPH ≥ 1000 mL avoided; and pound1,172,378 per major outcome averted. Including adverse events in the analysis showed oxytocin to be the least costly strategy. The incremental cost-effectiveness ratio for prevention of PPH with carbetocin compared with prevention with oxytocin was pound928 per case of PPH ≥ 500 mL avoided; pound22,900 per case of PPH ≥ 1000 mL avoided; and pound894,514 per major outcome averted. CONCLUSION The results suggest carbetocin, oxytocin and 'ergometrine plus oxytocin' could all be favourable options for being the most cost-effective strategy for preventing PPH. Carbetocin could be the preferred choice, especially if the price of carbetocin decreased. Mixed findings mean a clear-cut conclusion cannot be made as to which uterotonic is the most cost effective. Future research should focus on collecting more robust evidence on the probability of having adverse events from the uterotonic drugs, and on adapting the model for low- and middle-income countries.
Uterotonic agents for preventing postpartum haemorrhage: a network meta-analysis
The Cochrane database of systematic reviews. 2018;12:Cd011689
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.
Heat-Stable Carbetocin versus Oxytocin to Prevent Hemorrhage after Vaginal Birth
The New England Journal of Medicine. 2018;379((8):):743-752
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 mug) with oxytocin (at a dose of 10 IU) administered immediately after vaginal birth. Both drugs were kept in cold storage (2 to 8 degrees 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 .).
Tranexamic acid for preventing postpartum haemorrhage
Cochrane Database of Systematic Reviews.. 2015;((6)):CD007872.
BACKGROUND Postpartum haemorrhage (PPH) is a common and potentially life-threatening complication of labour. Several options for preventing PPH are available, but further advances in this field are important, especially the identification of safe, easy to use and cost-effective regimens. Tranexamic acid (TA), which is an antifibrinolytic agent that is used widely to prevent and treat haemorrhage, merits evaluation to assess whether it meets these criteria. OBJECTIVES To determine, from the best available evidence, whether TA is effective and safe for preventing PPH in comparison to placebo or no treatment (with or without uterotonic co-treatment), or to uterotonic agents. SEARCH METHODS We searched the Cochrane Pregnancy and Childbirth Group's Trials Register (28 January 2015) and reference lists of retrieved studies. SELECTION CRITERIA All published, unpublished and ongoing randomised controlled trials (RCTs) evaluating the use of TA alone or in addition to uterotonics in the third stage of labour or during caesarean section (CS) to prevent PPH. DATA COLLECTION AND ANALYSIS Two review authors independently assessed for inclusion all the potential studies identified as a result of the search strategy. We entered the data into Review Manager software and checked for accuracy. MAIN RESULTS Twelve trials involving 3285 healthy women at low risk of excessive bleeding undergoing elective CS (nine trials, 2453 participants) or spontaneous birth (three trials, 832 participants) satisfied inclusion criteria and contributed data to the analysis. All participants received routine prophylactic uterotonics in accordance with the local guideline in addition to TA or placebo or no intervention. Overall, included studies had moderate risk of bias for random sequence generation, allocation concealment, blinding, selective reporting and low risk of bias for incomplete data. The quality of evidence was also as assessed using GRADE.Blood loss greater than 400 mL or 500 mL, and more than 1000 mL was less common in women who received TA versus placebo or no intervention (risk ratio (RR) 0.52, 95% confidence interval (CI) 0.42 to 0.63, six trials, 1398 women; moderate quality evidence) and (RR 0.40, 95% CI 0.23 to 0.71, six trials, 2093 women; moderate quality evidence), respectively. TA was effective in decreasing the incidence of blood loss greater than 1000 mL in women who had undergone CS (RR 0.43, 95% CI 0.23, 0.78, four trials, 1534 women), but not vaginal birth (RR 0.28, 95% CI 0.06, 1.36, two trials 559 women). The effect of TA on blood loss greater than 500 mL or 400 mL was more pronounced in the group of women having vaginal birth than in women who had CS. Mean blood loss (from delivery until two hours postpartum) was lower in women who received TA versus placebo or no intervention (mean difference MD - 77.79 mL, 95% CI -97.95, -57.64, five trials, 1186 women) and this effect was similar following vaginal birth and CS.Additional medical interventions (moderate quality evidence) and blood transfusions were less frequent in women receiving TA versus placebo or no interventions. Mild side effects such as nausea, vomiting, dizziness were more common with the use of TA (moderate quality evidence). The effect of TA on maternal mortality, severe morbidity and thromboembolic events is uncertain (low quality evidence). AUTHORS' CONCLUSIONS TA (in addition to uterotonic medications) decreases postpartum blood loss and prevents PPH and blood transfusions following vaginal birth and CS in women at low risk of PPH based on studies of mixed quality. There is insufficient evidence to draw conclusions about serious side effects, but there is an increase in the incidence of minor side effects with the use of TA. Effects of TA on thromboembolic events and mortality as well as its use in high-risk women should be investigated further.