Prophylactic Methylergonovine for Twin Cesarean

Prophylactic Methylergonovine in Patients Undergoing Cesarean Delivery With Twin Gestations: A Randomized Controlled Trial

Obstetrical hemorrhage (excessive bleeding related to pregnancy) is a leading cause of maternal morbidity (disease or symptom of disease) and mortality (death) worldwide with a significantly higher frequency and severity following cesarean delivery. Twin gestations (twin pregnancy) are at particularly higher risk for postpartum hemorrhage, yet the management of obstetrical bleeding following twin delivery remains identical to singleton delivery.

The purpose of this study is to understand the effect of prophylactic methylergonovine on blood loss in scheduled twin pregnancy cesarean deliveries. Participants will be randomized (like tossing a coin) to Methylergonovine (investigational drug) or water with salt (saline) (placebo). Methylergonovine or saline will be given as an injection immediately after delivery.

Study Overview

• Status: Recruiting
• Conditions: Postpartum Hemorrhage; Twin; Complicating Pregnancy
• Intervention / Treatment: Drug: Methylergonovine; Drug: Placebo

Detailed Description

Obstetrical hemorrhage is a leading cause of maternal morbidity and mortality worldwide with a significantly higher frequency and severity following cesarean delivery. In 2020, 31.9 percent of pregnant women in the United States underwent cesarean delivery, making it the second most common operation performed. Though multiple complications can occur following cesarean delivery, hemorrhage morbidities are among the most common with significant cardiovascular implications. Twin gestations are at particularly higher risk for postpartum hemorrhage due to impaired myometrial contractility and atony following overdistention; increased maternal blood volume; and increased uterine blood flow compared to singletons, yet the management of obstetrical bleeding following twin delivery remains identical to singleton delivery. Current strategies to address intrapartum hemorrhage have relied on pharmacological and mechanical treatments after intraoperative identification. However, there is extensive work on prophylactic therapies administered intraoperatively to prevent obstetrical hemorrhage. Recent evidence has emerged about the utility of prophylactic Methylergonovine for the prevention of obstetrical hemorrhage. Methylergonovine, a semisynthetic ergot alkaloid, acts primarily on alpha adrenergic receptors of uterine and vascular smooth muscle, increasing uterine tone and promoting vasoconstriction. In a randomized trial of 80 women undergoing intrapartum cesarean delivery found that fewer patients who were allocated to the methylergonovine group received additional uterotonic agents (20% vs 55%, relative risk (RR) 0.4, 95% confidence interval (CI) 0.2-0.6). Participants receiving methylergonovine were more likely to have satisfactory uterine tone (80% vs 41%, RR 1.9, 95% CI 1.5-2.6), lower incidence of postpartum hemorrhage (35% vs 59%, RR 0.6, 95% CI 0.4-0.9), lower mean quantitative blood loss (967 mL vs 1,315 mL; mean difference 348, 95% CI 124-572), and a lower frequency of blood transfusion (5% vs 23%, RR 0.2, 95% CI 0.1-0.6). Investigators concluded that the administration of prophylactic methylergonovine in addition to oxytocin in patients undergoing intrapartum cesarean birth reduces the need for additional uterotonic agents. In a prospective study of 1210 participants found that intraoperative, prophylactic methylergonovine decreased post-operative blood loss with no adverse side effects. Randomized trials of Methylergonovine as prophylaxis to prevent hemorrhage in cesarean delivery have exclude twin gestations. Currently, there remains a paucity of research regarding prophylactic procedures for twin cesarean delivery. There is an opportunity to prophylactically address hemorrhage in high-risk groups. Therefore, the investigators propose a prospective randomized controlled trial which will compare maternal blood loss associated with prophylactic methylergonovine during cesarean delivery among patients with twin.

• Study Type: Interventional
• Enrollment (Anticipated): 66
• Phase: Phase 4

Contacts and Locations

• Study Contact: Name: Mirella Mourad; Phone Number: 212-305-6293; Email: mjm2246@cumc.columbia.edu

Study Locations

• United States
  • New York
    • New York, New York, United States, 10032
      • Recruiting
      • Columbia University Irving Medical Center
      • Contact: Mirella Mourad, MD; Phone Number: 212-305-6293; Email: mjm2246@cumc.columbia.edu

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: No older than 65 years (Child, Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Twin gestation
• Scheduled cesarean delivery (>=34 weeks)

Exclusion criteria:

• Patients with known hypertensive disease: history of chronic hypertension, gestational hypertension or preeclampsia with or without severe features
• Use of protease inhibitors given known vasoconstrictive side effects with concomitant methylergonovine administration
• Hypersensitivity to methylergonovine or any of the ingredients
• Participating in another intervention study where the primary outcome includes postpartum bleeding or thromboembolism, or the study intervention directly affects postpartum bleeding or thromboembolism
• Receipt of uterotonics, other than oxytocin, or planned or expected use of uterotonic prophylaxis
• Non-elective cesarean delivery

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Prevention
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Double

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Prophylactic methylergonovine; Prophylactic methylergonovine 200mcg IM	Drug: Methylergonovine; Methylergonovine 200mcg Intramuscular (IM); Other Names: Methergine
Placebo Comparator: Control group/placebo; Matching placebo	Drug: Placebo; Matching saline placebo; Other Names: Saline

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in maternal hemoglobin level	The change in maternal hemoglobin level as taken from blood samples. The change will be calculated from preoperative day 1 (baseline) to postoperative day 1.	Baseline and Postoperative Day 1 (Approximately 48 hours)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Surgical time	Surgical time measured from the time of incision to closure	Intraoperative (Approximately 24 hours)
Estimated blood loss	At the end of the surgery, the primary surgeon will estimate the blood loss throughout the case.	Intraoperative (Approximately 24 hours)
Quantitative blood loss	Quantitative blood loss is calculated by weighing the used towels during the operation. The number is calculated by the circulating nurse in the operating room.	Intraoperative (Approximately 24 hours)
Number of Participants with Postpartum hemorrhage	The number of participants with postpartum hemorrhage (defined as estimated blood loss >1000 cc)	Intraoperative (Approximately 24 hours)
Number of Participants Requiring Use of Uterotonics	Number of participants given uterotonics, such as prostaglandins	Intraoperative (Approximately 24 hours)
Number of Participants Requiring Use of Tranexamic acid Use of Tranexamic acid Use of Tranexamic acid	Number of participants given Tranexamic acid	Intraoperative (Approximately 24 hours)
Number of Participants Requiring Use of Open-Label Methylergonovine	Number of participants requiring the use of any amount of open-label methylergonovine (not blinded study drug)	Intraoperative (Approximately 24 hours)
Number of Participants Requiring Transfusion (Intraoperative)	Number of participants requiring transfusion of 1 or more units of packed red blood cells, including whole blood or cell saver.	Intraoperative (Approximately 24 hours)
Composite Number of Surgical or Radiological Interventions	Composite number of surgical or radiological interventions (such as: laparotomy, evacuation of hematoma, hysterectomy, uterine packing, intrauterine balloon tamponade, interventional radiology) to control bleeding and related complications or maternal death.	Intraoperative (Approximately 24 hours)
Number of Participants with Transfusion related acute lung injury (TRALI)	Number of participants with transfusion related acute lung injury (TRALI)	6 weeks
Number of Participants Requiring Transfusion (6 weeks)	Number of participants requiring transfusion of 1 or more units of fresh frozen plasma, cryoprecipitate, or platelets or administration of any factor concentrates.	6 weeks
Number of Participants with Acute Elevation of Serum Creatinine	Number of participants with acute elevation of serum creatinine of ≥ 0.3 mg/dL	48 hours
Number of Postpartum Infectious Complications	Number of Postpartum infectious complications such as: endometritis, surgical site infection, pelvic abscess	6 weeks
Number of Participants with Admission to the Intensive Care Unit	Number of participants with admission to the intensive care unit for more than 24 hours	6 weeks
Length of stay	Length of stay measured from the time of hospital admission to hospital discharge.	5 days
Number of Participants Re-Admitted to the Hospital	The number of participants who experienced hospital re-admission	6 weeks
Apgar scores	Apgar score is a measure of the physical condition of a newborn infant. Scores range from 0-10 with a higher score indicating a better outcome; 5-minute Apgar score of 0-3 is low, 4-6 is moderately abnormal, and 7-10 is reassuring.	Time of delivery (Approximately 24 hours)
Neonatal intensive care unit (NICU) admission	Number of newborns admitted to the neonatal intensive care unit (NICU).	Time of delivery (Approximately 24 hours)

Collaborators and Investigators

• Sponsor: Columbia University
• Investigators: Principal Investigator: Mirella Mourad, Columbia University

Publications and helpful links

General Publications

• Attilakos G, Psaroudakis D, Ash J, Buchanan R, Winter C, Donald F, Hunt LP, Draycott T. Carbetocin versus oxytocin for the prevention of postpartum haemorrhage following caesarean section: the results of a double-blind randomised trial. BJOG. 2010 Jul;117(8):929-36. doi: 10.1111/j.1471-0528.2010.02585.x. Epub 2010 May 19.
• Osterman M, Hamilton B, Martin JA, Driscoll AK, Valenzuela CP. Births: Final Data for 2020. Natl Vital Stat Rep. 2021 Feb;70(17):1-50.
• Sheehan SR, Montgomery AA, Carey M, McAuliffe FM, Eogan M, Gleeson R, Geary M, Murphy DJ; ECSSIT Study Group. Oxytocin bolus versus oxytocin bolus and infusion for control of blood loss at elective caesarean section: double blind, placebo controlled, randomised trial. BMJ. 2011 Aug 1;343:d4661. doi: 10.1136/bmj.d4661.
• Blitz MJ, Yukhayev A, Pachtman SL, Reisner J, Moses D, Sison CP, Greenberg M, Rochelson B. Twin pregnancy and risk of postpartum hemorrhage. J Matern Fetal Neonatal Med. 2020 Nov;33(22):3740-3745. doi: 10.1080/14767058.2019.1583736. Epub 2019 Mar 5.
• Chaudhuri P, Banerjee GB, Mandal A. Rectally administered misoprostol versus intravenous oxytocin infusion during cesarean delivery to reduce intraoperative and postoperative blood loss. Int J Gynaecol Obstet. 2010 Apr;109(1):25-9. doi: 10.1016/j.ijgo.2009.11.009. Epub 2010 Jan 13.
• Senturk S, Kagitci M, Balik G, Arslan H, Kir Sahin F. The Effect of the Combined Use of Methylergonovine and Oxytocin during Caesarean Section in the Prevention of Post-partum Haemorrhage. Basic Clin Pharmacol Toxicol. 2016 May;118(5):338-43. doi: 10.1111/bcpt.12500. Epub 2015 Nov 15.
• Masse N, Dexter F, Wong CA. Prophylactic Methylergonovine and Oxytocin Compared With Oxytocin Alone in Patients Undergoing Intrapartum Cesarean Birth: A Randomized Controlled Trial. Obstet Gynecol. 2022 Aug 1;140(2):181-186. doi: 10.1097/AOG.0000000000004857. Epub 2022 Jul 6.
• Horowitz E, Yogev Y, Ben-Haroush A, Rabinerson D, Feldberg D, Kaplan B. Routine hemoglobin testing following an elective Cesarean section: is it necessary? J Matern Fetal Neonatal Med. 2003 Oct;14(4):223-5. doi: 10.1080/jmf.14.4.223.225.

Study record dates

Study Major Dates

• Study Start (Actual): March 7, 2023
• Primary Completion (Anticipated): December 31, 2023
• Study Completion (Anticipated): January 30, 2024

Study Registration Dates

• First Submitted: March 6, 2023
• First Submitted That Met QC Criteria: March 6, 2023
• First Posted (Actual): March 16, 2023

Study Record Updates

• Last Update Posted (Actual): May 1, 2023
• Last Update Submitted That Met QC Criteria: April 28, 2023
• Last Verified: April 1, 2023

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Pathologic Processes; Obstetric Labor Complications; Puerperal Disorders; Uterine Hemorrhage; Hemorrhage; Pregnancy Complications; Postpartum Hemorrhage; Physiological Effects of Drugs; Reproductive Control Agents; Oxytocics; Methylergonovine
• Other Study ID Numbers: AAAU3902

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED

IPD Plan Description

It is currently undecided if the Individual participant data (IPD) will be shared.

If there is a plan to share the following will be shared: the IPD that underlie the results reported in this article, after deidentification (text, tables, figures, and appendices), the Study Protocol, Statistical Analysis Plan, and, Informed Consent Form documents. The timeframe for which the IPD will be shared is beginning 3 months and ending 5 years following article publication. Data will be shared with researchers who provide a methodologically sound proposal, so that they may achieve aims in the proposal.

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No