Second-Line Uterotonics in Postpartum Hemorrhage: A Randomized Clinical Trial

NCT ID: NCT03584854

Last Updated: 2025-10-16

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE4
• Total Enrollment: 100 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2019-03-01
• Study Completion Date: 2022-06-15

Brief Summary

The aim of this study is to evaluate in a randomized fashion the comparative efficacy of two second-line medications, methylergonovine and carboprost for treating atonic postpartum hemorrhage (PPH). The investigators hypothesize that administration of methylergonovine will produce superior uterine tone to carboprost in atonic PPH.

Detailed Description

Primary postpartum hemorrhage (PPH) is defined by the American College of Obstetricians and Gynecologists as a cumulative blood loss of >1000 mL within 24 hours of the birth process. PPH remains a leading source of maternal morbidity and mortality worldwide with uterine atony identified as the underlying cause in up to 80% of cases. Between 1994 and 2006, the rate of PPH increased by 26% in the United States, raising further concern for this problem.

Treatment of PPH typically begins with administration of exogenous oxytocin, a hormone responsible for uterine contraction. When postpartum bleeding persists despite oxytocin administration, a multidisciplinary approach combining mechanical, pharmacologic, and surgical measures is indicated. Approximately 3-25% of PPH cases require a second-line uterotonic agent in addition to oxytocin, with the two most commonly administered second-line agents in the U.S.A. being methylergonovine maleate (methylergonovine) and 15-methyl prostaglandin F2α (carboprost). The comparative efficacy of these two drugs is unknown and the most recent American College of Obstetricians and Gynecologists Practice Bulletin makes no recommendation on which second-line uterotonic agents to administer preferentially in the absence of contraindications.

This study will evaluate in a randomized fashion the comparative efficacy of methylergonovine and carboprost for treating atonic PPH. Patients undergoing non-emergent cesarean section (C/S) with uterine atony and no contraindications to either drug will be randomized to receive one of the two equivalent agents in a blinded fashion after oxytocin. After ten minutes, their uterine tone will be assessed by the obstetrician and reported on a 0-10 point scale.

A power calculation was performed to detect a mean difference in uterine tone between groups of 1 point on a 0-10 point scale with 80% power and significance level of 0.05. The investigators estimate 37 patients will be required in each arm. Allowing for a 20% rate of withdrawals or missing information, a total of 100 patients will be enrolled in this study.

Investigators will adhere to the FDA Expedited Safety Requirements in reporting any adverse event that is serious, unexpected, and associated with the use of the study drugs. Any such adverse event will be reported to the study site Institutional Review Board (IRB) and serious events will prompt the study to be halted until further discussion with the IRB.

Conditions

Postpartum Hemorrhage; Uterine Atony

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: DOUBLE

Study Groups

15-methyl prostaglandin F2α

IM Carboprost followed by Methylergonovine if needed.

Group Type: ACTIVE_COMPARATOR

15-methyl prostaglandin F2α

Intervention Type: DRUG

Participants will receive standard intraoperative care including an infusion of oxytocin immediately postpartum. If a second-line uterotonic is requested, patients randomized to the "carboprost" study group will receive an intramuscular dose of 0.25mg (1mL) carboprost. If another second-line uterotonic is requested, the patients will receive 0.2mg (1mL) intramuscular methylergonovine.

Methylergonovine Maleate

Intervention Type: DRUG

Participants will receive standard intraoperative care including an infusion of oxytocin immediately postpartum. If a second-line uterotonic is requested, patients randomized to the "methergine" study group will receive an intramuscular dose of 0.2mg (1mL) methylergonovine. If another second-line uterotonic is requested, the patients will receive 0.25mg (1mL) intramuscular carboprost.

Methylergonovine Maleate

IM Methylergonovine followed by Carboprost if needed.

Group Type: ACTIVE_COMPARATOR

15-methyl prostaglandin F2α

Intervention Type: DRUG

Participants will receive standard intraoperative care including an infusion of oxytocin immediately postpartum. If a second-line uterotonic is requested, patients randomized to the "carboprost" study group will receive an intramuscular dose of 0.25mg (1mL) carboprost. If another second-line uterotonic is requested, the patients will receive 0.2mg (1mL) intramuscular methylergonovine.

Methylergonovine Maleate

Intervention Type: DRUG

Participants will receive standard intraoperative care including an infusion of oxytocin immediately postpartum. If a second-line uterotonic is requested, patients randomized to the "methergine" study group will receive an intramuscular dose of 0.2mg (1mL) methylergonovine. If another second-line uterotonic is requested, the patients will receive 0.25mg (1mL) intramuscular carboprost.

Interventions

15-methyl prostaglandin F2α

Participants will receive standard intraoperative care including an infusion of oxytocin immediately postpartum. If a second-line uterotonic is requested, patients randomized to the "carboprost" study group will receive an intramuscular dose of 0.25mg (1mL) carboprost. If another second-line uterotonic is requested, the patients will receive 0.2mg (1mL) intramuscular methylergonovine.

Intervention Type: DRUG

Methylergonovine Maleate

Participants will receive standard intraoperative care including an infusion of oxytocin immediately postpartum. If a second-line uterotonic is requested, patients randomized to the "methergine" study group will receive an intramuscular dose of 0.2mg (1mL) methylergonovine. If another second-line uterotonic is requested, the patients will receive 0.25mg (1mL) intramuscular carboprost.

Intervention Type: DRUG

Other Intervention Names

Carboprost; Methylergonovine

Eligibility Criteria

Inclusion Criteria

• non-emergent cesarean delivery
• ASA I-III
• postpartum hemorrhage deemed the result of uterine atony (uterine atony at the time of delivery, despite the administration of oxytocin)

Exclusion Criteria

• non-English speaking patients requiring an interpreter for urgent, unscheduled delivery
• any hypertensive disorder
• cardiovascular disease
• asthma
• refusal of transfused blood products
• coagulopathy or abnormal coagulation lab values
• hypersensitivity to methylergonovine maleate or 15-methyl prostaglandin
• known or suspected delayed postpartum hemorrhage after leaving the operating room

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 50 Years
• Eligible Sex: FEMALE
• Accepts Healthy Volunteers: Yes

Sponsors

Northwestern Memorial Hospital

OTHER

Sponsor Role: collaborator

Brigham and Women's Hospital

OTHER

Sponsor Role: lead

Responsible Party

Jimin Kim, MD

Attending anesthesiologist

Responsibility Role: PRINCIPAL_INVESTIGATOR

Principal Investigators

Naida M Cole, MD

Role: PRINCIPAL_INVESTIGATOR

Brigham and Women's Hospital, 75 Francis Street, Boston MA 02115

Locations

Brigham and Women's Hospital

Boston, Massachusetts, United States

Countries

United States

References

Cole NM, Kim JJ, Lumbreras-Marquez MI, Fields KG, Mendez-Pino L, Farber MK, Carusi DA, Toledo P, Bateman BT. Second-Line Uterotonics for Uterine Atony: A Randomized Controlled Trial. Obstet Gynecol. 2024 Dec 1;144(6):832-841. doi: 10.1097/AOG.0000000000005744. Epub 2024 Sep 26.

Reference Type: DERIVED

PMID: 39326051 (View on PubMed)

Parry Smith WR, Papadopoulou A, Thomas E, Tobias A, Price MJ, Meher S, Alfirevic Z, Weeks AD, Hofmeyr GJ, Gulmezoglu AM, Widmer M, Oladapo OT, Vogel JP, Althabe F, Coomarasamy A, Gallos ID. Uterotonic agents for first-line treatment of postpartum haemorrhage: a network meta-analysis. Cochrane Database Syst Rev. 2020 Nov 24;11(11):CD012754. doi: 10.1002/14651858.CD012754.pub2.

Reference Type: DERIVED

PMID: 33232518 (View on PubMed)

Provided Documents

Document Type: Study Protocol

View Document

Document Type: Statistical Analysis Plan

View Document

Other Identifiers

2018P000775-A

Identifier Type: -

Identifier Source: org_study_id