Clinical trial NCT02408965
Conditions: Hemorrhage
Sponsor: University of California, San Francisco
Start date: 2015-03-01; Completion date: 2017-03-01
Enrollment: 284 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
Excessive bleeding after dilation and evacuation (D\&E) requiring interventions is common, occurring in approximately 30% of cases at one large abortion-providing clinic. Uterotonic prophylaxis at the time of D\&E, particularly with methylergonovine maleate (MM), is a common practice among D\&E providers despite nearly no evidence for its efficacy. Finding ways to decrease excessive bleeding after D\&E has the potential both to improve patient safety and to reduce costs of provider-initiated interventions. The investigators propose a randomized, controlled trial to investigate the efficacy of MM prophylaxis versus placebo in decreasing excessive bleeding measured by a composite outcome among women undergoing D\&E at 20 to 24 weeks.

Detailed description:

Arms: arm 1: Methergine group 0.2 mg of methylergonovine maleate single injection when manual cervical dilation begins the day before the procedure arm 2: Placebo group saline single injection when manual cervical dilation begins the day before the procedure
Interventions: intervention 1: Methergine intervention 2: placebo
Intervention descriptions: intervention 1: 0.2 mg of methylergonovine maleate intervention 2: saline placebo to maintain blinding

Protocol documents:
Prot_000.pdf: 
STUDY PROTOCOL 
Uterotonic prophylaxis after D&E 
PI:  Jennifer Kerns 
University of California, San Francisco 
 
STUDY PROTOCOL 
Study Design  
We propose a three-arm randomized, double-blinded, placebo-controlled trial of intramuscular 
MM versus rectal misoprostol versus placebo after D&E to evaluate the effect of prohylaxis on 
excessive bleeding. All English- or Spanish- speaking women undergoing D&E at San 
Francisco General Hospital’s Women’s Options Center (SFGH WOC) between 20 weeks’ 0 
days’ and 24 weeks’ 0 days’ gestation will be eligible for recruitment. Women will be excluded if 
they have a pre-operative diagnosis of hypertension, are using protease inhibitors, have known 
coagulopathy or history of obstetric hemorrhage requiring blood transfusion, placenta accreta, 
increta or percreta, and any other contraindication to MM or misoprostol use.   
Study Procedures  
Recruitment:  All eligible women will be identified on the pre-operative day by the research 
assistant, after clinical staff performs an ultrasound to determine the gestational age. For most 
women, the pre-operative day is one day prior to the D&E. For a minority of women, it is two 
days prior to the D&E. After eligibility is confirmed, the research assistant will approach the 
patient prior to dilator placement to explain the study, and obtain consent.  
Randomization:  On the day of the D&E, women who consented to participate in the trial will be 
assigned a study number and random assignment to one of three study arms will be made. We 
plan to use block randomization for two gestational age ranges (1) 20 weeks 0 days to 22 
weeks 0 days; (2) 22 weeks 1 day to 24 weeks 0 days. We plan to use a random number table 
to assign each study number to one of three arms. By randomizing women just prior to the D&E, 
we will minimize any negative effect on the randomization scheme if women either fail to return 
for the procedure or withdraw consent prior to the D&E.  
Blinding:  MM and saline syringes (placebo) will be prepared by the SFGH Pharmacy. 
Misoprostol tablets and placebo tablets will be prepared by Abbott Laboratories. The MM and 
placebo syringes will be identical as will the misoprostol and placebo tablets. No clinical 
providers or research staff will have access to the randomization scheme. Each subject will 
receive an intramuscular injection and placement of rectal tablets without knowledge of their 
contents. To assess the quality of blinding, providers will be asked by the research assistant at 
the end of the procedure to which group they thought a study patient was assigned.  


Version: April 10 2014 
D&E providers:  Ten faculty members at SFGH do D&Es at SFGH WOC. All are routine and 
experienced providers. D&Es are also done by a rotating third-year resident and a first- or 
second-year family planning fellow. For the purposes of this trial, only faculty members or the 
second-year family planning fellow will be performing the D&E. 
Reimbursement:  Women will be given a $15 gift card for participating in the trial.  
Intervention 
Women in this trial will be randomized to one of three arms: (1) MM 0.2 mg intramuscular 
injection and placebo rectal misoprostol, (2) saline (placebo) intramuscular injection and 
misoprostol 800 mcg rectal, (3) saline (placebo) intramuscular injection and placebo rectal 
misoprostol at the completion of the D&E. Completion will be defined as immediately after the 
last suction. At SFGH WOC, it is standard procedure for providers to perform a final suction at 
the completion of the procedure. Once the provider states that she/he is finished with the last 
suction, the nurse will administer the intramuscular injection. The assigned tablets will be given 
to the provider to place rectally. All study drugs and placebos will be prepared identically and 
labeled as, “Study drug”. 
Outcomes 
Primary outcome:  Our primary outcome of excessive bleeding will be measured with a 
composite outcome that includes measured post-operative blood loss greater than 125 cc or 
specific interventions done to manage the excessive bleeding (Table 1). Only one of the listed 
criteria is needed to qualify as a positive outcome. In addition to our primary, composite 
outcome, we will also record the number of interventions performed for what the provider deems 
excessive uterine bleeding. We plan to do sensitivity analyses as follows: (1) a dichotomous 
outcome of 2 or more interventions used versus less than 2; (2) excluding administration of 
uterotonics and uterine pressure. 
 
We are not aware of any literature measuring blood loss after D&E at 20 to 24 weeks’ gestation. 
In our clinic, we have observed that approximately 95% of women within this gestational age 
range have a total post-operative blood loss to be less than 125 cc. We are thus considering 
greater than 125 cc post-operative blood loss to be indicative of excessive bleeding, and thus 
have included it as one of the criteria for our composite outcome. For uterotonic medications 
administered or prescribed, we will record the type (misoprostol, hemabate, MM), dosage, and 
number of doses.  
 


Version: April 10 2014 
Many cases of excessive bleeding will fulfill more than one criterion listed in Table 1. For 
example, most women given a prescription for a uterotonic medication at discharge will likely 
have received a uterotonic medication. In addition, most women with > 125 cc blood loss post-
operatively will likely have received at least one uterotonic medication. In order to increase our 
sensitivity in detecting excessive bleeding, we have included all possible criteria, and will record 
the number of interventions someone received. Providers who wish to give a uterotonic 
medication to treat excessive bleeding will be instructed to wait 5 min after the study drug has 
been given. They will be able to choose any uterotonic as they normally would. 
 
Table 1.  Clinical factors included in composite outcome of excessive bleeding after D&E. 
 
Secondary outcome:  A 
secondary outcome will be 
overall blood loss after the 
D&E. Blood loss will be 
measured from the start of the 
procedure, defined as removal 
of cervical dilators, to the end 
of the procedure (after last 
suction). All bleeding that 
occurs after last suction will be 
considered post-operative bleeding. Blood loss will be measured by collecting the blood in a 
draped bag underneath the patient and by weighing all gauze used during the procedure. To 
assess post-procedure blood loss in the recovery room, we will also weigh pads and chux from 
the time of last suction to discharge, then converting grams into milliliters using the specific 
gravity of blood which is 1.06 grams per milliliter (Figure 1). We will compare mean total blood 
loss volume (TBLV) after D&E, a continuous outcome, among the three arms. We have 
successfully piloted this method of measuring blood loss in our clinic.  
 
Figure 1.  Measuring total blood loss after D&E 
 
 
 
 
Total blood loss > 125 cc (after D&E) 
Transfusion 
Admission for bleeding 
Re-aspiration for bleeding 
Balloon tamponade 
Uterine artery embolization 
Major surgery for bleeding 
At least 1 uterotonic medication given 
Prescription given for any uterotonic medication at discharge 
Uterine compression (uterine massage or manual pressure for 2 
minutes 
TPW (grams) 
 
Total pad weight = weight of all pads used  
 
 
 
 
TBLW (grams)  
Total blood loss weight = Total pad weight – (Dry pad weight * # of pads)  
TBLV (milliliters) 
Total blood loss volume = Total blood loss weight / 1.06 g/mL 
 
 

SAP_001.pdf: 
Version: April 10 2014 
Statistical Analysis Plan 
Uterotonic prophylaxis after D&E 
PI:  Jennifer Kerns 
University of California, San Francisco 
 
Statistical Analysis Plan 
We plan to use t-tests for continuous variables and a chi-square analysis for categorical 
variables for comparison of study groups at baseline. In the event that the groups are 
not comparable at baseline, we will do a multivariable analysis adjusting for possible 
confounders. We will do an intent-to-treat analysis as our primary analysis. If a woman 
is noted to have elevated blood pressure (>140/90) at the completion of the D&E, the 
study drug will be withheld as this would be a contraindication for MM. These women 
will still be analyzed in their original randomization group to ensure fidelity to 
randomization’s goal of balancing confounders. In addition to computing the 
dichotomous outcome of blood loss > 125cc and/or intervention for bleeding, we will 
also compare the number of interventions listed in Table 1 for each group. We will also 
do a sensitivity analysis of the composite outcome in which we exclude the more minor 
interventions for bleeding, use of uterotonics or manual pressure. For our secondary 
outcome of mean blood loss difference, we will also conduct a per-protocol analysis, 
comparing those who received any uterotonic medication (placebo plus additional doses 
as well as intervention arm plus or minus additional doses) versus those who received 
no utertonic.