Effect of Adjunctive Misoprostol on Blood Loss at Vaginal Delivery
Phase: NA
Conditions: Postpartum Hemorrhage
Sponsor: New York City Health and Hospitals Corporation

 
Version Dated February 1, 2017 
1
 
Queens Hospital Center 
Icahn School of Medicine at Mount Sinai  
Department of Obstetrics and Gynecology 
 
Clinical Investigation Protocol 
 
 
 
 
 
EFFECT OF ADJUNCTIVE MISOPROSTOL TREATMENT ON BLOOD LOSS AT 
VAGINAL DELIVERY 
 
Principal Investigator and Faculty Sponsor: Alexandr Fuks, MD 
Co- Investigator: Tricia Yusaf, MD 
Sub-investigator: Ayodeji Sanusi, MD 
 
 
 
Sub-investigator: Anubha Arora, MD      
        
 
 
 
Abstract 
This document defines the Clinical Investigation Protocol for a study designed to 
determine whether blood loss after spontaneous vaginal delivery is altered by the 
addition of misoprostol administration to the standard use of intravenous oxytocin after 
delivery. The protocol is an open-label randomized prospective trial to be carried out at 
Queens Hospital Center.  
Blood loss will be measured indirectly by comparing the maternal hemoglobin and 
hematocrit levels on admission in labor to those obtained within 24 hours after 
delivery. 

 
Version Dated February 1, 2017 
2
Principal contacts 
 
 
Faculty Sponsor/  
Principal investigator   
 
 
Alexandr Fuks, MD 
                                      
 
 
Chairman of Obstetrics and Gynecology 
                                   
 
 
 
Queens Hospital Center 
 
 
 
 
 
 
 
 
 
 
 
 
 
Assistant Professor of Obstetrics and Gynecology 
                                                   Icahn School of Medicine at Mount Sinai  
 
Co- Investigator:  
 
             Tricia Yusaf, MD 
                                       
Attending Physician  
                                       
Department of Obstetrics and Gynecology  
 
 
 
    
 
 
 
 
 
Queens Hospital Center 
 
 
 
Sub Investigator: 
 
 
 
 
Ayodeji Sanusi, MD 
 
 
 
 
 
 
 
 
 
 
Resident Physician 
                                               Department of Obstetrics and Gynecology 
 
 
 
 
 
 
 
 
 
     Queens Hospital Center 
 
 
 
Sub Investigator: 
 
 
 
 
Anubha Arora, MD 
 
 
 
 
 
 
 
 
 
 
Resident Physician 
                                               Department of Obstetrics and Gynecology 
 
 
 
 
 
 
 
 
 
     Queens Hospital Center 
 
 
 
 
 
 
 
                    
   
 
 
 
 
 
 
 
 
Sponsoring Department: 
 
Department of Obstetrics and Gynecology 
 
 
 
 
 
 
 
 
         Queens Hospital Center  
 
 
 
 
 
 
 
 
 
 
82-68 164th Street 
 
 
 
 
 
 
 
 
 
 
Jamaica, New York 11432 

 
Version Dated February 1, 2017 
3
Table of Contents 
BACKGROUND 
4 
PRELIMINARY DATA 
5 
STUDY DESIGN 
5 
SAMPLE SIZE AND ANALYSIS 
5 
INCLUSION AND EXCLUSION CRITERIA 
6 
RANDOMIZATION 
7 
CHARACTERISTICS OF MEDICATION 
7 
BENEFITS AND RISKS TO STUDY SUBJECTS 
8 
STUDY PROCEDURE 
9 
CONFIDENTIALITY 
10 
COSTS 
10 
REFERENCES: 
11 

 
Version Dated February 1, 2017 
4
 
Background 
Some maternal blood loss normally occurs at the time of vaginal delivery. The best 
estimates indicate that a loss of approximately 500 mL is average, with a range of about 
250-700 mL.[1,2] Some of this bleeding arises from birth canal lacerations or surgical 
incisions (i.e., episiotomy), but most derives from the vessels exposed in the uterine 
wall at the placental site once the placenta has separated.  
 
Under normal circumstances, shortly after placental separation intense myometrial 
contractions occur. These raise the pressure within the myometrial wall above that of 
the blood pressure in the vessels that traverse it, vessels that opened into the 
intervillous space. Flow in these vessels is thus mechanically attenuated by myometrial 
contraction, allowing for the formation of intravascular thrombi.  
 
This mechanism for controlling postpartum uterine blood loss works well most of the 
time. If, however, the uterus remains hypotonic or atonic after delivery, excessive blood 
loss can occur. In the worst cases, severe uterine hemorrhage ensues. Postpartum 
hemorrhage is, in fact, the leading cause of maternal mortality in the world, accounting 
for at least 100,000 deaths annually.[3] Even in the absence of frank hemorrhage, 
postpartum blood loss can result in maternal anemia. Recuperation of iron stores to 
recover from this blood loss takes time, and may not occur, especially in low 
socioeconomic areas where dietary iron consumption is often deficient, and 
pregnancies tend to occur in close succession.  
 
Postpartum anemia is a significant contributor to short- and long-term morbidity.[5-7] It 
increases the risk of infection and poor wound healing.  Also, the associated fatigue 
may interfere with the mother’s ability to administer child care and to bond appropriately 
with her infant. Anemic mothers tend to have more difficulty with nursing, and may 
produce iron-deficient milk. There is thus a strong rationale to minimize postpartum 
blood loss.  
 
In most US hospitals, parturients receive a high dose of intravenous or intramuscular 
oxytocin immediately after delivery. This approach has been shown in several studies to 
reduce the risk of postpartum hemorrhage, [8-11] and is practiced routinely at Queens 
Hospital Center. We employ an intravenous infusion of oxytocin (Pitocin®) at a rate of 
about 50-100 mU/minute. Despite this approach, there is still substantial blood loss at 
delivery, based on our preliminary observations shown below. This provides the 
rationale to determine whether use of an adjunctive drug, namely misoprostol 600 µg 
rectally, administered after delivery, might reduce blood loss further than does oxytocin 
alone, thus decreasing the risk of morbidity related to postpartum anemia. 
 
 
 
 
 

 
Version Dated February 1, 2017 
5
 
 Preliminary Data 
 
We examined the hemograms of a randomly chosen consecutive sample of 53 
spontaneous vaginal deliveries performed at Queens Hospital Center between 
September 15 and October 1, 2010. 
 
Among these patients, the admission hemoglobin concentration was 11.9±1.2 g/dL and 
that on the first postparutum day was 10.9±1.3. The mean fall was 1.02 (95% CI 0.74, 
1.29), a statistically significant decrease (P<0.0001). Hematocrit levels fell in parallel, by 
an average of 7.8% of the predelivery value. The mean fall in hemoglobin and 
hematocrit levels after delivery (1.02 g/dL and 2.81%) is consistent with an average 
blood loss of about 500 mL. The consistency of these changes and the small associated 
variance indicate that the change in hemoglobin and hematocrit levels is a meaningful 
proxy for the assessment of blood lost during vaginal delivery. 
 
 
Study Design 
The study is a prospective randomized open-label clinical trial to be performed in a 
single institution. It will compare the intrapartum and postpartum maternal blood 
hemoglobin concentrations and hematocrit measurements in a group of parturients who 
received standard prophylactic intravenous oxytocin immediately after delivery with a 
group that received oxytocin and adjuvant misoprostol.  
 
Sample size and analysis 
 
A total of 800 subjects will enter this two-treatment parallel design study. With that 
sample size, the probability is 90% that the study will detect a treatment difference at a 
two-sided 0.05 significance level if the difference in hemoglobin concentration between 
treatments is 0.3 g/dL. This analysis is based on the assumption that the standard 
deviation of the postpartum and intrapartum hemoglobin concentrations is not larger 
than 1.3 g/dL. 
 
Comparison of intrapartum and postpartum hemoglobin and hematocrit levels will be 
done using a paired t-test. A probability level of 0.05 will be used as the threshold for 
significance. 

 
Version Dated February 1, 2017 
6
 
Inclusion and exclusion criteria 
This study will include adult pregnant women regardless of age.  Pregnant minors under 
the age of 18 will not be eligible. 
 
A patient will be considered for inclusion in the study if she meets all of the following 
criteria: 
 She has a term (≥37 completed weeks) live singleton gestation in cephalic 
presentation and has been admitted to the Labor and Delivery Unit  
 She is in the latent phase of labor or has been admitted for induction of labor or at 
prenatal clinic visit 
 She has had fewer than four prior vaginal deliveries. 
 She reports no allergy to misoprostol. 
The following factors or conditions will exclude a patient from consideration as a 
subject: 
 The fetus has a known major fetal malformation or chromosome abnormality  
 The gestation is multiple. 
 There is a breech or other malpresentation  
  The patient reports involvement in another clinical trial currently or previously in 
this pregnancy. 
 The patient is expected to have a cesarean delivery. 
 The patient had a prior cesarean delivery. 
 There has been an intrauterine fetal death. 
 There is polyhydramnios (amniotic fluid index >22 cm). 
 Presence of acute or chronic renal disease 
 Presence of preeclampsia 
 
Of subjects who enter the study, the development of certain conditions will exclude 
them post hoc from receiving misoprostol under the protocol, and from the data 
analysis. These conditions include: 
 Unanticipated cesarean delivery. 
 Performance of episiotomy (third and fourth degree extensions will be excluded). 
 Vaginal or cervical laceration, or perineal laceration of more than second degree in 
depth. 
 Severe postpartum hemorrhage requiring intervention immediately after delivery. 
 Uterine rupture 
 Placental abruption. 
 Patient withdrawal of consent. 

 
Version Dated February 1, 2017 
7
 
Recruitment and Consent Procedures   
 
 
Patients who meet the inclusion criteria for the study will be identified during their 
prenatal clinical visits, in early latent-labor, or prior to induction of labor or active labor. 
Informed consent will be obtained by one of the investigators. Consent will be obtained 
prior to active labor.  The informed consenting process will not be initiated among 
patients in active labor. Patients will be recruited and consented with the consent 
document approved by the IRB.   Patient recruitment will commence after IRB approval 
is obtained. 
 
Once the subject has consented to participate in the study, it will be determined by the 
investigator whether the patient will receive oxytocin alone or oxytocin and misoprostol. 
Both drugs are on formulary and will be available on the Labor and Delivery Unit for 
immediate use. 
 
Randomization 
A computer-generated table of random numbers will be used to assign the recruited 
subject to a group. A locked file will be maintained in the Labor and Delivery area. The 
file will contain a series of sequentially-numbered sealed envelopes. Each envelope will 
contain a card with a randomly generated number. These numbers will have been taken 
in order from the computer-generated list. The investigator will choose the next 
envelope in sequence. If it contains an odd number, the patient will be assigned to the 
intervention group and will receive oxytocin and misoprostol. If the envelope contains an 
even number, the patient will be assigned to “oxytocin only” group.  
 
Characteristics of Medication 
Nature of misoprostol 
Misoprostol is a synthetic prostaglandin E1 analog. It is marketed primarily as a drug to 
prevent the development of gastric ulcers associated with use of nonsteroidal anti-
inflammatory drugs, and is part of the Queens Hospital Center formulary. Originally 
marketed as Cytotec®, misoprostol is available in a generic form as tablets containing 
contain either 100 µg or 200 µg. Misoprostol protects the gastric mucosa through 
several mechanisms. It also has the property of stimulating myometrial smooth muscle 
contraction.[12] That effect has resulted in the drug’s common use in obstetrics for 
termination of pregnancy, cervical ripening prior to induction of labor and, in large 
doses, for prevention and treatment of postpartum hemorrhage from uterine atony. [13-
19] 
 

 
Version Dated February 1, 2017 
8
Misoprostol can be administered by oral, sublingual, vaginal or rectal routes. It is well 
absorbed with all these modes of administration, but detailed pharmacokinetic data exist 
primarily concerning its oral administration. It is rapidly absorbed, and undergoes 
prompt de-esterification to its free acid, which is responsible for its clinical activity. Peak 
plasma levels after oral administration occur after 10-15 min. The half-life is 20-40 
minutes. The alpha side chain undergoes beta oxidation and the beta side chain 
undergoes omega oxidation followed by reduction of the ketone to give prostaglandin F 
analogs. Excretion is primarily in the urine. 
  
Very little misoprostol appears in breast milk. [20,21] After a single 600 µg oral dose of 
misoprostol to nursing mothers, misoprostol acid was excreted in breast milk.  One hour 
after dosing, the milk concentration was about 67% of the maternal serum level; by five 
hours, the misoprostol concentrations in breast milk declined to < 1 pg/mL. While no 
specific data exist for misoprostol concentrations in colostrum, given the very small 
ingested volume over the first few hours of life, neonatal exposure to the drug in our 
study can be expected to be minimal. There are no published reports of adverse effects 
of misoprostol in breast-feeding infants of mothers taking misoprostol  
 
Misoprostol is classified by the FDA as a Pregnancy Category X drug. This label is 
related to its possible association with congenital anomalies when used in the first 
trimester, as well as its abortifacient properties. In our study, patients will no longer be 
pregnant when they receive the drug. 
 
The use of misoprostol to enhance uterine activity postpartum is an off-label method, 
but one that has gained wide acceptance, and for which there is considerable 
experience.[8-10, 12-19] The drug can cause nausea, headache, dyspepsia, vomiting, 
and constipation or diarrhea with multiple doses. These side effects are usually mild to 
moderate and generally subside within a week. Serious side effects after a single dose 
are quite rare. In one study of 327 women who received 600 µg rectally (the dose we 
propose to use), the most common side effects were transient shivering (26%) and 
pyrexia (15%). Both were mild and short-lived. [16] 
 
 
 
Benefits and Risks to Study Subjects  
There will be no certain medical benefit to the subjects who participate in the study. It is 
possible that they will benefit from reduced postpartum blood loss.  
Risks to the subjects are those associated with administration or misoprostol. 
These include the following adverse events that have been reported in subjects 
receiving misoprostol for ulcer prophylaxis: diarrhea, abdominal pain, nausea, 
flatulence, headache, dyspepsia, vomiting, and constipation. All occurred in fewer than 
5% of patients. Other reported effects that occurred in clinical trials of misoprostol, but 
for which no cause-effect relation has been established included fatigue, fever, chills, 
rash, alopecia, pallor, breast pain, abnormal taste, abnormal vision, conjunctivitis, 

 
Version Dated February 1, 2017 
9
deafness, tinnitus, earache, chest pain, edema, diaphoresis, hypotension, hypertension, 
arrhythmia, phlebitis, increased cardiac enzymes, syncope, myocardial infarction, 
thromboembolism, abnormal hepatobiliary function, gingivitis, reflux, dysphagia, gout, 
polyuria, dysuria, hematuria, urinary tract infection, anxiety, depression, and 
thrombocytopenia. As with any drug, anaphylaxis is possible.  
We emphasize that in a number of published studies using a single postpartum dose of 
misoprostol of 600-1000 µg and including in aggregate in excess of 1000 patients, no 
serious side effect has been reported. 
 
Side effects after a single dose of misoprostol are rare. Misoprostol can cause nausea, 
headache, heartburn, vomiting, flatulence, and constipation or diarrhea with multiple 
doses. These side effects are usually mild to moderate and generally go away within a 
week. Mild shivering and slight fever are the most likely side effect of this medication. If 
they occur, they will probably disappear within an hour.  
 
 
Oxytocin commonly causes vomiting and nausea.  Oxytocin has the potential to cause 
muscle contractions.  In rare cases, Oxytocin can cause heart palpitations (rapid 
heartbeat) and allergic reaction of a rash or swelling. 
 
 
It is unknown whether Misoprostol and/or Oytocin are excreted in human milk. There is 
an unconfirmed relation with Misoprostol and/or Oytocin  causing digestive problems, 
such as diarrhea, and abdominal cramps in breast-fed newborns.  Pariticipants will be 
advised to discard breast mild for the first 24 hours to possibly avoid occurrence. 
 
 
Study Procedure 
Informed consent will be obtained by one of the investigators or informed consent 
delegates. The subject will then be assigned randomly to the control (oxytocin alone) or 
the study (oxytocin + misoprostol) group, as described above. The subject and her 
medical caretakers will be informed of which group she is in. If the labor eventuates in a 
vaginal delivery, all subjects will receive the standard dose of intravenous oxytocin, 
begun within one minute of delivery. Subjects in the study group who have not incurred 
any of the post-hoc exclusion criteria (episiotomy, major laceration, etc) will receive a 
dose of 600 µg of misoprostol in addition to their oxytocin. This will be administered in 
the form of six 100 µg tablets inserted approximately 2 cm into the anorectal canal by 
the obstetrician or midwife who has performed the delivery. The common method for 
administering Misoprostol for postpartum hemorrhaging is rectally for local absorption.  
Since this study is directed toward prevention instead of treatment, the dosage of 
600mg is a lower dosage from the 1000mg administered, as standard practices, for 
treating postpartum hemorrhaging of more than 500cc estimated blood loss.    The 
patient’s vital signs will be recorded after delivery according to standard protocols of the 
obstetric service. The Data Collection forms will be filled out after the delivery by one of 

 
Version Dated February 1, 2017 
10
the investigators. The measurement of postpartum hemoglobin and hematocrit (H & H) 
is automatically ordered at 06:00am for all patients who have delivered the day prior, 
constituting this measurement at "Postpartum Day 1", which is at a minimum of 6 hours 
after delivery and is enough time for H & H levels to stabilize. 
Within 36 hours of delivery, additional information will be collected from the patient’s 
record, including the postpartum hemogram and information about any symptoms or 
signs related to the misoprostol. 
 
Confidentiality 
 
After a subject has given informed consent, she will be assigned a Study Number. This 
number will be used on the study data collection form as the sole patient identifier, i.e., 
the form will not contain the subject’s name or hospital number. A single hard copy list 
of the subjects’ Study Numbers and their medical record numbers will be kept in a 
locked cabinet in the Principal Investigator’s sponsor’s office (Dr. Fuks).  This list will be 
destroyed once the study has been accepted for publication. Only Dr. Fuks will have 
access to this list.  
 
Costs 
The cost of each 600 µg dose of misproostol will be $4.80. There will be no charge to 
the patient. The drug will be paid for through the research fund of the Department of 
Obstetrics and Gynecology at Queens Hospital Center. 
 
 
Data Collection 
 
Data collection will include the following elements: 
 
Before Delivery 
 Age 
 Ethnicity/Race 
 Gestational age (in weeks) 
 Number of previous deliveries 
 Number of Fetus 
 Body-Mass Index (BMI) 
 Amniotic Fluid Index (AFI) 
 Cephalic presentation 
 Fetal Heart Rate (FHR) 
 Reported fetal Anomaly 

 
Version Dated February 1, 2017 
11
 Preeclampsia 
 Trial of Labor after Cesarean (TOLAC) 
After Delivery 
 Caesarean section (during delivery)  
 Epidural 
 Oxytocin in labor (if yes, number of hours before delivery 
 Other medication used in labor 
 Episiotomy 
 Duration of stage 1, 2, and 3 
 Degree and place of laceration 
 Estimated Blood Loss (EBL) 
 Transfusion 
 Placental  Abruption 
 Birth weight 
Results – includes Follow-up Data 
 Hemoglobin and Hematocrit (H& H) on admission and on post- partum day #1 
 Reported Side effect by patient 
 Post partum temperature 
 Reports of shivering 
 Diagnosis of chorioamnionitis  
 
Post- partum day #1- data collection 
Postpartum Day 1 is delineated as the first 12:01am clock time from the time of delivery.  
Post-partum measurements, such as postpartum hemoglobin and hematocrit (H & H), 
are taken automatically at 06:00am for all deliveries that occurred before midnight (at 
least 6 hours prior). 
 
 
References: 
 
1. Pritchard JA, Baldwin RM, Dickey JC, et al. Blood volume changes in pregnancy    
and the puerperium, 2. Red blood cell loss and changes in apparent blood 
volume during and following vaginal delivery, cesarean section, and cesarean 
section plus total hysterectomy. Am J Obstet Gynecol 1962;84:1271-1282 
 
2. Sosa CG, Althabe F, Belizan JM, Buekens P. Risk factors for postpartum 
hemorrhage in vaginal deliveries in a Latin-American population. Obstet Gynecol 
2009;113:1313-1319. 
 
3. Cohen WR. Hemorrhagic shock in obstetrics. J Perinat Med 2006;34:263-271 
 
 

 
Version Dated February 1, 2017 
12
4. Pontieri-Lewis V. The role of nutrition in wound healing. Medsurg Nurs 
1997;6:187-190 
 
 
5. Van Ramshorst GH, Nieuwenhulzen J, Hop WC, Arends P, Boom J, Jeekel J, 
Lange JF. Abdominal wound dehiscence in adults: development and validation of 
a risk model. World J Surg 2010;34:20-27 
 
6. Ezechi OC, Edet A, Akinlade H, Gab-Okafor CV, Herbertson E. Incidence and 
risk factors for caesarean wound infection in Lagos Nigeria. BMC Res Notes 
2009;2:186 
 
7. Teixeira ML, Coutinho SB, Eickmann SH, Lima MC. Influence of breastfeeding 
type and maternal anemia on hemoglobin concentration in 6-month-old infants. J 
Pediatr 2010;86:65-72. 
 
8. Chelmow D. Postpartum hemorrhage: prevention. Clin Evid (Online) 2011;4:1410 
 
9. Elati A, Elmahaishi MS, Elmahaishi MO, Esraiti OA, Weeks AD. The effect of 
misoprostol on postpartum contractions: a randomised comparison of three 
sublingual doses BJOG 2011:118:466-473. 
 
10. Soltani H, Hutchon DR, Poulose TA. Timing of prophylactic uterotonics for third 
stage 
of 
labour 
after 
vaginal 
birth. 
Cochrane 
Database 
Syst 
Rev 
2010;8:CD006173 
 
11. Elbourne DR, Prendiville WJ, Carroll G, Wood J, McDonald S. Prophylactic use 
of oxytocin in the third stage of labour. Cochrane Database Syst Rev 
2001;4:CD001808. 
 
12. Gemzell-Danielsson K, Bygdeman M, Aronsson A. Studies on uterine contractility 
following mefipristone and various routes of misoprostol. Contraception 
2006;74:31-35 
 
13. Cabrera Y, Fernandez-Guisasola J, Lobo P, Gamir S, Alvarez J. Comparison of 
sublingual 
versus 
vaginal 
misoprostol 
for 
second-trimester 
pregnancy 
termination: a meta-analysis. Aust NZJ Obstet Gynaecol 2011;51:158-165. 
 
14. Enakpene CA, Morhason-Bello IO, Enakpene EO, et al. Misoprostol for 
prevention of post-partum hemorrhage during third stage of labor. J Obstet 
Gynecol Res 2007;33:810-817 
 
15. Nasr A, Shahin AY, Elsamman AM, Zakherah MS, Shaaban OM. Rectal 
misoprostol versus intravenous oxytocin for prevention of postpartum 
hemorrhage. Int J Gynecol Obstet 2009;105:244-247. 
 
16. Mansouri HA, Alsahly N. Rectal versus oral misoprostol for active management 
of third stage of labor: a randomized controlled trial. Arch Gynecol Obstet 2010, 
April 27 (Epub ahead of print) 
 
17. Baruah M, Cohn GM. Efficacy of rectal misoprostol as second-line therapy for 
treatment of primary postpartum hemorrhage. J Reprod Med 2008;53:203-206. 
 

 
Version Dated February 1, 2017 
13
18. Lokugamage AU, Sullivan KR, Niculescu I, et al. A randomized study comparing 
rectally administered misoprostol versus synometrine combined with an oxytocin 
infusion for the cessation of primary postpartum hemorrhage. Acta Obstet 
Gynecol Scand 2001;80:835-839. 
 
 
19. Haque N, Bilkis L, Haque N, Bari MS, Haque S. Comparative study between 
rectally administered misoprostol as a prophylaxis versus conventional 
intramuscular oxytocin in post partum hemorrhage. Mymensingh Med J 
2009;18(1 suppl):S40-44 
 
20. Vogel D, Burkhardt T, Rentsch K, Schweer H, Watzer B, Zimmermann R, Von 
Mandach U. Misoprostol versus methylergometrine pharmacokinetics in human 
milk. Am J Obstet Gynecol 2004;19:2168-2173 
 
 
 
21. Tang OS, Schweer H, Lee SW, Ho PC. Pharmacokinetics of repeated doses of 
misoprostol. Hum Reprod 2009;24:1862-1869 
 
22. Garis RE, Kirkwood CF. Misoprostol: a prostaglandin E1 analogue. Clin Pharm 
1989;8:627-644