Clinical trial NCT06078501
Conditions: Blood Loss, Surgical Second Trimester Abortion
Sponsor: Stanford University
Start date: 2024-02-08; Completion date: 2024-07-12
Enrollment: 7 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
Although serious complications from second trimester abortion are rare hemorrhage is the most common cause of procedural abortion related morbidity and mortality. Misoprostol is a prostaglandin E1 analogue that is used by 75% of clinicians prior to procedural abortion for the purpose of cervical preparation. Misoprostol is also known to decrease blood loss in first trimester abortion and is used to treat postpartum hemorrhage, however the effect of preprocedural misoprostol on procedural blood loss is not well described.

We will conduct a double blinded placebo-controlled gestational age stratified superiority trial of those undergoing procedural abortion between 18 and 23 weeks gestation at Stanford Health care. Participants will be randomized to either 400mcg buccal misoprostol or placebo on the day of the procedure. A quantified blood loss (QBL) will be measured during the procedure and participants will complete a survey to assess symptoms. Our primary outcome is quantified blood loss. Secondary outcomes include clinical interventions to manage excess bleeding, total procedure time, provider reported experience, patient reported experience.

Detailed description:

Arms: arm 1: Participants will take 400mcg buccal misoprostol 2-3 hours prior to their procedure arm 2: Participants will take a placebo buccally 2-3 hours prior to their procedure
Interventions: intervention 1: Misoprostol 400mcg buccal intervention 2: Placebo
Intervention descriptions: intervention 1: Misoprostol 400mcg buccal administration 2-3 hours prior to procedure intervention 2: Placebo buccal administration 2-3 hours prior to procedure

Protocol documents:
Prot_000.pdf: 
 
 
 
Misoprostol Effect on Second Trimester 
Abortion Blood Loss 
 
 
Study Protocol 
NCT06078501 
August 23, 2023 
 
 


Title: Misoprostol Effect on Second Trimester Abortion Blood Loss 
Investigators: Simranvir Kaur, MD; Kate Shaw, MD, MS 
 
Non-technical summary:  
Although serious complications from second trimester abortion are rare hemorrhage is the 
most common cause of procedural abortion related morbidity and mortality (Zane et al., 2015). 
Misoprostol is a prostaglandin E1 analogue that is used by 75% of clinicians (White et al., 2018) 
prior to procedural abortion for the purpose of cervical preparation. Misoprostol is also known 
to decrease blood loss in first trimester abortion and is used to treat postpartum hemorrhage, 
however the effect of preprocedural misoprostol on second trimester abortion blood loss is not 
well described.  
 
We will conduct a double blinded placebo-controlled gestational age stratified superiority trial 
of those undergoing procedural abortion between 18 and 23 weeks gestation at Stanford Health 
care. Participants will be randomized to either 400mcg buccal misoprostol or placebo on the day 
of the procedure. A quantified blood loss (QBL) will be measured during the procedure and 
participants will complete a survey to assess symptoms. Our primary outcome is quantified 
blood loss. Secondary outcomes include clinical interventions to manage excess bleeding, total 
procedure time, provider reported experience, patient reported experience. We plan to recruit 
80 subjects powered to detect a 30% reduction in QBL in those who received misoprostol 
compared to the control group. 
 
This study has the potential to increase the safety of an already safe procedure and establish 
clinical benefits of choosing misoprostol as an agent for cervical preparation.  
 
 
 


Specific Aims:  
Primary aim:  
To investigate the impact of administering 400 micrograms of buccal misoprostol 90-120 
minutes prior to second trimester procedural abortion on quantified blood loss. 
 
Secondary aims:  
Patient experience: evaluate the subjective experiences of patients who receive misoprostol 
before second trimester abortion focusing on pain before and after administration of the 
treatment, side effects, and overall satisfaction with the experience. 
 
Procedure: analyze whether the use of misoprostol prior to second trimester abortion 
influences the procedure times, ease of procedure, provider estimated blood loss, provider 
satisfaction with cervical preparation, and whether the clinician could tell whether misoprostol 
was used. 
 
Background and Significance:  
The definition of hemorrhage in second trimester abortion varies across studies with some 
focusing on volume of blood loss whereas others focus on clinical outcomes or interventions 
related to blood loss. Given these variable definitions the incidence of hemorrhage ranges from 
0.9 to 10 per 1000 cases (Altman et al., 1985; Castleman et al., 2006; Frick et al., 2010; Patel et 
al., 2006; Schulz et al., 1985).  
 
Clinical guidelines from the Society of Family Planning (SFP) recommend adequate cervical 
preparation and to consider vasopressin in a paracervical block to prevent hemorrhage for all 
patients (J. Kerns & Steinauer, 2013). The same guidelines outline management of hemorrhage 
including uterine massage, uterotonic medications, re-aspiration, balloon tamponade, uterine 
artery embolization, and hysterectomy. A randomized controlled trial (RCT) in 2019 by 
Whitehouse et. Al. examined the effects of prophylactic oxytocin on blood loss during 
procedural abortion 18-24w duration with primary outcome of frequency of interventions to 
control excess bleeding(Whitehouse et al., 2019). While prophylactic oxytocin did not decrease 
interventions needed to control excess bleeding, it did decrease hemorrhage (defined as blood 
loss of 500mL or more) by 18% (95% CI -29 to -6.9) and median blood loss by 165mL (152mL in 
oxytocin group [interquartile range 98-235] versus 317mL [interquartile range 168-464; 95% CI 
71.6-181.5]). Another RCT by Kerns in 2021 examined the effects of prophylactic intramuscular 
methylergonovine for people undergoing procedural abortion 20-24 weeks (J. L. Kerns et al., 
2021). They found no improvement in the composite of indicators of excessive blood loss with a 
paradoxical increase in the number of individual excessive bleeding outcomes for the group that 
received methylergonovine.  
 
Misoprostol is a synthetic prostaglandin E1 analogue that is used in gynecologic, obstetric, and 
abortion care to induce uterine contractions and for cervical softening (Allen & O’Brien, 2009). 
It has been shown to overall decrease estimated blood loss in first trimester procedural 
abortion (Ngai et al., 1995, 1999; Saxena et al., 2003; Vimala et al., 2003) and is used to treat 
postpartum hemorrhage (“Practice Bulletin No. 183: Postpartum Hemorrhage,” 2017). Cervical 


preparation is required prior to second trimester procedural abortion and can be broadly 
understood in two different categories: mechanical and pharmacologic. Mechanical methods of 
cervical preparation include inserting osmotic dilators (Dilapan-S or laminaria tents) or 
transcervical balloons (foley balloon or Cook balloon). Pharmacologic methods of cervical 
preparation include mifepristone, misoprostol, and ulipristal acetate. Misoprostol is commonly 
used as part of cervical preparation for second trimester abortion (Diedrich et al., 2020; Fox & 
Krajewski, 2014) with 75% of clinicians report using misoprostol (White et al., 2018) it has not 
been shown to be a superior method of cervical preparation nor has it shown to improve clinical 
outcomes. The impact of use on procedural blood loss has not been consistently described 
(Cahill et al., 2020). Studies that do report on blood loss tend to use estimated blood loss which 
has been shown to consistently underestimate blood loss when compared to a measured blood 
loss (Serapio et al., 2018).  Some clinicians do not use misoprostol out of concern for unpleasant 
side effects, how the procedure is then performed, and impact on procedural times (Drey et al., 
2014). Further studies examining the specific effects of misoprostol on blood loss could help to 
better inform clinicians on the impact of misoprostol for cervical preparation on bleeding with 
second trimester procedural abortion.  
 
 
Project Design and Methods: 
Study Location 
Patients will be recruited at Stanford Gynecology Clinic in Palo Alto, CA. Stanford University is a 
large tertiary care center with patients referred from the seven Perinatal Diagnostic Centers 
(PDCs) across Northern California with fetal anomalies as well as local independent clinics.  
 
Research Design and General Methodological Approach 
The proposed study is a conduct a randomized, double-blinded, placebo-controlled, superiority 
trial. Participants will be consented and randomized using a computer-generated random 
number producing algorithm to receive either misoprostol 400mcg or placebo, buccally 90-120 
minutes prior to their scheduled procedure time. Pharmacy staff filled identical, opaque pill 
containers with either two 200mcg misoprostol tablets or two 50-mg vitamin B6 tablets 
(placebo) because no identical appearing placebo exists for misoprostol. To ensure blinding of 
research and clinical staff subjects will self-administer study tablets in private where a research 
assistant who is uninvolved with collection of data will be available to assist patients with 
correct buccal placement. All other clinical and research staff will be blinded to the study group 
assignments until data analysis is complete. 
 
The primary outcome will be proportion of participants with blood loss (QBL) above published 
medians by gestational duration(Serapio et al., 2018). To detect a 30% reduction in the 
proportion of participants with QBL greater than the median, with an alpha of 0.05 and a power 
of 80%, we would need 36 participants per group. Accounting for drop out, loss to follow up, 
and missing data, we plan to recruit 40 per group, for a total of 80 participants. With an 
estimated 180 procedures per year, 80% eligible, and 60% enrollment, we estimate the study 
will take 12-15 months to enroll. QBL will be measured using previously published 
protocols(Serapio et al., 2018). QBL was selected as the primary outcome because the incidence 


of hemorrhage in second trimester abortion is a rare outcome. Lower QBLs correspond to lower 
risks and rates of hemorrhage therefore QBL may be a reasonable proxy to understanding 
morbidity and mortality related to procedural second trimester abortion. 
 
Secondary outcomes will include clinical intervention to manage excess bleeding (use of 
uterotonics, uterine artery embolization, uterine balloon tamponade, blood transfusion, 
hysterectomy), total procedure time, provider-reported experience (ease of procedure, provider 
estimated blood loss, provider satisfaction with cervical dilation, and whether the clinician 
accurately predicted which treatment arm the subject was in), participant-reported experience 
(pain, side effects: nausea, vomiting, diarrhea, fevers), preoperative exam for dilation, need for 
mechanical dilation. Patient and provider experience are important outcomes to consider as 
some providers specifically chose methods of cervical preparation based on patient experiences 
and based on the way that the provider themselves perform the procedure. Because there is no 
one standard way to prepare cervices for second trimester procedural abortion providers 
choose methods of cervical preparation that they are most comfortable and familiar with based 
on how it changes the way they perform the procedure itself and how patients tolerate the 
various methods of cervical preparation. For example, pharmacologic preparation with 
misoprostol may cause side effects such as nausea, diarrhea, and fever, whereas osmotic 
dilators may cause more pain with placement and more pain overnight prior to procedure.  
 
Criteria for Selection of Subjects 
Inclusion: Pregnant people, 18 years of age or older; intrauterine pregnancy between 18/0-23/6 
weeks of gestational age (by ultrasound dating performed prior to same day of enrollment visit) 
consented for an induced abortion; English or Spanish speaking, able to consent for a research 
study, literate in English or Spanish. 
 
Exclusion: known coagulopathy, suspected morbidly adherent placenta spectrum, multiple 
gestation, current infection, ruptured membranes, or fetal demise at time of enrollment. 
 
Subject Recruitment and Allocation 
Subjects will be recruited from Stanford Gynecology Clinic on the day of their Family Planning 
consultation, after consent for, but prior to abortion. Only patients in the appropriate 
gestational ages will be approached. Potential participants will be screened for the study and if 
eligible and willing to participate in the project they will be consented for the study. 
 
Description of Drugs and Devices 
Misoprostol is a prostaglandin E1 analogue with two FDA labeled indications: 1. prevention of 
nonsteroidal anti-inflammatory drug-induced gastric ulcers and 2. Termination of intrauterine 
pregnancy through 70d gestation in combination with mifepristone. Various off label uses exist 
in obstetric, gynecologic, and abortion care including cervical preparation and labor induction, 
early pregnancy loss, incomplete abortion, postpartum hemorrhage (prevention/treatment), 
termination of intrauterine pregnancy as monotherapy.  
 


Data Management & Analysis  
Stanford University has a license for the RedCap data management system(Harris et al., 2009). 
RedCap is a web-based application that is secure, reliable, and HIPAA-compliant for strong 
research study data. RedCap is designed with build-in features to address confidentiality and 
compliance requirements. Electronic surveys will be administered via study iPad on the day of 
the procedure. Data associated with patient health identifiers (PHI) including the signed 
informed consent will be collected electronically. RedCap allows for easy data download into 
SAS or other statistical software programs. No data will be collected on paper forms. SAD 
OnDemand will be used for data analysis. Data will be analyzed with parametric or non-
parametric statistical tests, as appropriate.  
 
Summary 
Second trimester procedural abortion is safe. The uncommon experiences of morbidity and 
mortality are often from excessive blood loss. Misoprostol is a medication commonly used prior 
to second trimester abortion for cervical preparation. This study will investigate whether 
misoprostol influences second trimester procedural abortion blood loss. This trial represents an 
opportunity to improve patient outcomes during an otherwise difficulty, often stigmatized, 
reproductive event. 
 
 


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SAP_001.pdf: 
 
Misoprostol Effect on Second Trimester Abortion Blood Loss 
Statistical Analysis Plan 
NCT06078501 
August 23, 2023 
 
 
To detect a 30% reduction in the proportion of participants with quantitative blood loss (QBL) 
greater than the median, with a two-sided alpha of 0.05 and 80% power, we calculated that 36 
participants per group would be needed. To allow for attrition, we planned to recruit 40 
participants per group, for a total of 80 participants. 
 
Descriptive statistics will be used to summarize baseline characteristics. Continuous variables 
will be compared using t-tests or Wilcoxon rank-sum tests, depending on distribution. 
Categorical variables will be compared using chi-square or Fisher’s exact tests. Multivariable 
logistic regression was used to estimate the association between treatment group and the 
primary outcome (QBL greater than the median), adjusting for potential confounders.