Effect of Extracellular Calcium on Carbetocin Mediated Contractility in Human Myometrium

Effect of Extracellular Calcium on Carbetocin Mediated Contractility in Human Myometrium: An Ex-Vivo Study

Postpartum hemorrhage (PPH) continues to be an increasing problem globally. Uterotonics play an essential role in the pharmacological management of uterine atony. Carbetocin, a long acting analog of oxytocin has been recommended as a first line uterotonic for PPH prophylaxis at cesarean delivery. Considering many woman have associated comorbidities and are at high risk of PPH, finding alternative pharmacological agents is essential. Calcium is a key factor for myometrial contractions and calcium blood levels can be low at the end of pregnancy. Both hypocalcemia and hypercalcemia could lead to a decrease in myometrial contractions. It is already been demonstrated that in both desensitized and naïve myometrium, normocalcemia provides a better uterine tone compared to hypo and hypercalcemia when oxytocin is given as the first uterotonic drug.

Currently, the role of extracelullar calcium in carbetocin- induced contractility is unknown. This will be the first ex vivo study to test the effects of extracellular calcium on oxytocin pretreated and naive myometrium. The results of this study will provide evidence on the use of this safe drug in clinical practice, particularly in women with labour arrest, and provide alternative pharmacological strategies to both prevention and treatment of PPH, thus improving our clinical practice.

The investigators hypothesize that extracellular normocalcemia would provide superior carbetocin-mediated contractility in both naive and oxytocin-pretreated myometrium compared with hypercalcemia and hypocalcemia.

Study Overview

• Status: Recruiting
• Conditions: Postpartum Hemorrhage (Primary)
• Intervention / Treatment: Drug: Carbetocin; Drug: Calcium; Drug: Oxytocin

• Study Type: Interventional
• Enrollment (Estimated): 40
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Mrinalini Balki, MD; Phone Number: 5270 416-586-480; Email: mrinalini.balki@uhn.ca

Study Locations

• Canada
  • Ontario
    • Toronto, Ontario, Canada, M5G1X5
      • Recruiting
      • Mount Sinai Hospital
      • Principal Investigator: Mrinalini Balki, MD
      • Sub-Investigator: Ronald George, MD
      • Contact: Mrinalini Balki, MD; Phone Number: 5270 416-586-4800; Email: mrinalini.balki@uhn.ca
      • Sub-Investigator: Joseph Park, BSc
      • Sub-Investigator: Anuradha Baishnob, BSc
      • Sub-Investigator: Nicolas Muller, MD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult
• Accepts Healthy Volunteers: Yes

Description

Inclusion Criteria:

• non-laboring women with gestational age between 37 to 41 weeks
• not exposed to exogenous oxytocin, scheduled for a primary or first repeat cesarean delivery under neuraxial anesthesia.

Exclusion criteria:

• patients requiring general anesthesia
• more than 1 previous cesarean delivery
• history of uterine atony
• emergency cesarean section in labor
• patients using medications that could affect myometrial contractility such as nifedipine, labetalol, or magnesium sulphate.
• patients with any condition of predisposing to uterine atony and postpartum hemorrhage, such as abnormal placentation, multiple gestation, severe preeclampsia, macrosomia, polyhydroamnios, large uterine fibroids, chorioamnionitis, previous history of postpartum bleeding.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

6

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Calcium 1.25nM with NO oxytocin pre-exposure; Dose-response testing with 1.25nM calcium chloride, and increasing concentrations of carbetocin in a pattern of 1 log molar increase every 10 min, from 10-10 M to 10-5 M, with NO oxytocin pre-exposure	Drug: Carbetocin; Increasing concentrations of carbetocin in a pattern of 1 log molar increase every 10 min, from 10-10 M to 10-5 M; Drug: Calcium; Calcium chloride in the following concentrations:1.25mM, 2.5mM and 5.0mM.
Active Comparator: Calcium 2.5nM with NO oxytocin pre-exposure; Dose-response testing with 2.5nM calcium chloride, and increasing concentrations of carbetocin in a pattern of 1 log molar increase every 10 min, from 10-10 M to 10-5 M, with NO oxytocin pre-exposure	Drug: Carbetocin; Increasing concentrations of carbetocin in a pattern of 1 log molar increase every 10 min, from 10-10 M to 10-5 M; Drug: Calcium; Calcium chloride in the following concentrations:1.25mM, 2.5mM and 5.0mM.
Active Comparator: Calcium 5.0nM with NO oxytocin pre-exposure; Dose-response testing with 5.0nM calcium chloride, and increasing concentrations of carbetocin in a pattern of 1 log molar increase every 10 min, from 10-10 M to 10-5 M, with NO oxytocin pre-exposure	Drug: Carbetocin; Increasing concentrations of carbetocin in a pattern of 1 log molar increase every 10 min, from 10-10 M to 10-5 M; Drug: Calcium; Calcium chloride in the following concentrations:1.25mM, 2.5mM and 5.0mM.
Active Comparator: Calcium 1.25nM with oxytocin pre-exposure; Dose-response testing with 1.25nM calcium chloride, and increasing concentrations of carbetocin in a pattern of 1 log molar increase every 10 min, from 10-10 M to 10-5 M, with oxytocin pre-exposure	Drug: Carbetocin; Increasing concentrations of carbetocin in a pattern of 1 log molar increase every 10 min, from 10-10 M to 10-5 M; Drug: Calcium; Calcium chloride in the following concentrations:1.25mM, 2.5mM and 5.0mM.; Drug: Oxytocin; Oxytocin 10-5M will be added to 3 groups of myometrial strips for 2 hours to induce desensitization.
Active Comparator: Calcium 2.5nM with oxytocin pre-exposure; Dose-response testing with 2.5nM calcium chloride, and increasing concentrations of carbetocin in a pattern of 1 log molar increase every 10 min, from 10-10 M to 10-5 M, with oxytocin pre-exposure	Drug: Carbetocin; Increasing concentrations of carbetocin in a pattern of 1 log molar increase every 10 min, from 10-10 M to 10-5 M; Drug: Calcium; Calcium chloride in the following concentrations:1.25mM, 2.5mM and 5.0mM.; Drug: Oxytocin; Oxytocin 10-5M will be added to 3 groups of myometrial strips for 2 hours to induce desensitization.
Active Comparator: Calcium 5.0nM with oxytocin pre-exposure; Dose-response testing with 5.0nM calcium chloride, and increasing concentrations of carbetocin in a pattern of 1 log molar increase every 10 min, from 10-10 M to 10-5 M, with oxytocin pre-exposure	Drug: Carbetocin; Increasing concentrations of carbetocin in a pattern of 1 log molar increase every 10 min, from 10-10 M to 10-5 M; Drug: Calcium; Calcium chloride in the following concentrations:1.25mM, 2.5mM and 5.0mM.; Drug: Oxytocin; Oxytocin 10-5M will be added to 3 groups of myometrial strips for 2 hours to induce desensitization.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Motility index	Motility index (MI) is a calculated outcome, based on the formula: frequency/(10 x amplitude). Frequency and amplitude are secondary outcome measures as described below. The analysis is undertaken by attaching myometrial strips between an isometric force transducer and the base of an organ bath chamber.	4 hours

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Integrated area under response curve (AUC)		4 hours
Amplitude of contraction	The maximum extent of uterine muscle contraction, measured in grams (g). The analysis is undertaken by attaching myometrial strips between an isometric force transducer and the base of an organ bath chamber.	4 hours
Frequency of contraction	The number of contractions in uterine muscle (myometrium) over 10 minutes, spontaneously and in response to an agonist. The analysis is undertaken by attaching myometrial strips between an isometric force transducer and the base of an organ bath chamber.	4 hours

Collaborators and Investigators

• Sponsor: Samuel Lunenfeld Research Institute, Mount Sinai Hospital

Study record dates

Study Major Dates

• Study Start (Actual): September 15, 2025
• Primary Completion (Estimated): June 1, 2026
• Study Completion (Estimated): June 1, 2026

Study Registration Dates

• First Submitted: April 9, 2025
• First Submitted That Met QC Criteria: April 9, 2025
• First Posted (Actual): April 16, 2025

Study Record Updates

• Last Update Posted (Estimated): September 24, 2025
• Last Update Submitted That Met QC Criteria: September 22, 2025
• Last Verified: September 1, 2025

More Information

Terms related to this study

• Keywords: calcium; cesarean delivery; carbetocin; uterine contraction
• Additional Relevant MeSH Terms: Urogenital Diseases; Pathologic Processes; Female Urogenital Diseases and Pregnancy Complications; Obstetric Labor Complications; Pregnancy Complications; Hemorrhage; Puerperal Disorders; Uterine Hemorrhage; Pathological Conditions, Signs and Symptoms; Postpartum Hemorrhage; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Peptide Hormones; Peptides; Amino Acids, Peptides, and Proteins; Biological Factors; Inorganic Chemicals; Elements; Metals; Blood Coagulation Factors; Pituitary Hormones, Posterior; Pituitary Hormones; Metals, Alkaline Earth; Calcium; Oxytocin; carbetocin
• Other Study ID Numbers: 25-01 (St. Francis Hospital IRB)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No