Clinical trial NCT05772156
Conditions: Twin; Complicating Pregnancy Postpartum Hemorrhage
Sponsor: Columbia University
Start date: 2023-03-07; Completion date: 2024-03-11
Enrollment: 66 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
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.

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.

Arms: arm 1: Prophylactic methylergonovine 200mcg IM arm 2: Matching placebo
Interventions: intervention 1: Methylergonovine intervention 2: Placebo
Intervention descriptions: intervention 1: Methylergonovine 200mcg Intramuscular (IM) intervention 2: Matching saline placebo

Protocol documents:
Prot_SAP_000.pdf: 
 
 
 
 
 
 
 
 
Prophylactic Methylergonovine in Patients Undergoing 
Cesarean Delivery With Twin Gestations: A Randomized 
Controlled Trial 
 
 
 
NCT05772156 
 
September 27, 2023 
 
 


BACKGROUND 
 
Study Purpose and Rationale 
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, [1] 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 [2]. 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 [3]. 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 [4-6]. Recent evidence has emerged about the utility of prophylactic 
Methylergonovine for the prevention of obstetrical hemorrhage [7-8]. Methylergonovine, a 
semisynthetic ergot alkaloid, acts primarily on alphaadrenergic receptors of uterine and vascular 
smooth muscle, increasing uterine tone and promoting vasoconstriction. Masse et al [8] 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% 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. 
Similarly, Senturk et al [7], 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 [7-8]. Currently, there remains a paucity of research 
regarding prophylactic procedures for twin cesarean delivery. Similarly, the use of Hemabate 
(carboprost tromethamine) is an effective uterotonic to reduce obstetrical hemorrhage. 
Hemabate, a protaglandin F2 alpha agonist, similarly treats uterine atony by stimulating smooth 
muscle contraction. Unlike Methylergonovine, hemabate does not cause secondary vascular 
constriction and can be used in patients with blood pressure disorders. In a study of prophylactic 
Hemabate, Balki and colleagues assigned participants to receive either oxytocin 5 units 
intravenous alone, or with ergonovine 0.25 mg intravenous or carboprost 0.25 mg intramuscular 
immediately after delivery and found a reduction in postpartum hemorrhage.There is an 
opportunity to prophylactically address hemorrhage in high risk groups. Therefore, we propose a 
prospective randomized controlled trial which will compare maternal blood loss associated with 
prophylactic uterotonic treatment during cesarean delivery among patients with twin 
pregnancies. We hypothesize that prophylactic uterotonic therapy in cesarean delivery is 
associated with decreased maternal blood loss compared to standard care.  
 
RESEARCH AIMS & ABSTRACTS 
 
Research Question(s)/Hypothesis(es): To evaluate whether prophylactic uterotonic 
therapy reduces maternal blood loss among individuals with twin gestations undergoing cesarean 
delivery. 
Primary Research Question: Is the administration of prophylactic uterotonic therapy at 
the time of scheduled cesarean delivery after cord clamping of the second twin associated with 
decreased maternal blood loss among patients with twin pregnancies (based on primary outcome 
of maternal hemoglobin drop from preop to postoperative day #1)? 
Hypothesis: Prophylactic uterotonic therapy in cesarean delivery among patients with 
twin pregnancies is associated with decreased maternal blood loss compared to placebo. 
 
Scientific Abstract 
This is a randomized controlled trial of patients undergoing scheduled (daytime) cesarean 
section among patients with twin gestations. We propose a prospective randomized controlled 
trial which will compare maternal blood loss associated with prophylactic uterotonic therapy 


during cesarean delivery among patients with twin pregnancies. We hypothesize that 
prophylactic uterotonic therapy in cesarean delivery is associated with decreased maternal blood 
loss compared to standard care. The target patient population for this study is women with twin 
pregnancies undergoing scheduled cesarean delivery. Subjects will be expected to do the 
following once they agree to participate: 1) Sign the informed consent 2) Enroll - randomized in 
preop to prophylactic methylergonovine or placebo. 
 
STUDY DESIGN 
 
We propose a prospective randomized controlled trial which will compare maternal blood 
loss associated with prophylactic uterotonic therapy during cesarean delivery among patients 
with twin pregnancies. We hypothesize that prophylactic methylergonovine 200mcg IM or 
Hemabate carboprost tromethamine (250mcg/mL, 1mL syringe) in cesarean delivery is 
associated with decreased maternal blood loss compared to placebo. This is a randomized 
controlled trial of patients undergoing scheduled (daytime) cesarean section among patients with 
twin gestations. For our primary research question, we will compare the change in maternal 
hemoglobin from pre-op to postoperative day #1. 
 
Study Procedures 
Consented subjects who remain eligible for study participation on the day of their 
scheduled cesarean delivery will be randomized 1:1 by trained research personnel to one of two 
groups: Intervention group (Prophylactic methylergonovine 200mcg IM) or Control group 
(placebo same volume). If a blood pressure disorder of pregnancy is diagnosed, study 
participants will be randomized to one of two groups: Intervention group (Prophylactic 
carboprost tromethamine 250mcg IM) or Control group (placebo same volume). Randomization 
will occur on labor and delivery while the subject is in the preoperative area prior to delivery. 
The subjects will be taken to the operating room where anesthesia will be administered and 
cesarean delivery will be performed in routine fashion until delivery of the fetuses. Obstetricians, 
anesthesiologists, intraoperative research staff, and subjects will be blinded to study arm 
allocation. A trained member of the research team will perform randomization prior to delivery. 
Upon delivery of the second twin neonate, the anesthesiologist will administer the study drug; 


subjects will receive either prophylactic methylergonovine 200mcg IM or saline placebo 
(identical volume) IM. 
If patients are not candidates to receive methylergonovine due to a blood pressure 
disorder of pregnancy (gestational hypertension, chronic hypertension, preeclampsia with or 
without severe features), they will be randomized to Prophylactic carboprost tromethamine 
250mcg IM or Control group/placebo same volume Oxytocin will be administered (by the 
anesthesia team) in routine fashion immediately upon delivery. The remainder of the cesarean 
will proceed in routine fashion per surgical team. Uterotonics/blood transfusion may be 
administered per routine care as judged necessary by the surgical team. Blood loss at completion 
of the surgery will be estimated by the obstetric, nursing, and anesthesia teams with a final 
estimated blood loss (EBL) agreed on by all providers and recorded in the routine fashion in the 
medical record. Similarly, the quantitative blood loss (QBL) will be calculated and recorded. All 
mothers will receive routine postoperative and postpartum care. This includes administration of 
intravenous fluids (125 cc/h lactated ringers) until tolerating oral fluids. On postoperative day 1, 
maternal hemoglobin level will be assessed on a complete blood count per standard clinical care. 
Neonates will receive routine care. Race and ethnicity will be self-reported at the time of hospital 
registration and extraction from the medical record (fixed categories) to consider the 
generalizability of the results. All other data will be abstracted by the research team by review of 
both the maternal and neonatal medical records. All medical records will be reviewed through 30 
days after delivery to identify any postpartum or postnatal complications. 
 
Study Subjects 
Inclusion Criteria: 
- 
Twin gestation 
- 
Scheduled cesarean delivery (>=34 weeks) 
 
Exclusion criteria for methylergonovine: 
- 
Subjects 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 
 
If patients meet any of the exclusions above, they will be assessed for the use of 
Hemabate and excluded if: 
- 
Subjects with known asthma disease 
- 
Hypersensitivity to Hemabate or any of the ingredients 
 
Additionally, if subjects meet any of the following criteria, they will be excluded from 
participation: 
- 
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 
 
STATISTICAL ANALYSIS 
 
Based on the following parameters, the sample size was calculated for the primary 
outcome of mean hemoglobin change from pre-op to post-op day 1 between placebo and 
treatment groups. The analysis was conducted in Stata 17. From the protocol: Based on a prior 
study of cesarean deliveries in twin gestations [9], a mean (SD) change in hemoglobin level for 
elective cesarean delivery of 1.40 (0.83) g/dL was estimated. Up to 20% crossover rate from the 
treatment group to the placebo group will be assumed. Because there is no accepted definition of 
a minimum clinically important difference in postoperative hemoglobin change, effect size was 
based on the published SD of the mean. Given the burden of maternal morbidity and mortality 
due to postpartum hemorrhage, the investigators decided that even a 1-SD greater drop in 
postoperative maternal hemoglobin level with Methylergonovine treatment arm might alter 
clinical decision-making. Hence the parameters are as follows: 
Effect size / difference in means: 0.83SD: 0.83 (assumed to be the same for both groups) 
Allocation ratio: 1:1 


Crossover rate: 20% 
Power: 0.90 
Alpha: 0.05 (two-tailed) 
Assumed dropout rate: 10% 
The sample size is 33 per group, or 66 total on the more conservative end, including 
adjustment for potential loss to follow up. 
 
REFERENCES 
 
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Vol. 70, No. 17.  
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oxytocin bolus and infusion for control of blood loss at elective caesarean section: double blind, placebo 
controlled, randomised trial BMJ 2011; 343:d4661  
3. 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  
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10. Balki M, Downey K, Walker A, Seaward G, Carvalho JCA. Prophylactic Administration of Uterotonics to 
Prevent Postpartum Hemorrhage in Women Undergoing Cesarean Delivery for Arrest of Labor: A Randomized 
Controlled Trial. Obstet Gynecol. 2021 Mar 1;137(3):505-513.