Intramuscular Oxytocics: A Randomised Control Trial

Study Overview
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Brief Summary
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A quarter of all pregnancy and child-birth related deaths are due to excessive bleeding after the birth, post-partum haemorrhage (PPH). In the UK, PPH affects approx 10% of new mothers. PPH can be frightening for women and cause them to need additional treatments prolonging their hospital stay. Commonly PPH is caused by an inadequately contracted womb after childbirth. Giving the mother an injection of uterotonic medicine following the birth of their baby can prevent this. It reduces the risk of PPH by 66%. In the UK, the two medicines most commonly used are Syntocinon and Syntometrine. Syntometrine is longer acting, but a published review of trials concluded that Syntometrine is no better at preventing severe blood loss. Syntometrine is associated with more side effects including nausea, vomiting, and high blood pressure, and has been linked with rare, but fatal, cases of stroke. All guidelines therefore recommend Syntocinon for preventing PPH.Following a telephone survey of all maternity units in the UK, 71.4% of units still routinely use Syntometrine. Carbetocin is a newer medicine, already widely used after caesarean section, but not yet after vaginal birth. Other studies have shown that Carbetocin is slightly better at preventing bleeding after birth when compared to Syntometrine, has fewer side effects than Syntometrine, and that it may be just as good as Syntocinon at preventing PPH. No studies have directly compared all three medicines or compared their overall cost; information vital to the NHS. Investigators propose a trial of 5712 women over 13 months, in four maternity units to compare the effectiveness, side effects and cost of Syntocinon, Syntometrine and Carbetocin, for women having a vaginal birth. Women will be randomly allocated to receive one of these drugs. Women and staff will not know which drug they receive. Staff will collect data such as the number of extra drugs and treatments needed and the volume of blood lost. Women will be asked to complete a side effects questionnaire. Investigators will perform an analysis of cost effectiveness once all results are available. Aim: To directly compare the effectiveness, side effects and cost of Syntocinon, Syntometrine and Carbetocin given intramuscularly to prevent PPH in the 3rd stage of labour.

Detailed Description
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BACKGROUND Around a quarter of all global pregnancy and child-birth related deaths are due to excessive bleeding after the birth of the baby and placenta, or post-partum haemorrhage (PPH). In the UK, PPH affects approximately 10% of new mothers. PPH can be extremely frightening for women and can cause them to need additional treatments including blood transfusion and removal of the womb as well as prolonging their hospital stay. The most common cause of PPH is an inadequately contracted womb after childbirth. Giving the mother an injection of uterotonic medicine following the birth of their baby can prevent this. It reduces the risk of PPH by 66% and this should routinely be offered to all labouring women. In the UK, the two medicines most commonly used for this purpose are Syntocinon and Syntometrine. Both mimic natural hormones. Syntometrine is longer acting, but a published review of trials comparing these two medicines concluded that Syntometrine is no better at preventing severe blood loss. Syntometrine is associated with more side effects including nausea, vomiting, and high blood pressure, and has been linked with rare, but fatal, cases of stroke. All guidelines therefore recommend Syntocinon for preventing PPH. Our group conducted a telephone survey of all maternity units in the UK, and found that 71.4% of units still routinely use Syntometrine. Investigators estimate that 40,000-70,000 women per year are experiencing distressing nausea and vomiting in the emotionally important first few hours following childbirth. These women are also receiving a medicine with the potential to cause dangerous high blood pressure. Carbetocin is a newer medicine, already widely used after caesarean section, but not yet after vaginal birth. Other studies have shown that Carbetocin is slightly better at preventing bleeding after birth when compared to Syntometrine, that it has fewer side effects than Syntometrine, and that it may be just as good as Syntocinon at preventing PPH. No studies have directly compared all three medicines or compared their overall cost; information vital to the NHS. METHOD Investigators propose a trial of 5712 women over 13 months, in four maternity units in the South-West to compare the effectiveness, side effects and cost of Syntocinon, Syntometrine and Carbetocin, for women having a vaginal birth. Women will be randomly allocated to receive one of these drugs. Women and staff will not know which drug they receive, so as not to influence the results collected. Staff will collect data such as the number of extra drugs and treatments needed and the volume of blood lost. Women will be asked to complete a side effects questionnaire. Investigators will perform an analysis of cost effectiveness once all results are available. AIMS To directly compare the effectiveness, side effects and cost of Syntocinon, Syntometrine and Carbetocin given intramuscularly to prevent PPH in the 3rd stage of labour.

Official Title
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Intramuscular Oxytocics: A Randomised Control Trial of Intramuscular Carbetocin, Syntocinon and Syntometrine for the Third Stage of Labour Following Vaginal Birth

Conditions
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Post Partum Haemorrhage

Intervention / Treatment
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* Drug: Carbetocin
* Drug: Syntocinon
* Drug: Syntometrine


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: ≥18 years of age at time of delivery Singleton pregnancy Vaginal birth (spontaneous and instrumental) >24 weeks gestation Exclusion Criteria: Significant APH (>50ml) or suspected or proven placenta abruption Maternal coagulation disorder Intrauterine fetal death Patients who would decline blood products if required Known or suspected hypertensive disorders, including pre-eclampsia, pregnancy induced hypertension, essential hypertension (even if blood pressure well controlled) Hypertension in labour, or patients who have not had their blood pressure checked in labour Patients with peripheral, hepatic or cardiac disease Patients with an allergy or hypersensitivity to any of the active ingredients in Carbetocin, Syntometrine or Syntocinon Epilepsy

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Carbetocin<br>One dose of 100 micrograms intramuscular Carbetocin given for active management of the third stage of labour, immediately after the birth of the baby | Drug: Carbetocin<br>* The intervention is the administration of one dose of study drug to the recruited patient at the time of delivery. Carbetocin, listed here, is one of the of the three study drugs.<br>* Other names: Pabal;|
| Active Comparator: Syntocinon<br>One dose of 10 International Units intramuscular Syntocinon given for active management of the third stage of labour, immediately after the birth of the baby | Drug: Syntocinon<br>* The intervention is the administration of one dose of study drug to the recruited patient at the time of delivery. Syntocinon, listed here, is one of the of the three study drugs.<br>* Other names: Oxytocin;|
| Active Comparator: Syntometrine<br>One dose of 500micrograms/5 International Units intramuscular Syntometrine given for active management of the third stage of labour, immediately after the birth of the baby | Drug: Syntometrine<br>* The intervention is the administration of one dose of study drug to the recruited patient at the time of delivery. Syntometrine, listed here, is one of the of the three study drugs.<br>* Other names: Syntometrine 500 micrograms/5 IU Solution for Injection;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Requirement for additional uterotonic drugs within 24 hours of birth | Proportion of patients requiring additional uterotonic drugs after administration of study drug | From administration of prophylactic uterotonic agent to discharge from labour ward, within an expected average of 6 hours. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Estimated volume of blood loss at delivery | Estimated volume of blood loss at delivery | Within 24 hours of delivery | 
| Transfusion of blood products (type and number of units given) | Number of units of blood transfused, or volume of own blood returned to patient if intraoperative cell salvage used | From delivery until transfer from Labour Ward, within an expected average of 6 hours. | 
| Manual removal of placenta in theatre | The requirement for the placenta to be removed in theatre | From delivery until transfer from Labour Ward | 
| Requirement for surgical intervention to manage PPH | As a result of significant PPH a surgical intervention was required to manage the PPH | From delivery until transfer from Labour Ward, within an expected average of 2 days | 
| Maternal hypertension | Hypertension | First two postnatal hours following administration of study drug | 
| Maternal hypotension | BP <90/60 | In first two postnatal hours | 
| Maternally-reported health-related quality of life | health-related quality of life reported by mother | 24 hours after delivery and 14 days after delivery | 
| Abdominal pain in the first two postnatal hours, recorded in Case Report Form (CRF) by midwife | Patient reported secondary outcome | First 2 post natal hours | 
| Post-partum vomiting | Patient reported secondary outcome | First 2 post natal hours | 
| Need for anti-emetic | Patient reported secondary outcome By definition, labour starts when the patient is at least 3-4cm dilated with regular, painful contractions. | First 2 post natal hours | 
| Headache | Patient reported secondary outcome | First two post natal hours | 
| Maternal experience of side effects | Captured using maternal side effects questionnaire | In first two post natal hours | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Post partum haemorrhage, Active Management of Third Stage of Labour, Carbetocin, Syntocinon, Syntometrine, Birth experience, Labour