Plain language summary
Tranexamic acid for preventing bleeding after delivery
Postpartum haemorrhage is a common and an occasionally life-threatening complication of labour. The majority of women receive drugs that directly stimulate the uterus (prophylactic uterotonics) during childbirth to prevent haemorrhages resulting from failure of the uterine muscle to contract normally (uterine atony).
Tranexamic acid (TA) is used to decrease blood loss in surgery and health conditions associated with increased bleeding. It works by helping to prevent the breakdown of fibrin and maintenance of blood clots. This review found that TA was also effective in reducing excessive blood loss, need for additional medical interventions to control bleeding and blood transfusions after a mother gave birth based on studies of mixed quality. Twelve trials (3285 participants) were included in the review. TA was given before caesarean section in nine randomised trials or following the vaginal birth of a baby (three randomised trials) to generally healthy women.
TA decreased blood loss greater than 400 mL or greater than 500 mL and this effect was more apparent with vaginal births. The studies had methodological shortcomings. Blood loss greater than 1000 mL decreased with the use of TA in six trials (2093 women), however, the difference was most obvious in caesarean section (two trials, 1400 women) and not in vaginal birth in which there were few such outcomes (one trial, 439 women). Mean blood loss decreased with the use of TA by 77 mL, overall (five studies, 1186 women) and with both vaginal and caesarean section births. This finding was based on studies with methodological limitations.
The studies were too small to detect the effect of TA on maternal death or blood clots. Mild side effects, which include diarrhoea, nausea and vomiting, were more common in women who received TA versus placebo or no intervention. No differences in blood loss and side effects were found when two different doses of TA were evaluated. Further larger studies are needed to investigate the effects of TA on maternal deaths and formation of clots in the blood (thromboembolism).
Resumen en términos sencillos
Ácido tranexámico para la prevención de la hemorragia posparto
La hemorragia posparto es una complicación frecuente y, en ocasiones, potencialmente mortal del trabajo de parto. La mayoría de las pacientes recibe fármacos que estimulan directamente al útero (uterotónicos profilácticos) durante el parto para prevenir las hemorragias debido al fracaso del músculo uterino de contraerse normalmente (atonía uterina).
El ácido tranexámico (AT) se utiliza para reducir la pérdida de sangre en cirugía y en afecciones asociadas con un aumento de la hemorragia. Funciona al ayudar a prevenir la descomposición de la fibrina y mantener los coágulos sanguíneos. Esta revisión encontró que el AT también fue eficaz para reducir la pérdida de sangre excesiva, la necesidad de intervenciones médicas adicionales para controlar la hemorragia y las transfusiones de sangre después del parto, según estudios de calidad mixta. Se incluyeron 12 ensayos en la revisión (3285 participantes). El AT se administró antes de la cesárea en nueve ensayos aleatorios o después del parto vaginal del neonato (tres ensayos aleatorios) a pacientes generalmente sanas.
El AT redujo la pérdida de sangre mayor de 400 ml o mayor de 500 ml y este efecto fue más evidente en los partos vaginales. Los estudios presentaron deficiencias metodológicas. La pérdida de sangre mayor de 1000 ml disminuyó con la administración de AT en seis ensayos (2093 pacientes); sin embargo, la diferencia fue muy evidente en la cesárea (dos ensayos, 1400 pacientes) y no en el parto vaginal, en el que se observaron pocos de estos resultados (un ensayo, 439 mujeres). La pérdida de sangre media disminuyó con la administración de AT en 77 ml, en general (cinco estudios, 1186 pacientes) y en el parto vaginal y la cesárea. Este resultado se basó en estudios con limitaciones metodológicas.
Los estudios fueron demasiado pequeños para detectar el efecto del AT sobre la muerte materna o los coágulos sanguíneos. Los efectos secundarios leves que incluyen diarrea, náuseas y vómitos, fueron más frecuentes en las pacientes que recibieron AT versus placebo o ninguna intervención. No se encontraron diferencias en la pérdida de sangre y los efectos secundarios cuando se evaluaron dos dosis diferentes de AT. Se necesitan estudios adicionales más grandes para investigar los efectos del AT sobre las muertes maternas y la formación de coágulos en la sangre (tromboembolia).
Notas de traducción
La traducción y edición de las revisiones Cochrane han sido realizadas bajo la responsabilidad del Centro Cochrane Iberoamericano, gracias a la suscripción efectuada por el Ministerio de Sanidad, Servicios Sociales e Igualdad del Gobierno español. Si detecta algún problema con la traducción, por favor, contacte con Infoglobal Suport, email@example.com.
L'acide tranexamique pour la prévention des saignements après l'accouchement
L'hémorragie post-partum est un problème courant et une complication engageant parfois le pronostic vital lors de l'accouchement. La majorité des femmes reçoivent des médicaments qui stimulent directement l'utérus (des médicaments prophylactiques utérotoniques) durant l'accouchement pour prévenir les hémorragies résultant de l'incapacité des muscles de l'utérus à se contracter normalement (l'atonie utérine).
L'acide tranexamique (ATX) est utilisé pour réduire les pertes de sang au cours des opérations chirurgicales ainsi qu'en cas d'affections associées à des saignements. Il fonctionne en aidant à prévenir la dégradation de la fibrine et en préservant les caillots sanguins. Cette revue a découvert des études de qualité mixte indiquant que l'ATX était également efficace pour réduire les pertes de sang excessives, le besoin de recourir à des interventions médicales supplémentaires ou à des transfusions sanguines pour contrôler les saignements après qu'une mère ait donné naissance. Douze essais (3285 participants) ont été inclus dans la revue. L'ATX a été administré avant une césarienne dans neuf essais randomisés ou après l'accouchement par voie basse d'un bébé (trois essais randomisés) à des femmes généralement en bonne santé.
L'ATX a réduit les pertes de sang supérieures à 400 ml ou 500 ml, et cet effet était plus marqué lors des accouchements par voie basse. Les études présentaient des lacunes méthodologiques. Les pertes de sang supérieures à 1000 ml étaient moins fréquentes lorsque l'ATX avait été utilisé dans six essais (2093 femmes), cependant, la différence était plus évidente en cas de césariennes (deux essais, 1400 femmes) et invisible en cas d'accouchements par voie basse durant lesquels ces événements étaient restés rares (un essai, 439 femmes). La perte sanguine moyenne était de manière générale inférieure de 77 ml lorsque l'ATX avait été utilisé (cinq études, 1186 femmes) à la fois lors des accouchements par voie basse et par césarienne. Cette constatation était basée sur des études présentant des limitations méthodologiques.
Les études étaient trop petites pour détecter l'effet de l'ATX sur la mortalité maternelle ou les caillots sanguins problématiques. Des effets secondaires légers, comprenant des diarrhées, des nausées et des vomissements, étaient plus fréquents chez les femmes ayant reçu de l'ATX par rapport à un placebo ou à l'absence d'intervention. Aucune différence en termes de perte de sang et au niveau des effets secondaires n'a été trouvée lorsque deux doses différentes d'ATX ont été évaluées. D'autres études plus larges sont nécessaires pour étudier les effets de l'ATX sur la mortalité maternelle et la formation de caillots sanguins problématiques dans le sang (des thromboembolies).
Notes de traduction
Traduction réalisée par Martin Vuillème et révisée par Cochrane France
Traneksaminska kiselina za sprječavanje krvarenja nakon porođaja
Krvarenje poslije porođaja je česta i ponekad po život opasna komplikacija. Većina žena dobiva lijekove koji izravno stimuliraju maternicu (profilaktički uterotonici) tijekom porođaja da bi se spriječila krvarenja zbog nemogućnosti mišića maternice da se uredno stežu (mlohavost mišića maternice).
Traneksaminska kiselina se koristi za smanjenje gubitka krvi u kirurgiji i zdravstvenim stanjima povezanim s povećanim krvarenjem. Djeluje tako što pomaže spriječiti razgradnju fibrina i održava krvne ugruške. Ovaj je Cochrane sustavni pregled utvrdio da je Traneksaminska kiselina također učinkovita u smanjenju prekomjernog gubitka krvi, potrebe za dodatnim medicinskim intervencijama za kontrolu krvarenja i transfuzije krvi nakon porođaja, a taj se zaključak temelji na istraživanjima mješovite kvalitete. U sustavni je pregled uključeno 12 studija (3.285 sudionika). Traneksaminska kiselina je davana prije carskoga reza u 9 randomiziranih studija ili nakon vaginalnog rođenja djeteta (tri randomizirane studije), ženama dobrog općeg zdravlja.
Traneksaminska kiselina smanjila je gubitak krvi veći od 400 mL, ili veći od 500 mL, a taj učinak bio je očitiji pri vaginalnim rođenjima. Studije su imale metodoloških nedostataka. Gubitak krvi veći od 1000 mL smanjio se s primjenom traneksaminske kiseline u šest istraživanja (2.093 žena), međutim, razlika je bila najočitija u žena podvrgnutih carskom rezu (dva istraživanja, 1.400 žena), za razliku od vaginalnih rođenja u kojima je bilo malo takvih rezultata zabilježeno (jedno istraživanje, 439 žena). Prosječno je primjena traneksaminske kiseline smanjila gubitak krvi za 77 mL (5 studija, 1.186 žena) i to u žena koje su rađale i vaginalno i carskim rezom. Taj zaključak se temelji na studijama s metodološkim ograničenjima.
Studije su bile premale da bi otkrile učinke traneksaminske kiseline na smrt majke ili pojavu krvnih ugrušaka. Blage nuspojave, koje uključuju proljev, mučninu i povraćanje, bile su češće u žena koje su primale traneksaminsku kiselinu u odnosu na žene koje su primile placebo ili nikakvu terapiju. Nisu pronađene razlike u gubitku krvi i nuspojavama kada su procijenjene dvije različite doze traneksaminske kiseline. Potrebne su daljnje veće studije da bi se ispitali učinci transeksamske kiseline na smrt majke i formiranje krvnih ugrušaka u krvi (tromboemolija).
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Resumo para leigos
Ácido tranexâmico para prevenir a hemorragia pós-parto
A hemorragia pós-parto é uma complicação comum e que às vezes coloca em risco a vida da mulher. Para prevenir esse tipo de hemorragia, a maioria das mulheres recebe remédios para contrair o útero (uterotônicos profiláticos) logo após o parto. Isso evita as hemorragias que acontecem quando o útero não consegue contrair normalmente (uma condição chamada “atonia uterina”).
O ácido tranexâmico (AT) é usado para diminuir a perda de sangue durante cirurgias e em outras condições de saúde em que há aumento de hemorragias. Ele funciona ajudando a prevenir a quebra da fibrina (uma proteína fibrosa envolvida no controle de sangramentos) e na preservação dos coágulos sanguíneos (que são importantes para garantir que o sangramento cesse e ocorra a cicatrização). Esta revisão sistemática da literatura constatou que o AT também foi eficaz em reduzir a perda de sangue excessiva, a necessidade de intervenções médicas adicionais para controlar o sangramento e as transfusões de sangue depois de uma mãe dar à luz. No entanto, esses resultados estão baseados em estudos de qualidade variada. Esta revisão incluiu 12 ensaios clínicos randomizados envolvendo 3.285 mulheres saudáveis. Em 9 estudos, o AT foi dado antes da cesariana e em 3 estudos, ele foi dado após o parto normal.
O AT diminuiu a perda de sangue superior a 400 ml ou a 500 mL, e este efeito foi mais claro em partos normais. Porém, esses estudos tiveram falhas metodológicas. De acordo com os resultados de 6 estudos (incluindo 2.093 mulheres), o TA reduziu a perda de sangue superior a 1000 mL. Essa diferença foi mais evidente nas cesarianas (2 estudos, 1.400 mulheres) do que nos partos normais, já que ocorreram poucos episódios de sangramento grave nesse tipo de parto (1 estudo, 439 mulheres). A média de perda de sangue diminuiu em torno de 77 mL com o uso de AT, tanto em termos globais (5 estudos, 1.186 mulheres) como nos partos normais e cesarianos. Só que esta conclusão foi baseada em estudos com limitações metodológicas.
Os estudos foram pequenos demais para detectar algum efeito do AT sobre a morte materna ou sobre a formação de coágulos sanguíneos no corpo da mulher. Efeitos colaterais leves, tais como diarreia, náuseas e vômitos, foram mais comuns nas mulheres que receberam AT do que naquelas que receberam placebo (medicamento falso) ou nada (nenhuma intervenção). Não houve diferenças entre duas doses diferentes de AT quanto à perda sanguínea e efeitos colaterais. Estudos maiores são necessários para investigar os efeitos do AT sobre mortes e formação de coágulos (tromboembolismo) no sangue materno.
Notas de tradução
Tradução do Centro Cochrane do Brasil (Camila Bellão)
Ringkasan bahasa mudah
Asid tranexamic untuk mencegah perdarahan postpartum
Perdarahan postpartum adalah lazim dan kadang-kadang menjadi komplikasi pelahiran yang mengancam nyawa. Majoriti wanita menerima ubat-ubatan yang terus merangsang rahim (profilaksis uterotonik) semasa bersalin untuk mencegah perdarahan akibat kegagalan otot rahim mengecut seperti biasa (atoni rahim).
Asid tranexamic (TA) digunakan untuk mengurangkan kehilangan darah dalam pembedahan dan masalah kesihatan yang berkaitan dengan perdarahan berlebihan. Ia berfungsi membantu mengelakkan kerosakan fibrin dan mengekalkan klot darah. Ulasan ini mendapati TA juga efektif dalam mengurangkan kehilangan darah berlebihan, keperluan intervensi perubatan tambahan untuk mengawal perdarahan dan transfusi darah selepas ibu bersalin berasaskan kajian-kajian yang berlainan kualitinya. Dua belas kajian (3285 peserta) telah dimasukkan dalam ulasan ini. TA telah diberikan sebelum pembedahan caesarean dalam sembilan kajian rawak atau selepas kelahiran faraj (tiga kajian rawak) bagi wanita yang secara amnya sihat.
TA mengurangkan kehilangan darah lebih daripada 400 ml atau lebih daripada 500 ml dan kesan ini lebih jelas dengan kelahiran faraj. Kajian-kajian tersebut mempunyai kelemahan metodologi. Kehilangan darah melebihi 1000 ml dikurangkan dengan penggunaan TA dalam enam kajian (2093 wanita), namum, perbezaan adalah paling jelas dalam pembedahan caesarean (dua kajian, 1400 wanita) dan bukan dalam kelahiran faraj di mana terdapat sedikit hasil sedemikian(satu kajian, 439 wanita). Purata kehilangan darah menurun sebanyak 77 ml dengan penggunaan TA, keseluruhan (lima kajian, 1186 wanita) dan untuk kedua-dua kelahiran faraj dan kelahiran pembedahan caesarean. Dapatan ini adalah berdasarkan kajian-kajian dengan batasan metodologi.
Kajian-kajian adalah terlalu kecil untuk mengesan kesan TA terhadap kematian ibu atau klot darah. Kesan-kesan sampingan ringan, termasuk cirit-birit, loya dan muntah adalah lebih blazim dalam kalangan wanita yang menerima TA berbanding plasebo atau tiada intervensi. Tiada perbezaan dalam kehilangan darah dan kesan-kesan sampingan apabila dua dos TA berbeza dinilai. Kajian lanjutan yang lebih besar diperlukan untuk menyiasat kesan TA terhadap kematian ibu dan pembetukan darah beku dalam darah (thromboembolism).
Diterjemahkan oleh Julie Yeo (Taylor’s University, Malaysia). Disunting oleh Noorliza Mastura Ismail (Kolej Perubatan Melaka-Manipal). Untuk sebarang pertanyaan berkaitan terjemahan ini sila hubungi email@example.com
Description of the condition
Postpartum haemorrhage (PPH) remains a leading cause of maternal mortality, especially in developing countries (Ronsmans 2006). The majority (86%) of these deaths are preventable according to the committee for confidential enquiries into maternal death in South Africa (Confidential enquiries 2012). The incidence of PPH according to a recent study is 1.2% (Sheldon 2014). Up to 75% of PPH cases are caused by uterine atony (Ducloy-Bouthors 2011), However, the cases of mortality due to obstetric haemorrhage are mainly related to other causes of PPH (Confidential enquiries 2012). Uterine atony was found only in 6.4% of cases of maternal death related to obstetric haemorrhage. Other conditions such as abruption, placenta praevia, ruptured uterus, retained placenta, morbidly adherent placenta, vaginal and cervical trauma, inverted uterus, bleeding during and after caesarean section (CS) are the cause of the vast majority of maternal deaths (Confidential enquiries 2012). Considerable efforts to assure wide-spread access to uterotonics have been successful and the majority of women receive prophylactic uterotonics during childbirth (Sheldon 2014).
Current alternatives to tranexamic acid (TA) in preventing PPH include active management of the third stage of labour (involving administration of a prophylactic oxytocic before delivery of the placenta, and usually cord clamping and cutting, and controlled traction of the umbilical cord, over passive management: allowing the placenta to deliver spontaneously or aiding by gravity or nipple stimulation), uterotonics and prostaglandins. Widely used active management of labour is supported by a Cochrane review that showed reduced incidence of PPH greater than 1000 mL with this intervention (Begley 2015). However, assessment of individual components of active management of labour failed to identify the positive effects of early cord clamping on the amount of blood loss and the incidence of PPH in another Cochrane review (McDonald 2013). Controlled cord traction in comparison to standard placental expulsion does not decrease the incidence of PPH, but has a positive effect on the rate of retained placenta and intensity of pain and discomfort in the third stage of labour (Deneux-Tharaux 2013). On the other hand, prophylactic oxytocin decreases the incidence of PPH, therefore, it is the uterotonic component of the active management of the third stage of labour that actually prevents PPH. There is limited evidence to support the effect of prophylactic oxytocin over ergot alkaloids on blood loss, but less side effects are reported with oxytocin use versus ergot alkaloids. There is no evidence supporting combined use of oxytocin and ergot alkaloids. Oral or sublingual misoprostol is effective in reducing the incidence of severe PPH when compared to placebo, but is less effective than uterotonic agents Tunçalp 2012. However, the issue of maternal death due to PPH remains unresolved in low-resource settings. Attempts to address the problem need to go beyond the use of uterotonic drugs.
Description of the intervention
Tranexamic acid (TA) could be used in addition to current prophylactic uterotonic drugs in the third stage of labour, particularly in women at high risk of PPH, for example with placenta praevia, placental abruption, anaemia, multiple pregnancy or CS. It is used in the dose of 10 mg/kg given intravenously (IV) immediately after delivery of the baby (Astedt 1987) or in women undergoing CS, prior to the skin incision or after delivery of the baby. TA acts within two to three hours after oral administration and immediately after IV administration, and its half-life is two to 10 hours (Jurema 2008). The oral route of administration is possible, but it is not ideal in the third stage of labour, when an immediate effect of the drug is required. The sublingual route may be an alternative, but has not, to our knowledge, been investigated.
Prophylactic use of TA rather than waiting for a diagnosis of PPH is supported by evidence from the CRASH-2 study which found that TA was more effective the earlier it was administered in decreasing death due to bleeding in trauma patients (CRASH-2 trial collaborators).
The use of TA acid for the treatment of PPH is covered by another Cochrane review (Mousa 2014).
How the intervention might work
TA potentiates the blood clotting system and is used to treat and prevent bleeding. The mechanism of action of TA is related to its antifibrinolytic effect, which makes this drug potentially very effective in the third stage of labour. TA is an inhibitor of fibrinolysis that blocks the lysine-binding site of plasminogen to fibrin (Astedt 1987; Longstaff 1994). During placental delivery, rapid degradation of fibrinogen and fibrin occurs, as well as an increase in the activation of plasminogen activators and fibrin degradation products due to activation of the fibrinolytic system. This activation can last up to six to 10 hours postpartum, which may cause more haemorrhage. The antifibrinolytic effect of TA in the third stage of labour could make it a safe and effective alternative or adjunct to other regimens currently used in the third stage of labour for prevention of PPH.
TA could reduce blood loss associated with complications such as placenta praevia and lower genital tract trauma, as well as bleeding from the uterine body placental site. Use of TA could potentially have prevented some PPH cases if it was given to women with risk factors for PPH (Peitsidis 2011). Therefore, it may be particularly useful in preventing cases of PPH due to factors other than uterine atony, where uterotonic drugs would not be effective.
TA is an effective agent for the reduction of blood loss, which has been widely used in various areas of medicine. It has been used to decrease blood loss for many years in cases of haemorrhage, and is reported to reduce intraoperative and postoperative blood loss (Boylan 1996; Karski 1995; Katsaros 1996; Reid 1997; Vacharaksa 2002). TA is associated with a significant reduction in objective measurements of heavy menstrual bleeding when compared to placebo or other medical therapies (non-steroidal antiinflammatory drugs (NSAIDS), oral luteal phase progestagens and ethamsylate) according to a Cochrane review (Lethaby 2000).The concerns regarding the side effects of tranexamic acid, and in particular, thromboembolic events are difficult to address because of their rare occurrence and need for large trials to be able to explore the issue adequately. The CRASH-2 trial collaborators trial did not assess the risk of thromboembolic events associated with TA. The incidence of thromboembolic events was reported as low in a large retrospective study assessing different postoperative prophylactic anticoagulation regimens in patients with the use of TA undergoing primary total hip and knee arthroplasty (Gillette 2013). Ker and co-authors reported that effects of TA on thromboembolic events was uncertain (deep vein thrombosis risk ratio (RR) 0.86, 95% confidence interval (CI) 0.52, 1.39 and pulmonary embolism RR 0.61, 95% CI 0.25, 1.47) based on meta-analysis of 129 trials involving 10,488 surgical patients (Ker 2012). A Cochrane review on the use of antifibrinolytics for heavy menstrual bleeding reported no rise in side effects with TA in comparison to placebo, NSAIDS, oral luteal phase progestagens or ethamsylate (Lethaby 2000). The concerns regarding the risk of thromboembolic events related to the use of TA are especially important when this drug is used during the hypercoagulable state of pregnancy and the postpartum period. The MEGA study found that the risk of thromboembolic events was increased five-fold during pregnancy and increased 60-fold in the first three months after delivery compared with non-pregnant women. Deep vein thrombosis of the leg had a 14-fold increase and pulmonary embolism a six-fold increase in pregnancy in this study Pomp 2008. Another large retrospective trial reported the risk of venous thromboembolism to increase by five-fold among pregnant or postpartum women Heit 2008. Three cases of deep vein thrombosis were reported among 144 women (two in the TA group and one in the control group) in a trial on TA for treatment of PPH Ducloy-Bouthors 2011.
Why it is important to do this review
PPH remains an important cause of maternal morbidity and mortality. It is important to establish safe, inexpensive and easily available methods of PPH prevention. Administration of TA IV in the third stage of labour may be one of these methods. A particular advantage of TA is that its effect is not limited to uterine body placental site bleeding, thus, its use does not rely on accurate diagnosis of the site of the bleeding.
TA is a cost-effective drug. A study on total hip arthroplasty reported saving blood transfusion and money (47 Euro per patient) in cases where TA was used prophylactically prior to surgery (Johansson 2005). Using TA before CS may reduce the blood loss as well.
Use of TA for preventing PPH may contribute to a reduction in blood product use, which is associated with multiple risks (transfusion reactions, transmission of blood-borne viruses), is expensive and may be not available when it is needed. In low-resource settings, most of the maternal deaths due to PPH occur in level one hospitals or outside the hospital without any emergency access to formal blood transfusion services. Cost savings could also be gained from avoiding the use of expensive haematological agents such as Factor VIIa, which is establishing its place in the treatment of massive PPH in modern obstetrics in well-resourced settings despite the extreme cost and limited evidence (Welsh 2008).
The side effects described with the use of TA include gastrointestinal symptoms such as diarrhoea, nausea and vomiting that occur in about 10% of patients. Rare complications include hypotension, thrombosis, blurred vision, renal cortical necrosis and retinal artery obstruction (Astedt 1987). A study by Becassy and co-authors reported no side effects associated with TA (Bekassy 1990).
To determine, from the best available evidence, whether tranexamic acid (TA) is effective and safe for preventing postpartum haemorrhage (PPH) in comparison to placebo or uterotonic agents.
Criteria for considering studies for this review
Types of studies
We included all published, unpublished and ongoing randomised controlled trials (RCTs) comparing the use of tranexamic acid (TA) alone or in addition to uterotonics in the third stage of labour or prior to or during caesarean section (CS) to prevent postpartum haemorrhage (PPH). We excluded quasi-RCTs (for example, those randomised by date of birth or hospital number or alternation) from the analysis. We included studies published in abstract if they satisfied other inclusion criteria.
Types of participants
Women undergoing vaginal or CS birth who received TA for prophylaxis of PPH. TA is given immediately after delivery of the baby following vaginal birth or in women undergoing CS, prior to the skin incision.
Types of interventions
Tranexamic acid used for the third stage of labour or at CS to decrease blood loss compared with placebo or other agents such as uterotonics; comparisons of TA dosages or routes of administration.
TA versus placebo/no treatment
TA versus uterotonics
Different dosages of TA
Different routes of administration of TA
Types of outcome measures
1. Blood loss 500 mL or more
2. Blood loss 1000 mL or more
3. Mean blood loss volume (mL)
4. Use of additional medical interventions to control PPH
5. Use of additional surgical interventions to control PPH
6. Blood transfusion (not prespecified)*
7. Maternal death or severe maternal morbidity such as seizure, thromboembolic events, need for intensive care unit admission, hysterectomy, organ failure
8. Mild side effects such as nausea, vomiting, headache, skin reactions
9. Thromboembolic events
*Blood transfusion outcome was added in the current update of the review instead of haemoglobin below 6 g%. Blood transfusion was not included in the protocol and previously published version of the review. The reason behind this change is the importance of blood transfusion as an outcome when evaluating an intervention for preventing haemorrhage. Blood transfusions are used in the treatment of severe haemorrhage, they are costly, associated with significant adverse reactions and may not be available in low-resource settings. Blood transfusion is an outcome assessed in other Cochrane reviews on PPH (Mousa 2014; Tunçalp 2012; Westhoff 2013) and TA (Ker 2013; Perel 2013).
The methods section of this review is based on a standard template used by the Cochrane Pregnancy and Childbirth Group.
Search methods for identification of studies
The following methods section of this review is based on a standard template used by the Cochrane Pregnancy and Childbirth Group.
We searched the Cochrane Pregnancy and Childbirth Group’s Trials Register by contacting the Trials Search Co-ordinator (28 January 2015).
The Cochrane Pregnancy and Childbirth Group’s Trials Register is maintained by the Trials Search Co-ordinator and contains trials identified from:
monthly searches of the Cochrane Central Register of Controlled Trials (CENTRAL);
weekly searches of MEDLINE (Ovid);
weekly searches of Embase (Ovid);
monthly searches of CINAHL (EBSCO);
handsearches of 30 journals and the proceedings of major conferences;
weekly current awareness alerts for a further 44 journals plus monthly BioMed Central email alerts.
Details of the search strategies for CENTRAL, MEDLINE, Embase and CINAHL, the list of handsearched journals and conference proceedings, and the list of journals reviewed via the current awareness service can be found in the ‘Specialized Register’ section within the editorial information about the Cochrane Pregnancy and Childbirth Group.
Trials identified through the searching activities described above are each assigned to a review topic (or topics). The Trials Search Co-ordinator searches the register for each review using the topic list rather than keywords.
Searching other resources
We searched the reference lists of retrieved studies.
We did not apply any language or date restrictions.
Data collection and analysis
For methods used in the previous version of this review, see ' Novikova 2010'.
For this update, the following methods were used for assessing the 20 reports that were identified as a result of the updated search.
The following methods section of this review is based on a standard template used by the Cochrane Pregnancy and Childbirth Group.
Selection of studies
Two review authors independently assessed for inclusion all the potential studies we identified as a result of the search strategy. We resolved any disagreement through discussion.
Data extraction and management
We designed a form to extract data. For eligible studies, two review authors (NN and CAC) extracted the data using the agreed form. We resolved any discrepancies through discussion. NN entered the data into Review Manager software (RevMan 2014) and JH checked them for accuracy.
When information regarding any of the above was unclear, we attempted to contact the authors of the original reports to provide further details.
In addition to the main outcomes and details on trial design, we systematically extracted the following data for each study.
Inclusion and exclusion criteria.
Mode of delivery.
Management of the third stage of labour.
Duration and technique of assessment of blood loss.
Missing data after randomisation.
Assessment of risk of bias in included studies
Two review authors independently assessed the validity of each study using the criteria outlined in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011). We resolved any disagreement by discussion.
(1) Random sequence generation (checking for possible selection bias)
We describe for each included study the method used to generate the allocation sequence in sufficient detail to allow an assessment of whether it should produce comparable groups.
We assessed the method as:
low risk of bias (any truly random process, e.g. random number table; computer random number generator);
high risk of bias (any non-random process, e.g. odd or even date of birth; hospital or clinic record number);
unclear risk of bias.
(2) Allocation concealment (checking for possible selection bias)
We describe for each included study the method used to conceal allocation to interventions prior to assignment and assess whether intervention allocation could have been foreseen in advance of, or during recruitment, or changed after assignment.
We assessed the methods as:
low risk of bias (e.g. telephone or central randomisation; consecutively numbered sealed opaque envelopes);
high risk of bias (open random allocation; unsealed or non-opaque envelopes, alternation; date of birth);
unclear risk of bias.
(3) Blinding of participants, personnel and outcome assessors (checking for possible performance bias)
We describe for each included study the methods used, if any, to blind study participants and personnel from knowledge of which intervention a participant received. We considered studies to be at low risk of bias if they were blinded, or if we judge that the lack of blinding would be unlikely to affect results. We assessed blinding separately for different outcomes or classes of outcomes.
We assessed the methods as:
low, high or unclear risk of bias for participants;
low, high or unclear risk of bias for personnel;
low, high or unclear risk of bias for outcome assessors.
(4) Incomplete outcome data (checking for possible attrition bias due to the amount, nature and handling of incomplete outcome data)
We describe for each included study, and for each outcome or class of outcomes, the completeness of data including attrition and exclusions from the analysis. We state whether attrition and exclusions were reported and the numbers included in the analysis at each stage (compared with the total randomised participants), reasons for attrition or exclusion where reported, and whether missing data were balanced across groups or were related to outcomes. Where sufficient information was reported, or was supplied by the trial authors, we re-included missing data in the analyses which we undertook.
We assessed methods as:
low risk of bias (e.g. no missing outcome data; missing outcome data balanced across groups);
high risk of bias (e.g. numbers or reasons for missing data imbalanced across groups; ‘as treated’ analysis done with substantial departure of intervention received from that assigned at randomisation);
unclear risk of bias.
(5) Selective reporting (checking for reporting bias)
We describe for each included study how we investigated the possibility of selective outcome reporting bias and what we found.
We assessed the methods as:
low risk of bias (where it is clear that all of the study’s prespecified outcomes and all expected outcomes of interest to the review have been reported);
high risk of bias (where not all the study’s prespecified outcomes have been reported; one or more reported primary outcomes were not prespecified; outcomes of interest are reported incompletely and so cannot be used; study fails to include results of a key outcome that would have been expected to have been reported);
unclear risk of bias.
(6) Other bias (checking for bias due to problems not covered by (1) to (5) above)
We describe for each included study any important concerns we have about other possible sources of bias.
We assessed whether each study was free of other problems that could put it at risk of bias:
(7) Overall risk of bias
We made explicit judgements about whether studies were at high risk of bias, according to the criteria given in the Handbook (Higgins 2011). With reference to (1) to (6) above, we assessed the likely magnitude and direction of the bias and whether we considered it likely to impact on the findings. We explored the impact of the level of bias through undertaking sensitivity analyses - see Sensitivity analysis.
Assessment of quality of evidence
For this update the quality of the evidence was assessed using the GRADE approach (Schunemann 2009) in order to assess the quality of the body of evidence relating to the following outcomes for the main comparison:
Blood loss 500 mL or more
Blood loss 1000 mL or more
Mean blood loss volume (mL)
Use of additional medical interventions to control PPH
Maternal death or severe maternal morbidity such as seizure, thromboembolic events, need for intensive care unit admission, hysterectomy, organ failure
Mild side effects such as nausea, vomiting, headache, skin reactions
GRADE profiler (GRADEpro 2014) was used to import data from Review Manager 5.3 (RevMan 2014) in order to create ’Summary of findings’ tables. A summary of the intervention effect and a measure of quality for each of the above outcomes was produced using the GRADE approach. The GRADE approach uses five considerations (study limitations, consistency of effect, imprecision, indirectness and publication bias) to assess the quality of the body of evidence for each outcome. The evidence can be downgraded from 'high quality' by one level for serious (or by two levels for very serious) limitations, depending on assessments for risk of bias, indirectness of evidence, serious inconsistency, imprecision of effect estimates or potential publication bias.
Measures of treatment effect
For dichotomous data, we presented results as summary risk ratio (RR) with 95% confidence intervals (CI).
For continuous data, we used the mean difference (MD) as the outcomes were measured in the same way in both trials.
In future updates of this review, we will use the standardised mean difference to combine trials that measure the same outcome, but use different methods.
Unit of analysis issues
If, in future updates of this review, we identify cluster-randomised trials for inclusion, we will include them in the analyses along with individually-randomised trials. We will adjust their sample sizes using the methods described in the Handbook using an estimate of the intra-cluster correlation co-efficient (ICC) derived from the trial (if possible), from a similar trial or from a study of a similar population. If we use ICCs from other sources, we will report this and conduct sensitivity analyses to investigate the effect of variation in the ICC. If we identify both cluster-randomised trials and individually-randomised trials, we plan to synthesise the relevant information. We will consider it reasonable to combine the results from both if there is little heterogeneity between the study designs and the interaction between the effect of intervention and the choice of randomisation unit is considered to be unlikely.
We will also acknowledge heterogeneity in the randomisation unit and perform a subgroup analysis to investigate the effects of the randomisation unit.
Cross-over trials are irrelevant for this intervention, and, therefore we have not included them.
When analysing multi-armed trials, we combined all relevant experimental intervention groups of the study into a single group and all relevant control intervention groups into a single control group. If the authors considered one of the arms irrelevant, we excluded it from analysis.
For dichotomous outcomes, both the sample sizes and the numbers of people with events were added from all groups. For continuous outcomes, means and standard deviations were calculated using a formula available in Table 7.7.a in Chapter 126.96.36.199 in the Handbook (Higgins 2011).
Dealing with missing data
For included studies, we noted levels of attrition. We planned to explore the impact of including studies with high levels of missing data in the overall assessment of treatment effect by using sensitivity analysis.
For all outcomes, we carried out analyses, as far as possible, on an intention-to-treat basis, i.e. we attempted to include all participants randomised to each group in the analyses, and to analyse all participants in the group to which they were allocated, regardless of whether or not they received the allocated intervention. The denominator for each outcome in each trial was the number randomised minus any participants whose outcomes were known to be missing.
Assessment of heterogeneity
We used the Tau², I² and Chi² statistics to measure heterogeneity among the trials in each analysis. We regarded heterogeneity as substantial if an I² was greater than 30% and either a Tau² was greater than zero, or there was a low P value (less than 0.10) in the Chi² test for heterogeneity.
Assessment of reporting biases
We planned to assess reporting biases if 10 or more studies were included in the meta-analysis. In this update (2015), only two meta-analyses included more than 10 studies. In future updates, if more studies are included, we will investigate reporting biases (such as publication bias) using funnel plots. We will visually assess funnel plot asymmetry.
We carried out statistical analysis using the Review Manager software (RevMan 2014). We used fixed-effect meta-analysis for combining data where it was reasonable to assume that studies were estimating the same underlying treatment effect: i.e. where trials were examining the same intervention, and the trials’ populations and methods were judged sufficiently similar.
If there was clinical heterogeneity sufficient to expect that the underlying treatment effects differed between trials, or if substantial statistical heterogeneity was detected, we used random-effects meta-analysis to produce an overall summary if an average treatment effect across trials was considered clinically meaningful. The random-effects summary was treated as the average of the range of possible treatment effects and we discuss the clinical implications of treatment effects differing between trials. If the average treatment effect was not considered clinically meaningful, we planned not to combine trials. If we used random-effects analyses, the results were presented as the average treatment effect with 95% confidence intervals, and the estimates of Tau² and I².
Subgroup analysis and investigation of heterogeneity
For analyses with substantial heterogeneity we performed random-effects analysis and sensitivity analyses.
We assessed the following subgroup for all outcomes:
We plan to assess primary outcomes for following subgroup in the future updates of the review if the data become available:
We compared all outcomes in subgroup "vaginal birth versus CS" because of potential differences in these two modes of birth. The secondary outcomes (for example, thromboembolic events) are included in the subgroup analysis because of its potential association with the use of TA, which is especially important in women undergoing CS because their risk of thromboembolic events is higher than in women with vaginal birth.
We planned to assess subgroup differences by interaction tests available within RevMan (RevMan 2014) and report the results of subgroup analyses quoting the Chi² statistic and P value, and the interaction test I² value.
We performed sensitivity analyses for aspects of the review that might have affected the results, for example where there is a risk of bias associated with the quality of some of the included trials; or to explore the effects of fixed-effect or random-effects analyses for outcomes with statistical heterogeneity.
We planned to perform sensitivity analysis for the primary outcomes (blood loss greater than 500 mL and greater than 1000 mL).
We performed sensitivity analysis for primary outcomes by excluding the trials that did not use placebo.
Summary of main results
Tranexamic acid (TA) is used widely to prevent haemorrhage. Our review assessed 12 trials that fulfilled our inclusion criteria. The summary of the main results is presented in Summary of findings for the main comparison.
Our analysis showed that TA decreases blood loss greater than 400 mL or greater than 500 mL and this effect is more prominent in the vaginal birth comparison than in the CS comparison based on studies with methodological shortcomings. Blood loss greater than 1000 mL decreased with the use of TA, however, the difference was significant only in the caesarean section comparison and not in the vaginal birth comparison in which there were few outcomes.
The use of additional medical interventions to control PPH was higher in the placebo or no intervention groups versus the TA group with more prominent differences in the vaginal birth group in comparison to the CS group. No additional surgical procedures to control PPH were used in three trials that reported on this outcome. The sample size in this analysis is too small to evaluate this outcome and further trials are necessary.
All women in all studies received routine uterotonics. No comparison between TA and uterotonics was investigated, nor was the effect of TA in the absence of uterotonics, which may potentially be greater.
Maternal death or severe maternal morbidity such as seizure, need for intensive care unit admission, hysterectomy or organ failure did not occur according to the two trials that reported this outcome. A larger number of participants is required to evaluate this important outcome.
Based on pooled data from all included trials except one study (Yang 2001), we found no difference in thromboembolic episodes between the two groups (11 trials, 3012 participants). One trial (Xu 2013) evaluating TA in women undergoing CS reported two episodes of deep venous thrombosis in two participants out of 88 in the TA group and in two participants out of 86 in the control group. This is an unusual finding as the rate of this venous thromboembolism following CS reported in the literature is less than one per 1000 (James 2009). The participants in the Xu 2013 trial were low-risk women with routine postoperative care. It is not clear why deep venous thrombosis was more common in this study population. None of the participants in the other eight trials experienced this complication.
More women who received TA versus placebo or no intervention experienced side effects. This outcome had considerable heterogeneity (I² = 83%). There was no heterogeneity in this outcome in the subgroup of women who had vaginal birth.
Women who have had a CS are expected to have more mild common side effects such as nausea, vomiting and dizziness, which can be related to surgery and/or TA. Therefore, it is difficult to explain the heterogeneity of these results and the studies did not report on the same mild side effects. The studies that have introduced heterogeneity to this analysis reported on the following side effects - nausea, vomiting, headache and skin reaction in Abdel-Aleem 2013; only nausea in Goswami 2013, Gungorduk 2011 reported on nausea, vomiting and diarrhoea Xu 2013 reported nausea/vomiting, phosphenes, dizziness.
Only two trials with unclear risk of bias and limited sample size (Goswami 2013; Yang 2001) evaluated different doses of TA and they only reported on a few outcomes. One trial compared 10 mg/kg and 15 mg/kg of TA (Goswami 2013). This trial included women with average weight of 57 kg, therefore, women received TA in the average dose of 0.6 g in one group and 0.9 g in the other group. The other trial (Yang 2001) compared 0.5 g and 1 g TA given following vaginal birth. We pooled data from both trials and combined groups 10 mL/kg with 0.5 g TA and 15 mL/kg with 1 g TA. No difference was found in blood loss greater than 400 mL and mean blood loss following vaginal birth between 0.5 g and 1 g based on this single trial. Although mean blood loss following CS was lower in women who received 15 mg/kg versus 10 mg/kg TA, no difference was seen in the use of additional medical interventions to control PPH in the same study population. The number of side effects did not differ between the groups who received 10 mg/kg versus 15 mg/kg TA based on a small number of participants. No clear conclusions can be drawn from comparison of different doses of TA for preventing PPH. One study (Yang 2001), which was of limited quality, found marginally higher blood loss with the higher dose of TA versus the lower dose.
Overall completeness and applicability of evidence
The studies included in the meta-analysis were undertaken in low- and middle-resource settings, therefore, the results have wide applicability. The study population included only low-risk women, but there is no biological reason to expect that TA would not have similar effects in women at high risk of PPH, such as women with placenta praevia, placental abruption, multiple pregnancy, instrumental delivery, prolonged labour as well as in women for whom blood loss needs to be minimised, such as women with anaemia or those who are haemodynamically unstable.
Although we did not find any data on cost-effectiveness of TA for preventing PPH, it is worth noting that the cost of TA is low and in bleeding trauma patients it was found to provide significant savings in low-, middle- and high-income countries (Guerriero 2011). The cost of one vile of tranexamic acid (1 g) was reported to be GBP 3.75 Sepah 2011. It can be stored at room temperature (25°C). It is easily administered by intravenous injection.
Quality of the evidence
Included studies were mixed in terms of risk of bias. Five trials had a low risk of selection bias, one trial had an unknown risk of selection bias and six had either an unknown or a high risk of selection bias. The risk of performance bias was low in six trials and unknown or high in six trials. The risk of attrition bias was low in all included trials except one. The risk of selective reporting was generally unclear. Only two trials had registered the trial protocol.
All included trials except one used the standard method of measuring blood loss. Gungorduk 2011 used preoperative and postoperative haematocrit difference to calculate the blood loss and we did not use the data on mean blood loss from this trial.
Five trials reported on blood loss from birth until two hours postpartum (Gai 2004; Gungorduk 2013; Mirghafourvand 2013; Xu 2013; Yang 2001).We included the data on mean blood loss from these trials in our analysis. Other trials included in this review had estimated blood loss at different times points, e.g. one trial included the blood loss from the beginning of CS until two hours postpartum inclusive of amniotic fluid (Abdel-Aleem 2013); one trial reported blood loss from incision until opening of the amniotic sac and then from placental separation until the end of surgery (Senturk 2013); one trial reported intraoperative blood loss inclusive of amniotic fluid and blood loss from the end of CS until two hours postpartum (Movafegh 2011), two trials reported on blood loss from placental delivery until the end of surgery and from the end of surgery until two hours postpartum (Goswami 2013; Shahid 2013). The data from these trials were not included in this analysis.
High heterogeneity was observed in side effects outcome (I² = 83%) contributed by studies on the use of TA in CS (I² = 90%) and not vaginal birth (I² = 0%). The heterogeneity is likely to be due to different definitions of side effects in various trials. Interestingly, two trials reported no side effects in placebo (Gungorduk 2011) or no intervention (Yehia 2014) groups in women undergoing CS. Such findings are unusual as the rate of nausea and vomiting following CS is reported to be up to 35% (Noroozinia 2013). Nausea and vomiting were included as part of side effects in both trials.
Sensitivity analysis (excluding the trials that did not use placebo) did not add any further information to our results.
The quality of evidence was assessed using the GRADE approach for each of seven outcomes. The evidence was downgraded to moderate quality due to concerns regarding study design for blood loss 500 mL or more; blood loss 1000 mL or more; mean blood loss volume (mL); and use of additional medical interventions to control PPH. The evidence was downgraded to low quality for maternal death or severe maternal morbidity and thromboembolic events due to study design limitations and imprecision (sample size too small to detect this rare outcome). The evidence was downgraded to moderate quality for mild side effects due to inconsistency in the evidence (high heterogeneity I² = 83%).
Potential biases in the review process
We pooled results for PPH with blood loss greater than 400 mL with the prespecified outcome blood loss greater than 500 mL together. Only blood loss greater than 400 mL, which differed to the primary outcome selected for this review (greater then 500 mL) was reported in two trials (Gai 2004; Yang 2001).The reasons behind a choice of an outcome such as blood loss greater than 400 mL are not clear from these papers. The possibility exists that this end-point may have been chosen retrospectively.
We have updated the outcomes being assessed in this review, e.g. we added blood transfusion to secondary outcomes instead of haemoglobin below 6 g%. The reasons behind this change is the importance of blood transfusion as an outcome when evaluating an intervention for preventing haemorrhage. Blood transfusions are used in the treatment of severe haemorrhage, they are costly, associated with significant adverse reactions and may not be available in low-resource settings. Blood transfusion is an outcome assessed in other Cochrane reviews on PPH (Mousa 2014) and TA (Ker 2013; Perel 2013).
Mean blood loss following vaginal birth was measured at different time points (from birth till placental delivery, from placental delivery till two hours postpartum and from birth till two hours postpartum). Although initially our prespecified outcome was mean blood loss from placental delivery until two hours postpartum, we changed it to the mean blood loss from birth until two hours postpartum to be able to pool data from all three trials on TA for preventing PPH in vaginal birth.
All the above-mentioned measures increased the numbers in the meta-analysis. The heterogeneity remained low.
One study (Yang 2001) used aminomethylbenzoic acid in one group, which was considered a placebo by the trial authors, though there was also a group that did not received any intervention. We included only the latter group.
Agreements and disagreements with other studies or reviews
A recent meta-analysis of observational trials and randomised controlled trials (RCTs) on usage of TA for obstetric haemorrhage found that TA reduces the amount of blood loss following CS and vaginal birth, and reduces the requirement for blood transfusion (Peitsidis 2011), which is in agreement with our results. Peitsidis and co-authors published a meta-analysis, which included studies with considerable heterogeneity (Peitsidis 2011). Abdel-Aleem and co-authors presented a meta-analysis on TA effects on blood loss following CS and also found positive effects of TA with considerable heterogeneity (Abdel-Aleem 2013). Our results did not have heterogeneity because we included only RCTs that evaluated the prespecified outcomes in a similar manner.
One trial included in the Cochrane review on treatment of primary PPH (Mousa 2014) showed a trend to decrease the incidence of severe PPH (greater than 800 mL) in a group of women who received TA versus placebo (Ducloy-Bouthors 2011). TA decreases the probability of blood transfusion following emergency surgery (Perel 2013).
The effect of TA on mortality following emergency surgery was reported to be uncertain in a recent Cochrane review that included three trials (260 participants) (Perel 2013). A large high-quality RCT showed a decrease in all-causes mortality and death due to bleeding in trauma patients who received a short course of TA versus placebo (CRASH-2 trial collaborators). Mousa and co-authors did not show any benefits of TA for treatment of primary PPH in relation to maternal mortality, admission to intensive care unit and hysterectomy following vaginal birth based on the same trial (Ducloy-Bouthors 2011; Mousa 2014). This trial was underpowered to evaluate these rare outcomes. Findings of our review are consistent with previous reports on the need for further well-designed studies with a larger number of participants to evaluate the effect of TA on maternal mortality, severe morbidity and additional surgical interventions to control PPH.
Prophylactic oxytocin in comparison to placebo is effective in preventing PPH greater than 500 mL according to a recent Cochrane review (RR 0.53, 95% CI 0.38 to 0.74, 6 trials 4203 women) (Tunçalp 2012) and the relative risk is comparable to the effects of TA on PPH greater than 400 or 500 mL in our meta-analysis (0.53, 95% CI 0.41, 0.69, five trials, 1188 women). Prophylactic ergometrine-oxytocin is associated with a small reduction of PPH greater than 500 mL (OR 0.82, 95% CI 0.71 to 0.95) according to another Cochrane review (McDonald 2004). Interestingly, the effect of TA in addition to prophylactic oxytocin in our meta-analysis is more prominent than the effect of ergometrine.
A recent well-designed trial on the use of TA following vaginal birth for treatment of PPH (144 participants) reported three cases of deep vein thrombosis at the site of intravenous catheter (two in the tranexamic acid group and one in the control group) (Ducloy-Bouthors 2011). Although the association of TA with thromboembolic events has been hypothesised, but has not been proven to date (CRASH-2 trial collaborators; Gandhi 2013; Ker 2012; Ker 2013; Poeran 2014), this review is in agreement with other publications suggesting that larger studies are required to assess this outcome and establish the safety of TA.
Mild side effects are more common in TA versus placebo or no intervention (Ducloy-Bouthors 2011; Peitsidis 2011).
Cochrane Pregnancy and Childbirth Group team for technical support.
Andrew Weeks and Bukola Fawole for their comprehensive reviewers comments.
As part of the pre-publication editorial process, this review has been commented on by three peers (an editor and two referees who are external to the editorial team) and the Group's Statistical Adviser.
This project was supported by the National Institute for Health Research, via Cochrane Infrastructure funding to Cochrane Pregnancy and Childbirth. The views and opinions expressed therein are those of the authors and do not necessarily reflect those of the Systematic Reviews Programme, NIHR, NHS or the Department of Health.
Contributions of authors
N Novikova participated in designing the review, and writing the protocol and review. She undertook the initial data analysis. GJ Hofmeyr conceived the review, and provided guidance in designing the review. He also provided a clinical perspective, and performed duplicate data extraction.
For the current update N Novikova assessed the new studies, extracted the data, prepared the review. GJ Hofmeyr reviewed the drafts of the update. CAC performed the duplicate data extraction and reviewed the draft of the update.
Differences between protocol and review
The methods text has been updated to reflect the latest Cochrane Handbook (Higgins 2011) and the current standard methods text used by the Cochrane Pregnancy and Childbirth Group.
We have updated the outcomes being assessed in this review, e.g. we added blood transfusion to secondary outcomes instead of haemoglobin below 6 g%.