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Intramuscular oxytocin versus oxytocin/ergometrine versus carbetocin for prevention of primary postpartum haemorrhage after vaginal birth: study protocol for a randomised controlled trial (the IMox study).

ABSTRACT: BACKGROUND:Postpartum haemorrhage remains a major cause of maternal mortality and morbidity worldwide. Active management of the third stage of labour reduces the risk of postpartum haemorrhage. Oxytocin and oxytocin/ergometrine are commonly used in the UK, with oxytocin/ergometrine being more effective at preventing moderate, but not severe, blood loss. Many guidelines specifically recommend using oxytocin for all vaginal births, as it is associated with fewer adverse events. However, a survey conducted by the Southmead Hospital Maternity Research Team revealed that 71.4% of UK obstetric units still routinely use oxytocin/ergometrine. Carbetocin is a newer medication that may be as effective but has fewer side effects. No studies have directly compared all three medications. METHODS:The IMox study aims to determine the most effective, acceptable and cost-effective drug for primary prevention of postpartum haemorrhage following vaginal birth. The IMox study is a prospective, multi-centre, double-blind, randomised trial directly comparing oxytocin, oxytocin/ergometrine and carbetocin given intramuscularly for the prevention of postpartum haemorrhage in the third stage of labour. The primary effectiveness outcome is the use of an additional uterotonic drug. Secondary effectiveness outcomes reflect maternal morbidity and mortality within the immediate postpartum period. Participant questionnaires and subjective reporting of side effects will be used to evaluate maternal acceptability. Maternal quality of life utilities will be collected antenatally, and on days 1 and 14 after birth to enable a cost-effectiveness assessment of each studied drug. Participants will be pregnant women planning a vaginal birth in six hospitals in England. Participants will be approached and invited to provide consent to participate from 20?weeks gestation until in established labour. A complete sample of 5712 participants (1904 per arm) providing data for the primary outcome will allow for a robust determination of efficacy between all three study drugs. Data will be collected until participants are discharged from the hospital and on postnatal days 1 and 14 regardless of location. All analyses will be on a modified intention-to-treat basis, and additionally repeated on a per protocol basis. Data collection commenced in Feburary 2015 and was completed in August 2018. DISCUSSION:This study is the first to directly compare oxytocin, oxytocin/ergometrine and carbetocin in the same population for the prevention of postpartum haemorrhage following vaginal birth. Furthermore, this study will be the first to directly compute health economic outcomes from such a three-way comparison. This study is limited to using short-term outcomes, and so will not provide evidence for important outcomes such as long-term maternal psychological well-being and time to next conception. TRIAL REGISTRATION:ClinicalTrials.gov, NCT02216383 . Registered on 18 August 2014. EudraCT, 2014-001948-37. Registered on 23 September 2014. ISRCTN, ISRCTN10232550. Retrospectively registered on 6 March 2018).

SUBMITTER: van der Nelson H

PROVIDER: S-EPMC6319006 | biostudies-literature | 2019 Jan

REPOSITORIES: biostudies-literature

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Intramuscular oxytocin versus oxytocin/ergometrine versus carbetocin for prevention of primary postpartum haemorrhage after vaginal birth: study protocol for a randomised controlled trial (the IMox study).

van der Nelson Helen H O'Brien Stephen S Lenguerrand Erik E Marques Elsa E Alvarez Mary M Mayer Michelle M Burnard Sara S Siassakos Dimitrios D Draycott Timothy T

Trials 20190103 1

<h4>Background</h4>Postpartum haemorrhage remains a major cause of maternal mortality and morbidity worldwide. Active management of the third stage of labour reduces the risk of postpartum haemorrhage. Oxytocin and oxytocin/ergometrine are commonly used in the UK, with oxytocin/ergometrine being more effective at preventing moderate, but not severe, blood loss. Many guidelines specifically recommend using oxytocin for all vaginal births, as it is associated with fewer adverse events. However, a ...[more]

PMID: 30606246

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Project description:ObjectiveTo determine whether intravenous oxytocin is more effective than intramuscular oxytocin at preventing postpartum haemorrhage at vaginal delivery.DesignDouble blind placebo controlled randomised trial.SettingUniversity affiliated maternity unit in the Republic of Ireland.Participants1075 women aged 18 years or older, at term with a singleton pregnancy who were aiming for a vaginal delivery with an actively managed third stage of labour.InterventionsWomen were allocated to an intravenous bolus of oxytocin (10 IU in 1 mL given slowly over one minute) and placebo intramuscular injection (1 mL 0.9% saline) or an intramuscular bolus of oxytocin (10 IU in 1 mL) and placebo intravenous injection (1 mL 0.9% saline given slowly over one minute) at vaginal delivery. Allocation was by a secure web based randomisation service with masking of participants and clinicians to the trial intervention.Main outcome measuresThe primary outcome was postpartum haemorrhage (PPH, measured blood loss ≥500 mL). Secondary outcomes were severe PPH (measured blood loss ≥1000 mL), need for blood transfusion, admission to a high dependency unit, and side effects to oxytocin.ResultsBetween 4 January 2016 and 13 December 2017, 1075 women were randomised and 1035 (96.3%) included in the primary and secondary analyses (517 in the intravenous oxytocin group and 518 in the intramuscular oxytocin group). The incidence of PPH was not significantly lower in the intravenous group (18.8%, 97/517) compared with intramuscular group (23.2%, 120/518): adjusted odds ratio 0.75 (95% confidence interval 0.55 to 1.03). The incidence of severe PPH, however, was significantly lower in the intravenous group (4.6%, 24/517) compared with intramuscular group (8.1%, 42/518): 0.54 (0.32 to 0.91) as was the need for blood transfusion (1.5% v 4.4%, 0.31, 0.13 to 0.70) and admission to a high dependency unit (1.7% v 3.7%, 0.44, 0.20 to 0.98). The number needed to treat to prevent one case of severe PPH was 29 (95% confidence interval 16 to 201) and to prevent one case of blood transfusion was 35 (20 to 121). The incidence of side effects to oxytocin was not increased in the intravenous group compared with intramuscular group (4.1% v 5.2%, 0.75, 0.42 to 1.35).ConclusionIntravenous oxytocin for the third stage of labour results in less frequent severe PPH, blood transfusion, and admission to a high dependency unit than intramuscular oxytocin, and without excess side effects.Trial registrationCurrent Controlled Trials ISRCTN14718882.

Project description:Postpartum haemorrhage (PPH) is the leading cause of maternal mortality in low-income countries and is a significant contributor to severe maternal morbidity and long-term disability. Carbetocin may be an underused uterotonic for prevention of PPH. A number of studies are being conducted that may challenge the place of oxytocin as the first choice of uterotonics for prevention of PPH. This paper describes the current research into carbetocin and ranking of effectiveness of uterotonics that may provide important new information to assist healthcare decision makers to ensure that women receive an effective uterotonic for prevention of PPH.We searched the WHO International Clinical Trials Registry Platform for current studies on effectiveness of carbetocin for prevention of PPH following vaginal delivery with sample sizes large enough to provide quality evidence to support potential changes to international guidelines. We also searched the Cochrane Library for current systematic reviews including carbetocin used in prevention of PPH.Susceptibility to degradation from exposure to heat is one of the key causes of reduced effectiveness of oxytocin in preventing PPH from uterine atony. Although heat stable and effective in preventing PPH, misoprostol is also subject to degradation due to exposure to moisture and produces some side-effects. Other uterotonics (including ergometrine and combinations of oxytocin, ergometrine and misoprostol) are also available and used with varying safety and effectiveness profiles and quality issues. Efforts to reduce maternal mortality from PPH include research studies seeking to identify safe, stable, effective uterotonics. Heat stable carbetocin is the subject of two major clinical studies into its effectiveness in preventing PPH following vaginal deliveries, information that could expand its application for prevention of PPH.Heat stable carbetocin is being investigated as a potential alternative to oxytocin. This paper describes two current clinical trials on carbetocin and a network meta-analysis ranking of all uterotonic agents, including carbetocin, which combined may provide evidence supporting expansion of the use of the heat stable formulation of carbetocin in PPH prevention.

Project description:BackgroundPostpartum haemorrhage (PPH) is a leading cause of preventable maternal mortality worldwide. The World Health Organization (WHO) recommends uterotonic administration for every woman after birth to prevent PPH. There are no standardised data collected in large-scale measurement platforms. The Every Newborn Birth Indicators Research Tracking in Hospitals (EN-BIRTH) is an observational study to assess the validity of measurement of maternal and newborn indicators, and this paper reports findings regarding measurement of coverage and quality for uterotonics.MethodsThe EN-BIRTH study took place in five hospitals in Bangladesh, Nepal and Tanzania, from July 2017 to July 2018. Clinical observers collected tablet-based, time-stamped data. We compared observation data for uterotonics to routine hospital register-records and women's report at exit-interview survey. We analysed the coverage and quality gap for timing and dose of administration. The register design was evaluated against gap analyses and qualitative interview data assessing the barriers and enablers to data recording and use.ResultsObserved uterotonic coverage was high in all five hospitals (> 99%, 95% CI 98.7-99.8%). Survey-report underestimated coverage (79.5 to 91.7%). "Don't know" replies varied (2.1 to 14.4%) and were higher after caesarean (3.7 to 59.3%). Overall, there was low accuracy in survey data for details of uterotonic administration (type and timing). Register-recorded coverage varied in four hospitals capturing uterotonics in a specific column (21.6, 64.5, 97.6, 99.4%). The average coverage measurement gap was 18.1% for register-recorded and 6.0% for survey-reported coverage. Uterotonics were given to 15.9% of women within the "right time" (1 min) and 69.8% within 3 min. Women's report of knowing the purpose of uterotonics after birth ranged from 0.4 to 64.9% between hospitals. Enabling register design and adequate staffing were reported to improve routine recording.ConclusionsRoutine registers have potential to track uterotonic coverage - register data were highly accurate in two EN-BIRTH hospitals, compared to consistently underestimated coverage by survey-report. Although uterotonic coverage was high, there were gaps in observed quality for timing and dose. Standardisation of register design and implementation could improve data quality and data flow from registers into health management information reporting systems, and requires further assessment.

Project description:Postpartum hemorrhage (PPH) is a leading cause of maternal death in sub-Saharan Africa. Although the World Health Organization recommends use of oxytocin for prevention of PPH, misoprostol use is increasingly common owing to advantages in shelf life and potential for sublingual administration. There is a lack of data about the comparative efficacy of oxytocin and sublingual misoprostol, particularly at the recommended dose of 600 µg, for prevention of PPH during active management of labor.We performed a double-blind, double-dummy randomized controlled non-inferiority trial between 23 September 2012 and 9 September 2013 at Mbarara Regional Referral Hospital in Uganda. We randomized 1,140 women to receive 600 µg of misoprostol sublingually or 10 IU of oxytocin intramuscularly, along with matching placebos for the treatment they did not receive. Our primary outcome of interest was PPH, defined as measured blood loss ? 500 ml within 24 h of delivery. Secondary outcomes included measured blood loss ? 1,000 ml; mean measured blood loss at 1, 2, and 24 h after delivery; death; requirement for blood transfusion; hemoglobin changes; and use of additional uterotonics. At 24 h postpartum, primary PPH occurred in 163 (28.6%) participants in the misoprostol group and 99 (17.4%) participants in the oxytocin group (relative risk [RR] 1.64, 95% CI 1.32 to 2.05, p<0.001; absolute risk difference 11.2%, 95% CI 6.44 to 16.1). Severe PPH occurred in 20 (3.6%) and 15 (2.7%) participants in the misoprostol and oxytocin groups, respectively (RR 1.33, 95% CI 0.69 to 2.58, p = 0.391; absolute risk difference 0.9%, 95% CI -1.12 to 2.88). Mean measured blood loss was 341.5 ml (standard deviation [SD] 206.2) and 304.2 ml (SD 190.8, p = 0.002) at 2 h and 484.7 ml (SD 213.3) and 432.8 ml (SD 203.5, p<0.001) at 24 h in the misoprostol and oxytocin groups, respectively. There were no significant differences between the two groups in any other secondary outcomes. Women in the misoprostol group more commonly experienced shivering (RR 1.91, 95% CI 1.65 to 2.21, p<0.001) and fevers (RR 5.20, 95% CI 3.15 to 7.21, p = 0.005). This study was conducted at a regional referral hospital with capacity for emergency surgery and blood transfusion. High-risk women were excluded from participation.Misoprostol 600 µg is inferior to oxytocin 10 IU for prevention of primary PPH in active management of labor. These data support use of oxytocin in settings where it is available. While not powered to do so, the study found no significant differences in rate of severe PPH, need for blood transfusion, postpartum hemoglobin, change in hemoglobin, or use of additional uterotonics between study groups. Further research should focus on clarifying whether and in which sub-populations use of oxytocin would be preferred over sublingual misoprostol.ClinicalTrials.gov NCT01866241 Please see later in the article for the Editors' Summary.

Project description:ObjectiveTo assess whether secondary prevention, which preemptively treats women with above-average postpartum bleeding, is non-inferior to universal prophylaxis.DesignA cluster-randomised non-inferiority community trial.SettingHealth sub-centres and home deliveries in the Bijapur district of Karnataka, India.PopulationWomen with low-risk pregnancies who were eligible for delivery with an Auxiliary Nurse Midwife at home or sub-centre and who consented to be part of the study.MethodsAuxiliary Nurse Midwifes were randomised to secondary prevention using 800 mcg sublingual misoprostol administered to women with postpartum blood loss ≥350 ml or to universal prophylaxis using 600 mcg oral misoprostol administered to all women during the third stage of labour.Main outcome measuresPostpartum haemoglobin ≤7.8 g/dl, mean postpartum blood loss and postpartum haemoglobin, postpartum haemorrhage rate, transfer to higher-level facilities, acceptability and feasibility of the intervention.ResultsMisoprostol was administered to 99.7% of women as primary prevention. In secondary prevention, 92 (4.7%) women had postpartum bleeding ≥350 ml, of which 90 (97.8%) received misoprostol. The proportion of women with postpartum haemoglobin ≤7.8 g/dl was 5.9 and 8.8% in secondary and primary prevention clusters, respectively [difference -2.9%, one-sided 95% confidence interval (CI) <1.3%]. Postpartum transfer and haemorrhage rates were low (<1%) in both groups. Shivering was more common in primary prevention clusters (P = 0.013).ConclusionSecondary prevention of postpartum haemorrhage with misoprostol is non-inferior to universal prophylaxis based on the primary outcome of postpartum haemoglobin. Secondary prevention could be a good alternative to universal prophylaxis as it medicates fewer women and is an acceptable and feasible strategy at the community level.Tweetable abstractSecondary prevention of postpartum haemorrhage with misoprostol is non-inferior to universal prophylaxis.

Project description:Objectives Postpartum haemorrhage (PPH) is a major cause of maternal mortality and morbidity worldwide. Experimental studies support the hypothesis that oxytocin administration during labour, a common although not evidence-based practice, may increase the risk of atonic PPH. The clinical studies, however, are inconclusive. The objectives of this study was to investigate the association between the level of oxytocin exposure during labour and the risk of severe PPH and to explore whether the prophylactic use of oxytocin after birth modifies this association. Design Population-based, cohort-nested case-control study. Setting 106 French hospitals from December 2004 through November 2006. Participants Women with term singleton vaginal deliveries, after an uncomplicated pregnancy. Cases were 1483 women with severe PPH, defined by peripartum change in haemoglobin of ?4 g/dl or need for blood transfusion. Controls were 1758 women from a random sample of parturients without PPH. Main outcome measures The independent association between the level of oxytocin during labour and the risk of severe PPH was tested and quantified with ORs through two-level multivariable logistic regression modelling. Results Oxytocin was administered during labour to 73% of cases and 61% of controls (crude OR: 1.7, 95% CI 1.5 to 2.0). After adjustment for all potential confounders, oxytocin during labour was associated with a significantly higher risk of severe PPH (adjusted OR: 1.8, 95% CI 1.3 to 2.6) in women who did not receive prophylactic oxytocin after delivery; the OR for haemorrhage increased from 1 to 5 according to the level of oxytocin exposure. In women who had prophylactic oxytocin after delivery, this association was significant only for the highest exposure categories. Conclusions Oxytocin during labour appears to be an independent risk factor for severe PPH. The results emphasise the need for guidelines clarifying the evidence-based indications for this procedure and the minimal useful regimens.

Dataset Information

Intramuscular oxytocin versus oxytocin/ergometrine versus carbetocin for prevention of primary postpartum haemorrhage after vaginal birth: study protocol for a randomised controlled trial (the IMox study).

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Intramuscular oxytocin versus oxytocin/ergometrine versus carbetocin for prevention of primary postpartum haemorrhage after vaginal birth: study protocol for a randomised controlled trial (the IMox study).

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