Postpartum Hemorrhage, Uterine Atony
Conditions
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.
Interventions
DRUG15-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.
DRUGMethylergonovine 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.
Sponsors
Northwestern Memorial Hospital
Brigham and Women's Hospital
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Outcomes Assessor)
Eligibility
Sex/Gender
FEMALE
Age
18 Years to 50 Years
Healthy volunteers
Yes
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Uterine Tone Score | at 10 minutes following administration of the first study drug | 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'. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Subjects Receiving Additional Uterotonic | from time of delivery until surgery completion, approximately 1-2 hours | An additional second-line uterotonic which is given in the operating room after administration of the first study drug |
| Number of Subjects Requiring Transfusion | within the first 24 hours after delivery of the fetus | The need for RBC transfusion due to postpartum blood loss. |
| Number of Subjects Requiring Additional Intervention | within the first 24 hours after delivery of the fetus | The need for an additional surgical or radiologic intervention to control postpartum hemorrhage |
| Uterine Tone Score | at 5 minutes following administration of the first study drug | 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' |
| Hematocrit Drop | from time of preoperative hematocrit value before delivery until time of first postoperative hematocrit (within 24 hours postoperatively). | Comparison of the preoperative and first postoperative hematocrit values |
| Length of Hospital Stay | from day of surgery to day of hospital discharge, approximately 3 days in most cases | Total duration of hospital stay (in days) |
| Number of Subjects Experiencing Severe Maternal Morbidity | from time of delivery until time of hospital discharge | Any unplanned adverse reaction or event with clinical consequences (e.g., cardiovascular event, intubation, ICU admission, hypovolemic shock, transfusion reaction, or adverse study drug reaction) |
| Quantitative Blood Loss (QBL) | from entry to exit from the OR, approximately 2 to 3 hours | The total volume of blood loss (in mL), calculated as a conversion from the measured blood loss in weight into its equivalent volume. Weight of blood loss is measured on a QBL scale that weighs surgical drapes, towels, sponges and suction fluid. |
Countries
United States
Participant flow
Recruitment details
March 2019- April 2022
Participants by arm
| Arm | Count |
|---|---|
| 15-methyl Prostaglandin F2α IM Carboprost followed by Methylergonovine if needed.
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.
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. | 50 |
| Methylergonovine Maleate IM Methylergonovine followed by Carboprost if needed.
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.
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. | 50 |
| Total | 100 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Primary outcome not measured | 1 | 2 |
Baseline characteristics
| Characteristic | Methylergonovine Maleate | Total | 15-methyl Prostaglandin F2α |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 50 Participants | 100 Participants | 50 Participants |
| Age, Continuous | 34.4 years STANDARD_DEVIATION 4.4 | 33.6 years STANDARD_DEVIATION 5.1 | 32.7 years STANDARD_DEVIATION 5.6 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 9 Participants | 14 Participants | 5 Participants |
| Race (NIH/OMB) Black or African American | 5 Participants | 15 Participants | 10 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 10 Participants | 20 Participants | 10 Participants |
| Race (NIH/OMB) White | 26 Participants | 51 Participants | 25 Participants |
| Region of Enrollment United States | 100 participants | 100 participants | 100 participants |
| Sex: Female, Male Female | 50 Participants | 100 Participants | 50 Participants |
| Sex: Female, Male Male | 0 Participants | 0 Participants | 0 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 50 | 0 / 50 |
| other Total, other adverse events | 14 / 50 | 13 / 50 |
| serious Total, serious adverse events | 0 / 50 | 0 / 50 |
Outcome results
Primary
Uterine Tone Score
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'.
Time frame: at 10 minutes following administration of the first study drug
Population: In the carboprost group, 50 participants were enrolled and data for 49 participants were analyzed since the primary outcome was not measured in 1 participant. In the methylergonovine group, 50 participants were enrolled and data for 48 were analyzed since 2 participants did not have the primary outcome measured.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| 15-methyl Prostaglandin F2α | Uterine Tone Score | 4.7 score on a scale | Standard Deviation 1.9 |
| Methylergonovine Maleate | Uterine Tone Score | 4.4 score on a scale | Standard Deviation 1.8 |
Secondary
Hematocrit Drop
Comparison of the preoperative and first postoperative hematocrit values
Time frame: from time of preoperative hematocrit value before delivery until time of first postoperative hematocrit (within 24 hours postoperatively).
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| 15-methyl Prostaglandin F2α | Hematocrit Drop | 28.3 percentage of initial Hct | Standard Deviation 3.7 |
| Methylergonovine Maleate | Hematocrit Drop | 27.7 percentage of initial Hct | Standard Deviation 5 |
Secondary
Length of Hospital Stay
Total duration of hospital stay (in days)
Time frame: from day of surgery to day of hospital discharge, approximately 3 days in most cases
| Arm | Measure | Value (GEOMETRIC_MEAN) |
|---|---|---|
| 15-methyl Prostaglandin F2α | Length of Hospital Stay | 4.1 days |
| Methylergonovine Maleate | Length of Hospital Stay | 4.4 days |
Secondary
Number of Subjects Experiencing Severe Maternal Morbidity
Any unplanned adverse reaction or event with clinical consequences (e.g., cardiovascular event, intubation, ICU admission, hypovolemic shock, transfusion reaction, or adverse study drug reaction)
Time frame: from time of delivery until time of hospital discharge
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| 15-methyl Prostaglandin F2α | Number of Subjects Experiencing Severe Maternal Morbidity | 0 Participants |
| Methylergonovine Maleate | Number of Subjects Experiencing Severe Maternal Morbidity | 0 Participants |
Secondary
Number of Subjects Receiving Additional Uterotonic
An additional second-line uterotonic which is given in the operating room after administration of the first study drug
Time frame: from time of delivery until surgery completion, approximately 1-2 hours
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| 15-methyl Prostaglandin F2α | Number of Subjects Receiving Additional Uterotonic | 17 Participants |
| Methylergonovine Maleate | Number of Subjects Receiving Additional Uterotonic | 15 Participants |
Secondary
Number of Subjects Requiring Additional Intervention
The need for an additional surgical or radiologic intervention to control postpartum hemorrhage
Time frame: within the first 24 hours after delivery of the fetus
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| 15-methyl Prostaglandin F2α | Number of Subjects Requiring Additional Intervention | 4 Participants |
| Methylergonovine Maleate | Number of Subjects Requiring Additional Intervention | 5 Participants |
Secondary
Number of Subjects Requiring Transfusion
The need for RBC transfusion due to postpartum blood loss.
Time frame: within the first 24 hours after delivery of the fetus
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| 15-methyl Prostaglandin F2α | Number of Subjects Requiring Transfusion | 2 Participants |
| Methylergonovine Maleate | Number of Subjects Requiring Transfusion | 3 Participants |
Secondary
Quantitative Blood Loss (QBL)
The total volume of blood loss (in mL), calculated as a conversion from the measured blood loss in weight into its equivalent volume. Weight of blood loss is measured on a QBL scale that weighs surgical drapes, towels, sponges and suction fluid.
Time frame: from entry to exit from the OR, approximately 2 to 3 hours
| Arm | Measure | Value (GEOMETRIC_MEAN) |
|---|---|---|
| 15-methyl Prostaglandin F2α | Quantitative Blood Loss (QBL) | 713 milliliters (mL) |
| Methylergonovine Maleate | Quantitative Blood Loss (QBL) | 758 milliliters (mL) |
Secondary
Uterine Tone Score
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'
Time frame: at 5 minutes following administration of the first study drug
Population: 50 participants were enrolled in the 15-methyl prostaglandin F2alpha group, and this secondary outcome was measured in all participants. 50 participants were enrolled in the methylergonovine group, but 1 did not have this secondary outcome (uterine tone score 5 minutes after administration of the first study drug) measured, therefore 49 were analyzed.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| 15-methyl Prostaglandin F2α | Uterine Tone Score | 6.8 score on a scale | Standard Deviation 1.9 |
| Methylergonovine Maleate | Uterine Tone Score | 6.4 score on a scale | Standard Deviation 1.9 |