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Misoprostol for primary versus secondary prevention of postpartum haemorrhage: a cluster-randomised non-inferiority community trial.

ABSTRACT: OBJECTIVE:To assess whether secondary prevention, which preemptively treats women with above-average postpartum bleeding, is non-inferior to universal prophylaxis. DESIGN:A cluster-randomised non-inferiority community trial. SETTING:Health sub-centres and home deliveries in the Bijapur district of Karnataka, India. POPULATION:Women 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. METHODS:Auxiliary 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 MEASURES:Postpartum 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. RESULTS:Misoprostol 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). CONCLUSION:Secondary 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 ABSTRACT:Secondary prevention of postpartum haemorrhage with misoprostol is non-inferior to universal prophylaxis.

SUBMITTER: Raghavan S

PROVIDER: S-EPMC5014137 | biostudies-literature | 2016 Jan

REPOSITORIES: biostudies-literature

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Misoprostol for primary versus secondary prevention of postpartum haemorrhage: a cluster-randomised non-inferiority community trial.

Raghavan S S Geller S S Miller S S Goudar S S SS Anger H H Yadavannavar M C MC Dabash R R Bidri S R SR Gudadinni M R MR Udgiri R R Koch A R AR Bellad M B MB Winikoff B B

BJOG : an international journal of obstetrics and gynaecology 20150901 1

<h4>Objective</h4>To assess whether secondary prevention, which preemptively treats women with above-average postpartum bleeding, is non-inferior to universal prophylaxis.<h4>Design</h4>A cluster-randomised non-inferiority community trial.<h4>Setting</h4>Health sub-centres and home deliveries in the Bijapur district of Karnataka, India.<h4>Population</h4>Women with low-risk pregnancies who were eligible for delivery with an Auxiliary Nurse Midwife at home or sub-centre and who consented to be pa ...[more]

PMID: 26333044

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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:There is a lack of evidence evaluating cryoprecipitate transfusion in severe postpartum haemorrhage. We performed a pilot cluster-randomised controlled trial to evaluate the feasibility of a trial on early cryoprecipitate delivery in severe postpartum haemorrhage. Pregnant women (>24 weeks gestation), actively bleeding within 24 h of delivery and who required at least one unit of red blood cells were eligible. Women declining transfusion in advance or with inherited clotting deficiencies were not eligible. Four UK hospitals were randomly allocated to deliver either the intervention (administration of two pools of cryoprecipitate within 90 min of first red blood cell unit requested plus standard care), or the control group treatment (standard care, where cryoprecipitate is administered later or not at all). The primary outcome was the proportion of women who received early cryoprecipitate (intervention) vs. standard care (control). Secondary outcomes included consent rates, acceptability of the intervention, safety outcomes and preliminary clinical outcome data to inform a definitive trial. Between March 2019 and January 2020, 199 participants were recruited; 19 refused consent, leaving 180 for analysis (110 in the intervention and 70 in the control group). Adherence to assigned treatment was 32% (95%CI 23-41%) in the intervention group vs. 81% (95%CI 70-90%) in the control group. The proportion of women receiving cryoprecipitate at any time-point was higher in the intervention (60%) vs. control (31%) groups; the former had fewer red blood cell transfusions at 24 h (mean difference -0.6 units, 95%CI -1.2 to 0); overall surgical procedures (odds ratio 0.6, 95%CI 0.3-1.1); and intensive care admissions (odds ratio 0.4, 95%CI 0.1-1.1). There was no increase in serious adverse or thrombotic events in the intervention group. Staff interviews showed that lack of awareness and uncertainty about study responsibilities contributed to lower adherence in the intervention group. We conclude that a full-scale trial may be feasible, provided that protocol revisions are put in place to establish clear lines of communication for ordering early cryoprecipitate in order to improve adherence. Preliminary clinical outcomes associated with cryoprecipitate administration are encouraging and merit further investigation.

Project description:BACKGROUND: Postpartum haemorrhage remains an important cause of maternal death despite treatment with conventional therapy. Uncontrolled studies and one randomised comparison with conventional oxytocics have reported dramatic effects with high-dose misoprostol, usually given rectally, for treatment of postpartum haemorrhage, but this has not been evaluated in a placebo-controlled trial. METHODS: The study was conducted at East London Hospital Complex, Tembisa and Chris Hani Baragwanath Hospitals, South Africa. Routine active management of the third stage of labour was practised. Women with more than usual postpartum bleeding thought to be related to inadequate uterine contraction were invited to participate, and to sign informed consent. All routine treatment was given from a special 'Postpartum Haemorrhage Trolley'. In addition, participants who consented were enrolled by drawing the next in a series of randomised treatment packs containing either misoprostol 5 x 200 microg or similar placebo, which were given 1 orally, 2 sublingually and 2 rectally. RESULTS: With misoprostol there was a trend to reduced blood loss >/=500 ml in 1 hour after enrolment measured in a flat plastic 'fracture bedpan', the primary outcome (6/117 vs 11/120, relative risk 0.56; 95% confidence interval 0.21 to 1.46). There was no difference in mean blood loss or haemoglobin level on day 1 after birth < 6 g/dl or blood transfusion. Side-effects were increased, namely shivering (63/116 vs 30/118; 2.14, 1.50 to 3.04) and pyrexia > 38.5 degrees C (11/114 vs 2/118; 5.69, 1.29 to 25). In the misoprostol group 3 women underwent hysterectomy of whom 1 died, and there were 2 further maternal deaths. CONCLUSIONS: Because of a lower than expected incidence of the primary outcome in the placebo group, the study was underpowered. We could not confirm the dramatic effect of misoprostol reported in several unblinded studies, but the results do not exclude a clinically important effect. Larger studies are needed to assess substantive outcomes and risks before misoprostol enters routine use.

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:BackgroundPostpartum 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.MethodsThe 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.DiscussionThis 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 registrationClinicalTrials.gov, NCT02216383 . Registered on 18 August 2014. EudraCT, 2014-001948-37. Registered on 23 September 2014. ISRCTN, ISRCTN10232550. Retrospectively registered on 6 March 2018).

Dataset Information

Misoprostol for primary versus secondary prevention of postpartum haemorrhage: a cluster-randomised non-inferiority community trial.

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Misoprostol for primary versus secondary prevention of postpartum haemorrhage: a cluster-randomised non-inferiority community trial.

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