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

Study Overview
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Brief Summary
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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
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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.

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

Conditions
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Postpartum Hemorrhage, Uterine Atony

Intervention / Treatment
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* Drug: 15-methyl prostaglandin F2α
* Drug: Methylergonovine Maleate


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: pregnant with a fetus >/=24 weeks gestational age non-emergent cesarean delivery postpartum hemorrhage deemed the result of uterine atony Exclusion Criteria: non-English speaking patients requiring an interpreter 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

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 50 Years

Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: 15-methyl prostaglandin F2α<br>IM Carboprost followed by Methylergonovine if needed. | Drug: 15-methyl prostaglandin F2α<br>* 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.<br>* Other names: Carboprost;Drug: Methylergonovine Maleate<br>* 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.<br>* Other names: Methylergonovine;|
| Active Comparator: Methylergonovine Maleate<br>IM Methylergonovine followed by Carboprost if needed. | Drug: 15-methyl prostaglandin F2α<br>* 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.<br>* Other names: Carboprost;Drug: Methylergonovine Maleate<br>* 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.<br>* Other names: Methylergonovine;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Uterine Tone | Uterine contractile tone will be measured on a 0-10 score as assessed by the obstetrician; 0 is 'no tone', 10 is 'perfect tone' or 'excellent tone' | at 10 minutes following administration of the first study drug | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Uterine Tone | Uterine contractile tone will be measured on a 0-10 score as assessed by the obstetrician; 0 is 'no tone', 10 is 'perfect tone' or 'excellent tone' | at 5 minutes following administration of the first study drug | 
| Additional Uterotonic | An additional second-line uterotonic which is given in the operating room after administration of the first study drug | from time of delivery until surgery completion | 
| Transfusion | The number of blood products transfused for anemia due to postpartum blood loss | within the first 24 hours after delivery of the fetus | 
| Additional Intervention | The need for an additional surgical or radiologic intervention to control postpartum hemorrhage | within the first 24 hours after delivery of the fetus | 
| Quantitative Blood Loss (QBL) | The total volume of blood loss measured by a QBL scale weighing surgical drapes, towels, sponges and suction fluid | within the first 24 hours after delivery of the fetus | 
| Hematocrit Drop | Comparison of the preoperative and first postoperative hematocrit values | from time of preoperative hematocrit value closest to delivery until time of first postoperative hematocrit | 
| Length of Hospital Stay | Total duration of hospital stay (in days) after cesarean delivery | from day of surgery to day of hospital discharge | 
| Maternal Morbidity | Any unplanned adverse reaction or event with clinical consequences e.g. cardiovascular event, intubation, ICU admission, hypovolemic shock or adverse study drug reaction | from time of delivery until time of hospital discharge |