Postpartum HemorrhageNCT02762669
Recovery of Oxytocin Responsiveness in Pregnant Human Myometrial Explants After Oxytocin-Induced Desensitization: an In-vitro Analysis of Oxytocin Receptor Expression and Signaling
A study testing Oxytocin in people with Postpartum Hemorrhage, run by Samuel Lunenfeld Research Institute, Mount Sinai Hospital at 1 site in Canada.
Trial summary
Postpartum hemorrhage (PPH) is a leading cause of maternal mortality and morbidity worldwide, and is caused most commonly by poor uterine muscle contraction after delivery of the baby and placenta. Read more about this study
- Who is it for?
- Ages 16 to 40 years, women onlyHealthy volunteers can take part
- Conditions the study is for
- Postpartum Hemorrhage
- What is being tested?
- Oxytocin
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 4 participants
- Where
- 1 siteCanada
- Study dates
- 3 Aug 2016to 31 Dec 2023
- Phase
- Interventional
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 16 to 40 years
- Women only
- Healthy volunteers accepted
- Child, Adult
Who may be able to join
- Patients who give written consent to participate in this study
- Patients with gestational age 37-41 weeks
- Non-laboring patients, not exposed to exogenous oxytocin
- Patients requiring primary Cesarean delivery or first repeat Cesarean delivery
Who cannot join
- Patients who refuse to give written informed consent
- Patients who require general anesthesia
- Patients who had previous uterine surgery or more than one previous Cesarean delivery
- Patients with any condition predisposing to uterine atony and postpartum hemorrhage, such as abnormal placentation, multiple gestation, preeclampsia, macrosomia, polyhydramnios, uterine fibroids, bleeding diathesis, chorioamnionitis, or a previous history of postpartum bleeding
- Emergency Cesarean section in labor
- Patients on medications that could affect myometrial contractility, such as nifedipine, labetolol or magnesium sulphate.
Trial locations and contacts
1 site in 1 country.
About this study
Postpartum hemorrhage (PPH) is a leading cause of maternal mortality and morbidity worldwide, and is caused most commonly by poor uterine muscle contraction after delivery of the baby and placenta. The first line agent used in the prevention and treatment of PPH is oxytocin, which acts by binding with the oxytocin receptor (OTR) found on myometrial cells to cause uterine contraction.
Oxytocin is also used for the augmentation of labor when spontaneous labor has been deemed ineffective. It is administered intravenously at progressively higher doses, until effective contractions are achieved and vaginal delivery results. However, if augmentation is determined to have failed, a Cesarean delivery (CD) is performed.
Read more
One of the potential problems with oxytocin use during delivery is that it loses its effectiveness if the uterus has previously been pre-exposed to its high doses and/or for a prolonged duration during labor. This phenomenon is termed OTR desensitization, and can result in the attenuation of myometrial contractility induced by subsequent oxytocin administration, as well as PPH due to poor uterine tone. Furthermore, oxytocin can produce potentially fatal maternal hemodynamic adverse effects when administered at high doses, so it is advantageous to be able to use as low a dose as possible to obtain good uterine muscle tone.
The objective of this study is to get a better understanding of the signaling pathways governing desensitization, resensitization and contractility in pregnant human myometrium. The investigators wish to investigate the effects of increasing recovery period on the expression patterns of the OTR and its signaling pathways in desensitized pregnant human myometrium.
This study will help shed light on the molecular mechanisms responsible for desensitization and oxytocin-induced myometrial contractility, and will provide some insight into potential therapeutic targets to reduce the incidence of PPH and complications associated with using increasing concentrations of oxytocin.
The hypothesis is that the expression and phosphorylation patterns of the OTR and downstream proteins will be altered in desensitized myometrium, and that these patterns will change with increasing rest periods and re-exposure to oxytocin.
Read the detailed description
Clinically, women who require augmentation of labor are at increased risk of PPH due to their greater exposure to oxytocin in both duration and dose through exogenous administration, presumably mediated by OTR desensitization. In current practice, upon diagnosis of failure to progress during labor augmentation, oxytocin administration is discontinued, and as long as there is no indication for immediate delivery, there is a variable duration to proceed to CD. Due to the high likelihood of OTR desensitization in this patient population, it would be clinically relevant to determine the molecular mechanisms underlying this action.
A recent study from the investigators' group, looking at the rest time required for recovery and resensitization of the OTR following desensitization, showed that there were no improvements in oxytocin-induced myometrial contractility after either a 30, 60 or 90 minute rest period. The reason for why resensitization does not occur remains unknown, but a possible explanation is that the OTRs undergo structural and functional changes during desensitization that prohibit their recovery.
The investigators propose to use our previously established in-vitro model of labour augmentation and OTR desensitization (using pregnant human myometrium and an isometric tension recording device) to investigate the molecular mechanisms governing OTR desensitization and resensitization after stopping administration of oxytocin. Investigation of the signaling pathways responsible for these processes, as well as for oxytocin-induced contractions in a controlled in-vitro system will aid in the understanding of the kinetics of the OTR-oxytocin system and provide insight into potential pharmacotherapeutic targets to reduce the incidence of PPH.
- Conditions
- Postpartum Hemorrhage
- Being tested
- Oxytocin
- Keywords
- Uterine contraction, Oxytocin desensitization
- Medical subject headings
- Postpartum Hemorrhage
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
OxytocinDrug
Also called pitocin
Oxytocin, 10-7mol/L to 10-5mol/L
| Study group | Role | What they receive |
|---|---|---|
| Control (no oxytocin) + No recovery | No intervention | A control experiment will be undertaken in which the myometrial explants will be exposed to PSS for 2-hours without any oxytocin. No recovery time. |
| Continuous oxytocin + No recovery | Active comparator | 10-5M oxytocin for 2 hours. No recovery time. Receives: Drug: Oxytocin |
| Continuous oxytocin + 30 minute recovery | Active comparator | 10-5M oxytocin for 2 hours. After 2 hours, the solution will be drained from the organ baths, and any residual solution will be removed by washing three times with PSS. Following this, the strip will be exposed to PSS for 30 minutes. Receives: Drug: Oxytocin |
| Continuous oxytocin + 60 minute recovery | Active comparator | 10-5M oxytocin for 2 hours. After 2 hours, the solution will be drained from the organ baths, and any residual solution will be removed by washing three times with PSS. Following this, the strip will be exposed to PSS for 60 minutes. Receives: Drug: Oxytocin |
| Control (no oxytocin) + No recovery + 10-7 oxytocin | Active comparator | A second control experiment will be undertaken in which the myometrial explants will be exposed to PSS for 2-hours without any oxytocin. After 2 hours, the solution will be drained from the organ baths, and replaced with fresh PSS. Following this, the strip will be exposed to 10-7 oxytocin for 10 minutes. Receives: Drug: Oxytocin |
| Continuous oxytocin + No recovery + 10-7 oxytocin | Active comparator | 10-5M oxytocin for 2 hours. After 2 hours, the solution will be drained from the organ baths, and any residual solution will be removed by washing three times with PSS. Following this, the strip will be exposed to 10-7 oxytocin for 10 minutes. Receives: Drug: Oxytocin |
| Continuous oxytocin + 30 minute recovery + 10-7 oxytocin | Active comparator | 10-5M oxytocin for 2 hours. After 2 hours, the solution will be drained from the organ baths, and any residual solution will be removed by washing three times with PSS. Following this, the strip will be exposed to PSS for 30 minutes. The strip will then be exposed to 10-7 oxytocin for 10 minutes. Receives: Drug: Oxytocin |
| Continuous oxytocin + 60 minute recovery + 10-7 oxytocin | Active comparator | 10-5M oxytocin for 2 hours. After 2 hours, the solution will be drained from the organ baths, and any residual solution will be removed by washing three times with PSS. Following this, the strip will be exposed to PSS for 60 minutes. The strip will then be exposed to 10-7 oxytocin for 10 minutes. Receives: Drug: Oxytocin |
What is being measured
The primary outcome is the main question the study is designed to answer.
Oxytocin receptor (OTR) protein expression and localization
Western blotting will be performed to detect expression levels of the OTR protein and its localization within the plasma membrane, cytoplasmic or nuclear cell fractions.
Measured: 24 hours
Secondary outcomes (2)
Oxytocin receptor (OTR) phosphorylation patterns
Proximity assays will be used to detect OTR phosphorylation patterns, by looking at the extent of OTR-β-arrestin binding.
Measured: 24 hours
Protein expression levels of PLC, MEK5 and ERK5
Western blotting will be performed to detect protein expression levels of PLC, MEK5 and ERK5
Measured: 24 hours
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted5 May 2016 (estimated)
- Study start3 Aug 2016
- Primary completion31 Dec 2023
- Study completion31 Dec 2023
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Other trials for Postpartum HemorrhageStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase N/A
- Primary purpose
- Treatment
- Allocation
- Non-randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Enrolment
- 4 participants (actual)
Sponsor and investigators
- Lead sponsor
- Samuel Lunenfeld Research Institute, Mount Sinai Hospital
- Sponsor type
- University, hospital or other
- Responsible party
- Sponsor
- Investigators
- Mrinalini Balki, MD, Principal investigator, MOUNT SINAI HOSPITAL
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT02762669
- Sponsor's protocol ID
- 16-05
- Status last verified
- Mar 2024
- First submitted
- 3 May 2016
- Last updated
- 27 Aug 2024
- Results posted
- No
- Data monitoring committee
- No
- Individual data sharing
- No
Study at a glance
From the registry record, last updated by the sponsor on 27 Aug 2024. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Recovery of Oxytocin Responsiveness in Pregnant Human Myometrial Explants After Oxytocin-Induced Desensitization: an In-vitro Analysis of Oxytocin Receptor Expression and Signaling
- ClinicalTrials.gov ID
- NCT02762669
- Acronym / sponsor ID
- 16-05
- Conditions
- Postpartum Hemorrhage
- Keywords
- Uterine contraction, Oxytocin desensitization
- Study type
- Interventional
- Recruitment status
- Terminated
- Enrolment
- 4 participants (actual)
- Lead sponsor
- Samuel Lunenfeld Research Institute, Mount Sinai HospitalUniversity, hospital or other
- Study start
- 3 Aug 2016 (actual)
- Primary completion
- 31 Dec 2023 (actual)
- Study completion
- 31 Dec 2023 (actual)
- First posted
- 5 May 2016 (estimated)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
Postpartum hemorrhage (PPH) is a leading cause of maternal mortality and morbidity worldwide, and is caused most commonly by poor uterine muscle contraction after delivery of the baby and placenta. The first line agent used in the prevention and treatment of PPH is oxytocin, which acts by binding with the oxytocin receptor (OTR) found on myometrial cells to cause uterine contraction.
Oxytocin is also used for the augmentation of labor when spontaneous labor has been deemed ineffective. It is administered intravenously at progressively higher doses, until effective contractions are achieved and vaginal delivery results. However, if augmentation is determined to have failed, a Cesarean delivery (CD) is performed.
One of the potential problems with oxytocin use during delivery is that it loses its effectiveness if the uterus has previously been pre-exposed to its high doses and/or for a prolonged duration during labor. This phenomenon is termed OTR desensitization, and can result in the attenuation of myometrial contractility induced by subsequent oxytocin administration, as well as PPH due to poor uterine tone. Furthermore, oxytocin can produce potentially fatal maternal hemodynamic adverse effects when administered at high doses, so it is advantageous to be able to use as low a dose as possible to obtain good uterine muscle tone.
The objective of this study is to get a better understanding of the signaling pathways governing desensitization, resensitization and contractility in pregnant human myometrium. The investigators wish to investigate the effects of increasing recovery period on the expression patterns of the OTR and its signaling pathways in desensitized pregnant human myometrium.
This study will help shed light on the molecular mechanisms responsible for desensitization and oxytocin-induced myometrial contractility, and will provide some insight into potential therapeutic targets to reduce the incidence of PPH and complications associated with using increasing concentrations of oxytocin.
The hypothesis is that the expression and phosphorylation patterns of the OTR and downstream proteins will be altered in desensitized myometrium, and that these patterns will change with increasing rest periods and re-exposure to oxytocin.
Detailed description
Clinically, women who require augmentation of labor are at increased risk of PPH due to their greater exposure to oxytocin in both duration and dose through exogenous administration, presumably mediated by OTR desensitization. In current practice, upon diagnosis of failure to progress during labor augmentation, oxytocin administration is discontinued, and as long as there is no indication for immediate delivery, there is a variable duration to proceed to CD. Due to the high likelihood of OTR desensitization in this patient population, it would be clinically relevant to determine the molecular mechanisms underlying this action.
A recent study from the investigators' group, looking at the rest time required for recovery and resensitization of the OTR following desensitization, showed that there were no improvements in oxytocin-induced myometrial contractility after either a 30, 60 or 90 minute rest period. The reason for why resensitization does not occur remains unknown, but a possible explanation is that the OTRs undergo structural and functional changes during desensitization that prohibit their recovery.
The investigators propose to use our previously established in-vitro model of labour augmentation and OTR desensitization (using pregnant human myometrium and an isometric tension recording device) to investigate the molecular mechanisms governing OTR desensitization and resensitization after stopping administration of oxytocin. Investigation of the signaling pathways responsible for these processes, as well as for oxytocin-induced contractions in a controlled in-vitro system will aid in the understanding of the kinetics of the OTR-oxytocin system and provide insight into potential pharmacotherapeutic targets to reduce the incidence of PPH.
Study design
- Primary purpose
- Treatment
- Allocation
- Non-randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Number of arms
- 8
| Arm | Type | Receives |
|---|---|---|
| Control (no oxytocin) + No recovery | No intervention | –A control experiment will be undertaken in which the myometrial explants will be exposed to PSS for 2-hours without any oxytocin. No recovery time. |
| Continuous oxytocin + No recovery | Active comparator | Drug: Oxytocin10-5M oxytocin for 2 hours. No recovery time. |
| Continuous oxytocin + 30 minute recovery | Active comparator | Drug: Oxytocin10-5M oxytocin for 2 hours. After 2 hours, the solution will be drained from the organ baths, and any residual solution will be removed by washing three times with PSS. Following this, the strip will be exposed to PSS for 30 minutes. |
| Continuous oxytocin + 60 minute recovery | Active comparator | Drug: Oxytocin10-5M oxytocin for 2 hours. After 2 hours, the solution will be drained from the organ baths, and any residual solution will be removed by washing three times with PSS. Following this, the strip will be exposed to PSS for 60 minutes. |
| Control (no oxytocin) + No recovery + 10-7 oxytocin | Active comparator | Drug: OxytocinA second control experiment will be undertaken in which the myometrial explants will be exposed to PSS for 2-hours without any oxytocin. After 2 hours, the solution will be drained from the organ baths, and replaced with fresh PSS. Following this, the strip will be exposed to 10-7 oxytocin for 10 minutes. |
| Continuous oxytocin + No recovery + 10-7 oxytocin | Active comparator | Drug: Oxytocin10-5M oxytocin for 2 hours. After 2 hours, the solution will be drained from the organ baths, and any residual solution will be removed by washing three times with PSS. Following this, the strip will be exposed to 10-7 oxytocin for 10 minutes. |
| Continuous oxytocin + 30 minute recovery + 10-7 oxytocin | Active comparator | Drug: Oxytocin10-5M oxytocin for 2 hours. After 2 hours, the solution will be drained from the organ baths, and any residual solution will be removed by washing three times with PSS. Following this, the strip will be exposed to PSS for 30 minutes. The strip will then be exposed to 10-7 oxytocin for 10 minutes. |
| Continuous oxytocin + 60 minute recovery + 10-7 oxytocin | Active comparator | Drug: Oxytocin10-5M oxytocin for 2 hours. After 2 hours, the solution will be drained from the organ baths, and any residual solution will be removed by washing three times with PSS. Following this, the strip will be exposed to PSS for 60 minutes. The strip will then be exposed to 10-7 oxytocin for 10 minutes. |
Who may qualify
- Ages
- 16 to 40 years
- Sex
- Female only
- Healthy volunteers
- Accepted
- Age groups
- Child, Adult
Key inclusion criteria (4 listed)
- Patients who give written consent to participate in this study
- Patients with gestational age 37-41 weeks
- Non-laboring patients, not exposed to exogenous oxytocin
- Patients requiring primary Cesarean delivery or first repeat Cesarean delivery
Key exclusion criteria (6 listed)
- Patients who refuse to give written informed consent
- Patients who require general anesthesia
- Patients who had previous uterine surgery or more than one previous Cesarean delivery
- Patients with any condition predisposing to uterine atony and postpartum hemorrhage, such as abnormal placentation, multiple gestation, preeclampsia, macrosomia, polyhydramnios, uterine fibroids, bleeding diathesis, chorioamnionitis, or a previous history of postpartum bleeding
- Emergency Cesarean section in labor
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| OxytocinAlso: pitocinOxytocin, 10-7mol/L to 10-5mol/L | Drug | Continuous oxytocin + 30 minute recovery, Continuous oxytocin + 30 minute recovery + 10-7 oxytocin, Continuous oxytocin + 60 minute recovery, Continuous oxytocin + 60 minute recovery + 10-7 oxytocin, Continuous oxytocin + No recovery, Continuous oxytocin + No recovery + 10-7 oxytocin, Control (no oxytocin) + No recovery + 10-7 oxytocin |
Primary outcome
Oxytocin receptor (OTR) protein expression and localization
Time frame: 24 hours
Western blotting will be performed to detect expression levels of the OTR protein and its localization within the plasma membrane, cytoplasmic or nuclear cell fractions.
2 secondary outcomes
Oxytocin receptor (OTR) phosphorylation patterns
Time frame: 24 hours
Protein expression levels of PLC, MEK5 and ERK5
Time frame: 24 hours
Results and safety
The study was stopped early. Results are not available in the source record.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 27 Aug 2024.
- Individual participant dataSharing planned: No
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Mrinalini Balki, MD principal investigator
MOUNT SINAI HOSPITAL
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A study testing Oxytocin in people with Postpartum Hemorrhage, run by Samuel Lunenfeld Research Institute, Mount Sinai Hospital at 1 site in Canada.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 4 inclusion and 6 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: stopped early, as of the sponsor's last update on 27 Aug 2024. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in Canada. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
Are results available for this study?
The study was stopped early. Results are not available in the source record.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Oxytocin receptor (OTR) protein expression and localization (time frame: 24 hours). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 27 Aug 2024.