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Obstetrics & Gynecology 2004;104:1282-1288
© 2004 by The American College of Obstetricians and Gynecologists
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ORIGINAL RESEARCH

Buccal Misoprostol to Decrease Blood Loss After Vaginal Delivery: A Randomized Trial

Aman Bhullar, MD, S. J. Carlan, MD, Jennifer Hamm, MD, Norman Lamberty, MD, Leigh White, MD and Kris Richichi, ARNP

From the Department of Obstetrics and Gynecology, Arnold Palmer Hospital for Children and Women, Orlando, Florida.


   ABSTRACT
TOP
ABSTRACT
MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
OBJECTIVE: To assess the efficacy of buccal misoprostol to decrease bleeding after vaginal delivery.

METHODS: This was a randomized study of patients between 22 weeks and 42 weeks of gestation with anticipated vaginal delivery. Patients were given either a 200-µg misoprostol tablet or placebo in the buccal space at the time of cord clamping. A continuous dilute intravenous oxytocin infusion was given to all patients at delivery of the placenta. Postpartum hemorrhage was defined as blood loss exceeding 500 mL. Sample size calculations based on previous studies assumed a 13% incidence of postpartum hemorrhage in the control group. To show a statistically significant reduction of postpartum hemorrhage a total of 1,604 patients would be required in each group.

RESULTS: A total of 848 patients were enrolled and 756 randomly assigned, 377 in the misoprostol group and 379 in the placebo group. Demographic, antepartum, and intrapartum characteristics were similar between the groups. The incidence of postpartum hemorrhage, 3% compared with 5%, (relative risk 0.65, 95% confidence interval 0.33–1.29, P = .22), mean estimated blood loss, 322 compared with 329 mL, (P = .45), and mean minutes of the third stage of labor, 6.7 compared with 6.9 (P = .52) were similar between the groups, misoprostol and placebo, respectively. Hemoglobin difference before and after delivery, need for second or third uterotonic agent, and all measured neonatal variables including birth weights, and umbilical cord pH were similar between the groups.

CONCLUSION: Buccal misoprostol at cord clamping is no more effective than placebo in reducing postpartum hemorrhage.

LEVEL OF EVIDENCE: I

Postpartum hemorrhage is a common complication of childbirth and a leading cause of maternal morbidity and mortality.1 The most common cause is atony, and its frequency seems to be related to both risk factors2 and the management of the third stage of labor. Blood loss exceeding 500 mL occurs in approximately 5% when managed actively with injectable oxytocics and early cord clamping and traction, and 13–16% when managed expectantly.3–7

Prostaglandins (PGs) have strong uterotonic properties and have been used in the postpartum period since 1976 to treat uterine atony and established postpartum hemorrhage.8,9 Interest in PGs as routine prophylactic agents in the third stage of labor increased when the uterotonic properties of misoprostol were recognized. Misoprostol is a PGE1 analogue that has wide clinical applications in obstetrics and is systemically absorbed when given orally and across mucous membranes.10–13 In 1996 its use for the prophylactic management in the third stage of labor was first reported in a small observational study.14 Multiple controlled trials investigating misoprostol as a prophylactic agent to prevent postpartum bleeding followed.15–21 A systematic review of randomized controlled trials of oral or rectal misoprostol to prevent postpartum hemorrhage concluded that the traditional injectable preparations were more effective than misoprostol as a part of the active management of the third stage of labor.22 None of the reports to date, however, addressed misoprostol given by the buccal route. The purpose of this study was to evaluate the effect of misoprostol given in the buccal space at cord clamp on postpartum bleeding.


   MATERIALS AND METHODS
TOP
ABSTRACT
 MATERIALS AND METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
From October 2000 through December 2002, pregnant women between 22 and 42 weeks of gestation admitted to the obstetric ward at Arnold Palmer Hospital for Children and Women who were in active labor or undergoing induction of labor and when a vaginal delivery was anticipated were candidates for participation. Those who met study criteria were invited to participate, and if they agreed, signed written informed consent. Participants were enrolled by the house staff assigned to the labor and delivery unit. This study was approved by the Orlando Regional Healthcare institutional review board. Women undergoing cesarean delivery and those with a bleeding disorder were excluded. Women with multiple pregnancies, preeclampsia, chorioamnionitis, or previous postpartum hemorrhage were not excluded.

After obtaining written informed consent, the labor and delivery nurse selected a small opaque vial from the central labor and delivery drug cabinet containing either a 200-µg misoprostol tablet or a placebo. The vial was not opened until delivery occurred. The placebo tablets were similar in size and color, but not identical in shape to the misoprostol tablet. Cabinets were kept stocked by the pharmacy based on inventory surveillance as reported by the nursing staff. Agent vials were coded with a number, which had been assigned using a random number table. Identification as to which agent (misoprostol or placebo) had been administered was maintained in a secured confidential logbook in the pharmacy. At no time before data analysis were the group assignments available to anyone but the pharmacy. The allocation sequence was generated in the pharmacy. After pulling the vial the nurse notified the pharmacy in writing as to the patient identification and vial number listed on the label. After delivery of the baby and at the time of cord clamping, the medication was taken from the opaque vial and placed in the patient's buccal space by the nurse. If intravenous oxytocin was used during the second stage of labor, it was stopped immediately after delivery. All women received the standard intravenous continuous oxytocin infusion of 20 units in 1,000 mL saline solution at approximately 10 mL/min for 30 minutes after the placenta delivered.

The third stage of labor was managed by early cord clamping and controlled cord traction until placental expulsion according to our institution's traditional technique. This involved applying steady, gentle downward traction to the cord with a Kelly clamp while providing counter traction against the uterine fundus. With signs of placental separation, such as the appearance of bleeding or lengthening of the cord, greater traction was applied until placental delivery. The uterine fundus was then massaged bimanually for at least 15 seconds.

If the placenta was not delivered within 30 minutes of delivery, it was removed manually. No additional oxytocics were used postpartum except the study medication given at cord clamping and the intravenous oxytocin given after delivery of the placenta. The physician recorded estimated blood loss. Successive uterotonic agents given, as well as the need for manual removal of the placenta before 30 minutes, was based on the physician's impression of bleeding and uterine tone. All episiotomies were performed using the midline technique throughout the study period. A blood sample was obtained before delivery for determination of hemoglobin concentration. A second blood sample for hemoglobin concentration was obtained 24 hours postpartum. Blood transfusions were performed at the discretion of the resident physician when clinically indicated. Postpartum hemorrhage was defined as estimated loss exceeding 500 mL. Length of the third stage of labor, uterotonic agents used postpartum other than the allocated study drug, and adverse effects, including nausea and vomiting, diarrhea, and shivering, were recorded prospectively. A resident physician evaluated all patients until 24 hours after delivery. The primary outcome was postpartum hemorrhage as estimated by the physician. Secondary outcome variables were estimated blood loss, length of the third stage of labor, the need for additional uterotonic drugs, and adverse effects. The research hypothesis was that buccal misoprostol would decrease the incidence of postpartum hemorrhage in women who received a routine intravenous infusion of dilute oxytocin at the conclusion of the third stage of labor.

Statistical analysis was conducted by using the Mann-Whitney U test for comparing difference of medians, Student t test for comparing differences of means and Pearson {chi}2 analysis or Fisher exact test for categoric data (SPSS, Chicago, IL). To determine sample size we assumed 13% of patients managed with early cord clamping and cord traction but without oxytocin in the third stage of labor would have a blood loss exceeding 500 mL.3,7 To reduce this by half to 6.5%, 312 patients in each group would be required, which would yield a power of 80% at a 95% confidence level. Statistical significance was defined as P < .05. We analyzed data based on intention to treat. Two-tailed P values are reported throughout.


   RESULTS
TOP
ABSTRACT
 MATERIALS AND METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
We enrolled 848 women, and 756 were randomly assigned (Figure 1), 377 to the misoprostol group and 379 to the placebo group. The reasons for nonassignment included nursing error in 71, unexpected cesarean delivery in 18, patient refusal after enrollment in 2, and physician error in 1. There were no differences between the groups in important demographic variables, (Table 1). Forty-one (11%) of the women in each group had misoprostol for cervical ripening and labor induction, (P = .98, {chi}2). The number of women at a gestational age of 37 weeks or higher was 303 of 377 (80%) and 319 of 379 (84%), misoprostol and placebo, respectively, P = .17, {chi}2. There were no differences between the groups in antepartum or intrapartum variables, or important conditions known to increase the risk of postpartum hemorrhage (Table 2). The most common indication for labor induction was preeclampsia with 45 of 377 (12%) and 51 of 379 (14%), in the misoprostol compared with placebo groups, respectively, P = .53, {chi}2. There was no difference between the groups in the number of labor epidurals at 321 of 377 (85%) and 320 of 379 (85%), misoprostol compared with placebo, respectively, P = .78, {chi}2. Labor and delivery variables were similar including the length of the third stage of labor (Table 3). The number of episiotomies performed was similar between the groups at 196 of 377 (52%) compared with 201 of 379 (53%), misoprostol compared with placebo, respectively, P = .77, {chi}2. Postpartum features are shown in Table 4. The incidence of postpartum hemorrhage was similar between the groups at 13 of 377 (3%) and 20 of 379 (5%), misoprostol and placebo, respectively, (relative risk 0.65, 95% confidence interval 0.33, 1.29, P = .22, {chi}2). The mean ± standard deviation estimated blood loss and minutes of the third stage of labor were similar between the groups at 322 ± 114 mL compared with 329 ± 122 mL (P = .45), and 6.7 ± 5.1 minutes compared with 6.9 ± 5.5 minutes, (P = .52), misoprostol compared with placebo, respectively. The number of women undergoing elective postpartum sterilization was similar at 35 of 377 (9%) and 33 of 379 (9%), misoprostol and placebo, respectively, P = .78, {chi}2. There was no difference between the groups in the incidence of adverse effects thought to be related to the study drug, with nausea and vomiting occurring in 5 of 377 (1%) and 2 of 379 (0.5%), misoprostol and placebo, respectively, (P = .29, Fisher exact test). Shivering occurred in 2 of 377 (0.5%) and 1 of 379 (0.3%), misoprostol and placebo, respectively, (P = .62, Fisher exact test). To show a statistically significant benefit reduction of postpartum hemorrhage a total of 1,604 patients would be required in each group.



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  		Fig. 1. Flow of patients through the study.

Bhullar. Buccal Misoprostol Postpartum. Obstet Gynecol 2004.

 

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  		Table 1. Demographics Characteristics of the Two Treatment Groups

 

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  		Table 2. Antepartum and Intrapartum Variables

 

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  		Table 3. Labor and Delivery and Infant Variables

 

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  		Table 4. Postpartum Features

 


   DISCUSSION
TOP
ABSTRACT
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
Postpartum hemorrhage after a vaginal birth is traditionally defined as the loss of blood exceeding 500 mL within the first 24 hours. Postpartum hemorrhage and excessive uterine bleeding can occur before or after placental delivery. Although there are many potential causes of postpartum hemorrhage, the most common cause is uterine atony. Effective uterine contraction after child birth leads to both detachment and expulsion of the placenta as well as optimal blood vessel compression at the placental implantation site.23 Consequently, any intervention that safely promotes timely uterine contraction can potentially reduce blood loss and prevent hemorrhage from atony. Most but not all24 studies have reported that early cord clamping, controlled cord traction and prophylactic uterotonic drugs administered to the mother immediately after delivery of the baby could reduce postpartum blood loss4 and decrease the occurrence of postpartum hemorrhage.3,4,7 The prophylactic uterotonic drugs most commonly studied have included oxytocin6,25 or combination preparations of oxytocin and ergometrine.3,26 Oxytocin is given parenterally, and ergometrine has known adverse effects, contraindications, and several disadvantages,25,27 therefore other methods for postpartum bleeding prophylaxis are needed, especially for the developing world where there may be a lack of widespread availability of drugs and sterile supplies.

PGs are effective myometrial stimulants and have been used to treat established postpartum hemorrhage for years.8,28 Because of the concerns of safety, cost and adverse effects of PGs, they were not, however, considered a reasonable prophylactic treatment22,29,30 until the uterotonic properties of misoprostol were recognized. Misoprostol is inexpensive, easy to store, and systemically absorbed orally and across mucous membranes, thus it was projected to be a promising substitute for other established injectable agents. Multiple studies investigating third stage oral or rectal misoprostol at different doses and with different control agents were reported with equivocal results,15–17,20,31–33 but a systematic review of 16 randomized trials with a total of 28,138 women concluded that injectable oxytocics are more effective than misoprostol in the active management of the third stage of labor.22 Our findings support the impression that misoprostol given at birth may be no better than placebo in reducing postpartum hemorrhage.

Misoprostol clearly is an effective myometrial stimulant, therefore why the drug given prophylactically to reduce postpartum bleeding complications would not be superior to expectant management or be inferior to the established agents is not clear. It may be that either the dose of misoprostol studied has been too low or possibly the time to achieve sufficient bioavailability too long when given orally or rectally. Adverse effects of misoprostol are dose related and can last up to 12 hours. In fact, Lumbiganon et al34 reported that of 843 women treated with 600 µg of oral misoprostol, 13% had shivering within 1 hour of delivery and more than 11% had pyrexia between 2 and 6 hours postpartum. Another study investigating 600 µg of oral misoprostol given in the third stage of labor reported an incidence of shivering of 22%.18 A more recent study reported the incidence of shivering and fever decreased to 11% and 4%, respectively with 400 µg of misoprostol given orally at cord clamping.33 One small study evaluating 70 women who received either 400 µg or 200 µg of rectal misoprostol in the postpartum period reported an overall incidence of shivering in 7%, but whether the patient received 400 or 200 µg was not clearly noted.35 Because of the incidence of adverse effects it is unlikely that higher doses of misoprostol could be evaluated for routine use to prevent postpartum hemorrhage.

Absorption of misoprostol is very rapid, being detected within 2 minutes after oral ingestion36 and peaking between 1237 and 30 minutes.38 Because the time from term delivery until placental expulsion is usually less than 10 minutes2,39,40 it seems the maximum benefit of misoprostol would occur after the end of the third stage. Possibly a different route of administration may improve its absorption dynamics and bioavailability and thus its effectiveness as a third stage prophylactic uterotonic agent. In 1998 Hofmeyr et al16 described an unpublished pilot study of 70 postpartum women who chewed 400 µg of misoprostol and left the medication in the mouth until it was dissolved. There was no noted difference in blood loss between the groups, but their control group was not described, and complete outcome variables were not provided. They concluded that buccal absorption was poor because of the lack of an acid environment in the mouth, which would promote absorption. In 2002 absorption of misoprostol through the buccal space was confirmed clinically in a cervical ripening and labor induction study.13 Also in 2002, Tang et al38 reported misoprostol serum levels in 40 pregnant women receiving 400 µg for pregnancy termination. In that study sublingual misoprostol achieved a higher plasma peak concentration than the oral or vaginal route, suggesting that, despite the nonacid environment, absorption across the mucous membranes of the oral cavity was effective. Neither rectal nor buccal administration was studied.

Since absorption of misoprostol across the buccal mucous membrane clearly must occur, the most likely explanation of our inability to demonstrate efficacy is that the lower dose of 200 µg does not provide adequate bioavailability quickly enough to promote a meaningful increase in uterine tone. This may also explain why we had such a low incidence of adverse effects. Possibly increasing the dose of buccal misoprostol past 400 µg may help, but the limiting adverse effect variable remains operative. One possible solution to achieving a more favorable drug level without having to increase the dose may be to use the sublingual space rather than the buccal space.

The increased vascularity of the sublingual space would suggest the sublingual route may result in more efficient absorption, which is consistent with both Tang's pharmacokinetic study and a recent clinical observation.41 Because atony and bleeding are known to occur even after placental separation and expulsion, the sublingual route of delivery may have more potential for both prophylactic and active postpartum hemorrhage treatment.

Whether we should even expect improved safety and decreased maternal bleeding with intravenous oxytocin at cord clamp has recently been challenged.24 In a double-blinded study of 1,486 women, Jackson et al24 reported that the administration of prophylactic oxytocin before placental delivery does not reduce the incidence of postpartum hemorrhage or third stage duration when compared with giving oxytocin after placental delivery when both groups were managed with controlled cord traction. These women were delivered under controlled circumstances in a hospital setting and were not exclusively high risk for postpartum hemorrhage.

Our study could be improved in several ways. First, we included all gestational ages admitted to our labor and delivery ward. It is known that third stage of labor complications increase as gestation decreases39 but the allocation process resulted in equal numbers of preterm women in each group, which should have eliminated bias. Second, 92 of 848 (11%) of our patients were enrolled but not randomized, with the most common protocol violation listed as failure of the nurse to follow protocol by informing the pharmacy of the vial number in 71 of 848 (8%) cases. Over the entire study period this represents less than 3 protocol violations per month. Moreover, when the randomization schedule was revealed there was only a total difference of 2 between the groups with 377 misoprostol and 379 placebo. Third, we did not weigh drapes32,42 or attempt to collect blood and clots in jars, which may be a more precise method of estimating blood loss than clinical estimation alone.22 It is known that reported blood loss is influenced by the assessment technique, and is frequently underestimated. This may have affected the total amount of blood loss estimated and thus the incidence of postpartum hemorrhage, but since the blood loss in both of our groups was assessed in the same way the differences between the groups would not have been affected. Fourth, we did not have a look-alike placebo tablet. However, the masked vials used and the fact that no member of the physician clinical team had knowledge of which agent the patient received should have insured allocation concealment. Fifth, we did not check serum misoprostol levels, but the test was not available to us. Sixth, we enrolled all women regardless of their predelivery risk for postpartum hemorrhage. Including only women with known risk factors for postpartum hemorrhage may have resulted in different conclusions, but most high-quality evidence shows a conclusive benefit for the active management of the third stage of labor using prophylactic uterotonic agents in all women regardless of risk status.3,4 One other possible explanation of why we did not see improvement with misoprostol is that the occurrence of clinically significant postpartum bleeding is so uncommon in women receiving intravenous oxytocin at placental delivery that we would need many more patients allocated. However, data available at the time of this study design suggested the number of patients was adequate.

In this comparative study, buccal misoprostol was compared with placebo as prophylactic pharmacological management of the third stage of labor. Although the buccal route has the advantage of ease of administration and absorption without being involuntarily expelled through the vagina or rectum postpartum, a single 200-µg dose was no more effective than placebo in reducing postpartum bleeding.


   Footnotes
 
Reprints are not available. Address correspondence to: S. J. Carlan, MD, Department of Obstetrics and Gynecology, Orlando Regional Healthcare, 105 West Miller Street, Orlando, Florida 32806; e-mail: scarlan{at}orhs.org.

Received June 6, 2004. Received in revised form July 26, 2004. Accepted August 5, 2004.

doi:10.1097/01.AOG.0000144119.94565.18


   REFERENCES
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ABSTRACT
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
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6. Nordstrom L, Fogelstam K, Fridman G, Larsson A, Rydhstroem H. Routine oxytocin in the third stage of labour: a placebo controlled randomized trial Br J Obstet Gynecol 1997;104:781–6.

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9. Oleen MA, Mariano JP. Controlling refractory atonic postpartum hemorrhage with Hemabate sterile solution. Am J Obstet Gynecol 1990;162:205–8.[Medline]

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