Uterotonics for Postpartum Hemorrhage

Overseen By Mrinalini Balki, MD

Age: 18 - 65

Sex: Female

Trial Phase: Academic

Sponsor: Samuel Lunenfeld Research Institute, Mount Sinai Hospital

Must not be taking: Insulin, Nifedipine, Labetalol, Magnesium

Disqualifiers: General anesthesia, Labor, Emergency CD, others

Compensation: Varies

Number of Visits: 1

32 Participants Needed

Trial Summary

What is the purpose of this trial?

This study will investigate the effects of drugs called "uterotonics" that help with the contraction of the uterus after a baby is born. This uterine contraction is very important to stop the bleeding after delivery. An uncontracted uterine state is called "uterine atony", which can lead to an excessive amount of post-delivery bleeding. Carbetocin is an uterotonic drug that works well to prevent post-delivery bleeding. In some cases, carbetocin is not enough to contract the uterus, and ongoing bleeding continues. When that happens, there are other uterotonic medications that can be used. In this study, we aim to find which uterotonic drug, amongst those available (oxytocin, carbetocin, ergometrine or carboprost), is more effective to lower the risk of post-delivery bleeding once carbetocin has already been administered. This study will be done by using a very small sample of uterine tissue, taken from the incision site, following delivery by cesarean section. The sample is taken to the laboratory and will be exposed to carbetocin followed by other uterotonic drugs. The information obtained from this study will help modify the treatment for uterine atony and post-delivery bleeding to lower the risk further.

Will I have to stop taking my current medications?

Yes, you may need to stop taking certain medications. The trial excludes patients on medications that could affect uterine muscle contractions, like insulin, nifedipine, labetalol, or magnesium sulfate.

What data supports the effectiveness of the drug for postpartum hemorrhage?

Research shows that carbetocin, a drug similar to oxytocin, is effective in preventing postpartum hemorrhage (excessive bleeding after childbirth) and can be used without refrigeration, making it more accessible in low-income countries. Studies have found it to be as effective as oxytocin in reducing blood loss after vaginal delivery. ^{1 2 3 4 5}

Is carbetocin safe for humans?

Carbetocin, a medication used to prevent excessive bleeding after childbirth, has been studied for its safety in several trials. These studies generally show that carbetocin is well-tolerated in humans, with safety profiles similar to other medications used for the same purpose, like oxytocin. ^{1 2 3 4 6}

How does the drug carbetocin differ from other treatments for postpartum hemorrhage?

Carbetocin is unique because it is available in a room temperature stable formulation, unlike oxytocin, which requires refrigeration. This makes carbetocin particularly useful in low-income countries where maintaining a cold chain for drug storage is challenging. ^{1 2 3 4 7}

Research Team

Mrinalini Balki, MD

Principal Investigator

MOUNT SINAI HOSPITAL

Eligibility Criteria

This trial is for individuals who have recently given birth and are experiencing postpartum hemorrhage, a condition where the uterus does not contract strongly enough to stop bleeding. The study focuses on those who do not respond adequately to initial treatment with carbetocin.

Inclusion Criteria

Patients who give written consent to participate in this study

I am pregnant and between 37 to 41 weeks along.

I have not been given oxytocin for labor induction.

Exclusion Criteria

Emergency CD

I have chosen not to participate in this trial.

Placenta accreta spectrum disorder

Timeline

Screening

Participants are screened for eligibility to participate in the trial

1-2 weeks

Sample Collection

Uterine tissue samples are collected from the incision site following delivery by cesarean section

Immediate post-delivery

1 visit (in-person)

Laboratory Testing

Uterine tissue samples are exposed to carbetocin followed by other uterotonic drugs to assess dose-response profiles

4 hours

Follow-up

Participants are monitored for any adverse effects post-sample collection and testing

1-2 weeks

Treatment Details

Interventions

• Comparing the Dose-response Profiles of Uterotonics After Initial Carbetocin Administration - an Ex-vivo Study in Desensitized Human Myometrium

Trial Overview The study tests the effectiveness of additional uterotonic drugs (ergonovine, carboprost, oxytocin) after carbetocin has been used. It aims to determine which drug best reduces the risk of continued bleeding in an ex-vivo setting using uterine tissue samples.

Participant Groups

Group I: Carbetocin Active Control 2 Interventions

Dose-response testing with increasing concentrations of carbetocin in a pattern of 1 log molar increase every 10 min, from 10-5 M to 10-5 M

Group II: Oxytocin Active Control 2 Interventions

Dose-response testing with increasing concentrations of oxytocin from 10-10 M to 10-5 M.

Group III: Ergometrine Active Control 3 Interventions

Dose-response testing with increasing concentrations of ergometrine from 10-10 M to 10-5 M

Group IV: Carboprost Active Control 3 Interventions

Dose-response testing with increasing concentrations of carboprost from 10-10 M to 10-5 M

Group V: Control Placebo Group 2 Interventions

No drug added to physiological salt solution (PSS).

Who Is Running the Clinical Trial?

Samuel Lunenfeld Research Institute, Mount Sinai Hospital

Lead Sponsor

Trials

132

Recruited

11,400+

Findings from Research

A large-scale trial involving approximately 30,000 women across 22 centers in 10 countries is evaluating the effectiveness of a new room temperature stable formulation of carbetocin compared to oxytocin for preventing postpartum hemorrhage (PPH) after vaginal birth.

If proven non-inferior to oxytocin, the new carbetocin formulation could significantly improve maternal health outcomes in low-resource settings where maintaining cold storage for medications is challenging.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Room temperature stable carbetocin for the prevention of postpartum haemorrhage during the third stage of labour in women delivering vaginally: study protocol for a randomized controlled trial. Widmer, M., Piaggio, G., Abdel-Aleem, H., et al.[2022]

In a study of 102 women with postpartum hemorrhage, the combination of carbetocin and ergometrine maleate significantly reduced blood loss and hemostasis time compared to carbetocin alone, indicating improved efficacy in managing postpartum hemorrhage.

The combination treatment also enhanced coagulation function and maintained stable hemodynamic parameters without increasing the incidence of adverse reactions, suggesting it is a safe and effective option for postpartum hemorrhage management.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effects of carbetocin combined with ergometrine maleate on blood loss and coagulation function of puerperae with postpartum haemorrhage. Xue, H., Wang, W.[2023]

A meta-analysis of 5 randomized controlled trials involving 30,314 women found that carbetocin is as effective as oxytocin in preventing postpartum hemorrhage during vaginal delivery, with no significant difference in blood loss of 500 ml or more.

Both carbetocin and oxytocin showed similar safety profiles, with no notable differences in side effects or the need for additional interventions, suggesting that the choice between them may depend on cost-effectiveness rather than efficacy or safety.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Carbetocin vs oxytocin for prevention of postpartum hemorrhage after vaginal delivery: A meta-analysis. Jin, XH., Li, D., Li, X.[2022]

Carbetocin significantly reduces the need for additional uterotonic agents compared to oxytocin in women after cesarean delivery, indicating its efficacy in preventing postpartum hemorrhage.

Carbetocin has a lower risk of adverse effects compared to syntometrine during vaginal delivery, making it a potentially safer alternative for preventing postpartum hemorrhage, with similar effectiveness to other uterotonics.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Carbetocin for the prevention of postpartum hemorrhage: a systematic review and meta-analysis of randomized controlled trials. Jin, B., Du, Y., Zhang, F., et al.[2022]

A single 100 microgram intramuscular injection of carbetocin was found to be as effective as a 2-hour intravenous infusion of oxytocin in reducing the need for additional uterotonic interventions in women at risk for postpartum hemorrhage, with fewer women requiring uterine massage in the carbetocin group (43.4% vs. 62.3%).

Both treatments showed no significant differences in laboratory indicators of postpartum hemorrhage, suggesting that carbetocin may be a viable alternative to oxytocin for managing this condition.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Comparison of carbetocin and oxytocin for the prevention of postpartum hemorrhage following vaginal delivery:a double-blind randomized trial. Boucher, M., Nimrod, CA., Tawagi, GF., et al.[2019]

The maximum tolerated dose (MTD) of carbetocin, a synthetic analogue of oxytocin, was determined to be 200 micrograms when administered to 45 women immediately after vaginal delivery.

At the 200 microgram dose, there were significant adverse events, including increased blood loss and a higher incidence of retained placenta, indicating that while this dose is the MTD, it may pose safety risks compared to lower doses.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Ascending dose tolerance study of intramuscular carbetocin administered after normal vaginal birth. van Dongen, PW., Verbruggen, MM., de Groot, AN., et al.[2019]

Uterotonics are essential for managing post-partum hemorrhage, but clinical studies often face confounding factors that can affect results, making in vitro studies important for controlled comparisons.

This review highlights the mechanisms of action for different uterotonic drugs, including insights into oxytocin desensitization, which enhances our understanding of effective dosing and treatment strategies for post-partum hemorrhage.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

What does basic science tell us about the use of uterotonics? Drew, T., Balki, M.[2020]

References

1. England pubmed.ncbi.nlm.nih.gov

Room temperature stable carbetocin for the prevention of postpartum haemorrhage during the third stage of labour in women delivering vaginally: study protocol for a randomized controlled trial. [2022]

2. United States pubmed.ncbi.nlm.nih.gov

Effects of carbetocin combined with ergometrine maleate on blood loss and coagulation function of puerperae with postpartum haemorrhage. [2023]

3. United States pubmed.ncbi.nlm.nih.gov

Carbetocin vs oxytocin for prevention of postpartum hemorrhage after vaginal delivery: A meta-analysis. [2022]

4. England pubmed.ncbi.nlm.nih.gov

Carbetocin for the prevention of postpartum hemorrhage: a systematic review and meta-analysis of randomized controlled trials. [2022]

5. Netherlands pubmed.ncbi.nlm.nih.gov

Comparison of carbetocin and oxytocin for the prevention of postpartum hemorrhage following vaginal delivery:a double-blind randomized trial. [2019]

6. Ireland pubmed.ncbi.nlm.nih.gov

Ascending dose tolerance study of intramuscular carbetocin administered after normal vaginal birth. [2019]

7. Netherlands pubmed.ncbi.nlm.nih.gov

What does basic science tell us about the use of uterotonics? [2020]