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

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial investigates which uterotonic drug best prevents excessive bleeding after childbirth, especially when carbetocin has already been used. Uterotonics help the uterus contract and reduce bleeding after delivery. Researchers will compare carbetocin, oxytocin, ergometrine, and carboprost to determine which is most effective in these cases. Women undergoing planned cesarean delivery who haven't received oxytocin to induce labor might be suitable for this study. As an unphased trial, this study allows participants to contribute to important research that could enhance postpartum care for many women.

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.

Is there any evidence suggesting that this trial's treatments are likely to be safe?

Research has shown that the drugs under study, including carbetocin, oxytocin, ergometrine, and carboprost, are generally safe for managing postpartum bleeding. Carbetocin tends to cause fewer side effects, such as vomiting, compared to other drugs. One study found that oxytocin, often the first choice, has few side effects and effectively prevents heavy bleeding after childbirth. Ergometrine acts quickly to control bleeding but can sometimes cause side effects like nausea or high blood pressure. Carboprost serves as an alternative when other treatments are insufficient, and while it can raise blood pressure, this is uncommon.

Overall, these medications are well-tolerated and have been safely used in many patients. However, since this study uses uterine tissue samples in a lab, it will not directly study effects on people. Participants should consult their healthcare providers to determine the best treatment options for their needs. ^{1 2 3 4 5}

Why are researchers excited about this trial?

Researchers are excited about this trial because it explores how different uterotonic drugs, like carbetocin, oxytocin, ergometrine, and carboprost, work on the human uterus after childbirth. Postpartum hemorrhage, excessive bleeding after delivery, is typically treated with oxytocin as the standard care. However, understanding the dose-response effects of these drugs can help find the most effective and safest option. By examining how these drugs behave at various concentrations, the trial aims to improve treatment strategies, potentially offering better outcomes for new mothers facing this serious condition.

What evidence suggests that this trial's treatments could be effective for postpartum hemorrhage?

This trial will compare the effectiveness of different uterotonics for postpartum hemorrhage. Research has shown that carbetocin, one of the treatments tested in this trial, effectively reduces blood loss and the risk of heavy bleeding after childbirth (postpartum hemorrhage or PPH) compared to oxytocin. Studies have found that carbetocin can help prevent the costs and serious complications related to PPH. Oxytocin, another treatment option in this trial, significantly lowers the risk of PPH and severe PPH compared to no intervention. Ergometrine, often used with oxytocin and also tested in this trial, effectively reduces major blood loss. Carboprost, another treatment arm in this trial, has successfully treated ongoing bleeding due to the uterus not contracting properly. Each of these medications helps the uterus tighten, which is crucial for stopping bleeding after delivery. ^{6 7 8 9 10}

Who Is on the Research Team?

Mrinalini Balki, MD

Principal Investigator

MOUNT SINAI HOSPITAL

Are You a Good Fit for This Trial?

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 for a Trial Participant

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

What Are the Treatments Tested in This Trial?

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.

How Is the Trial Designed?

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+

Published Research Related to This Trial

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]

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 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]

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]

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]

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]

Citations

1. ncbi.nlm.nih.gov ncbi.nlm.nih.gov/books/NBK546425/

Carbetocin for the Prevention of Post-Partum Hemorrhage In the primary studies, carbetocin was associated with similar or more effectiveness regarding the prevention of PPH, reducing additional ...

2. journals.plos.org journals.plos.org/plosone/article?id=10.1371/journal.pone.0279130

Cost-effectiveness analysis of carbetocin for prevention of ... In base-case analysis, carbetocin (versus oxytocin) reduced PPH-related cost (by USD29 per birth), PPH ≥500 mL and ≥1,500 mL (by 13.7 and 1.9 per 1,000 births), ...

3. obgyn.onlinelibrary.wiley.com obgyn.onlinelibrary.wiley.com/doi/10.1111/1471-0528.18358

Carbetocin for Postpartum Haemorrhage Prophylaxis in All ... Carbetocin is associated with reduced blood loss and the rate of PPH compared to Oxytocin. Associated reductions in admissions to high ...

4. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/36520799/

Cost-effectiveness analysis of carbetocin for prevention ... PPH prevention with carbetocin appeared to reduce major unfavorable outcomes, and save cost and QALYs.

5. nejm.org nejm.org/doi/full/10.1056/NEJMoa1805489

Heat-Stable Carbetocin versus Oxytocin to Prevent ... However, in our trial, this outcome occurred in 1.51% of the participants in the carbetocin group and in 1.45% of those in the oxytocin group.

6. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/35243717/

Effectiveness and safety of carboxytocin versus oxytocin in ... Objective: This study compared the effectiveness and safety of carbetocin and oxytocin in preventing postpartum hemorrhage (PPH).

7. ghsupplychain.org ghsupplychain.org/sites/default/files/2023-07/HSC_20230630.pdf

HEAT-STABLE CARBETOCIN Unlike oxytocin, misoprostol and ergometrine, carbetocin is not indicated for treatment of PPH, and it is contraindicated during pregnancy and must not be used ...

8. bpspubs.onlinelibrary.wiley.com bpspubs.onlinelibrary.wiley.com/doi/full/10.1002/prp2.745

Side‐effects of carbetocin to prevent postpartum hemorrhage ... The use of carbetocin had a lower risk of vomiting in intravenously (0.53, 0.30 to 0.93) and cesarean birth (0.51, 0.32 to 0.81) women, and had ...

9. sciencedirect.com sciencedirect.com/science/article/pii/S1028455916301917

Carbetocin in prevention of postpartum hemorrhage In Taiwan, prophylactic use of carbetocin resulted in significantly less blood loss and incidence of PPH in cesarean than in vaginal deliveries.

10. clinicaltrials.gov clinicaltrials.gov/study/NCT02304055

Carbetocin Versus Oxytocin in the Management of Atonic ... Oxytocin is currently the uterotonic of first choice. It has proven to decrease the incidence of PPH by 40 % and has a rapid onset of action and a good safety ...