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Oral Misoprostol for Third Stage of Labor: A Randomized Placebo-Controlled Trial

From the Department of Obstetrics and Gynecology, University of Basel, Basel, Switzerland.

Address reprint requests to: Daniel V. Surbek, MD Department of Obstetrics and Gynecology University of Basel Schanzenstrasse 46 CH-4031 Basel Switzerland E-mail: surbek{at}ubaclu.unibas.ch

	Abstract

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Objective: To investigate whether orally administered misoprostol during the third stage of labor is efficient in reducing postpartum blood loss.

Methods: In a double-masked trial, during vaginal delivery women were randomly assigned to receive a single oral dose of misoprostol (600 µg) or placebo in third stage of labor, immediately after cord clamping. The third stage of labor was managed routinely by early cord clamping and controlled cord traction; oxytocin was administered only if blood loss seemed more than usual. Blood loss was estimated by the delivering physician and differences in hematocrit were measured before and after delivery.

Results: Mean ( ± standard error of the mean) estimated blood loss (345 ± 19.5 mL versus 417 ± 25.9 mL, P = .031) and hematocrit difference (4.5 ± 0.9% versus 7.9 ± 1.2%, P = .014) were significantly lower in women who received misoprostol than those who received placebo. Fewer women in the misoprostol group had postpartum hemorrhage (blood loss of at least 500 mL), but that difference was not statistically significant (7% versus 15%, P = .43). Additional oxytocin before or after placental separation was used less often in the misoprostol group (16% versus 38%, P = .047). There were no differences in the length of third stage of labor (8 ± 0.9 minutes versus 9 ± 1 minutes, P = .947). There were no differences in pain during third stage of labor, postpartum fever, or diarrhea, but shivering was more frequent in the misoprostol group.

Conclusion: Oral misoprostol administered in the third stage of labor reduced postpartum blood loss and might be effective in reducing incidence of postpartum hemorrhage.

Postpartum hemorrhage is a major cause of maternal morbidity and death. Hemorrhage might lead to severe postpartum anemia and hemorrhagic shock requiring blood transfusions or major surgical interventions to stop uncontrollable uterine bleeding. In industrialized countries,¹ and particularly in the developing world,² postpartum hemorrhage is an important cause of maternal death.

Several strategies have reduced postpartum blood loss and the incidence of severe postpartum hemorrhage. Active management of third-stage labor,³ including early cord clamping and controlled cord traction⁴ and administration of oxytocic drugs such as oxytocin,⁵ with or without ergometrine, have been beneficial. Risk of postpartum hemorrhage by routine use of oxytocic drugs has been estimated to be reduced by approximately 40%.⁶

Timing and combination of prophylactic measures vary widely between countries and institutions, and remain controversial. Current oxytocic drugs are far from ideal, particularly for routine use in developing countries, where simple routes of administration and stable, inexpensive drugs are needed because many deliveries take place far from hospitals or medical facilities and are supervised solely by birth attendants. Oxytocin must be injected and lacks stability in tropical conditions, and ergometrine has been ineffective when administered orally.⁷ Prostaglandin E₂ derivatives such as sulprostone are effective oxytocic drugs, but they are expensive and not storable at room temperature.

Misoprostol, a synthetic prostaglandin E₁ analogue, is used widely for prophylaxis and treatment of peptic ulcer disease.⁸ It is rapidly absorbed after oral administration,⁹ has few side effects, is stable at room temperature, and is inexpensive. It stimulates uterine contractions, and has been used for first- and second-trimester termination of pregnancy, and labor induction at term.¹⁰ Its use in the third stage of labor was suggested in a recent letter ( El-Refaey H, O’Brien P, Morafa W, Walder J, Rodeck C. Misoprostol for third stage of labour [letter]. Lancet 1996;347:1257). The aim of our study was to assess the effect of misoprostol on postpartum blood loss.

	Materials and Methods

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We conducted a double-masked, randomized study in women at low risk for postpartum hemorrhage between May 1997 and April 1998. The study protocol was approved by the University of Basel Hospital institutional review board. Women who planned to have vaginal deliveries and who attended the hospital’s outpatient clinic were asked to participate, and written informed consent was obtained from all willing to enter the trial. Women with multiple pregnancies, preeclampsia, previous postpartum hemorrhage, or antepartum hemorrhage, and those undergoing cesarean deliveries, were excluded.

Using random number-generated tables, parturients were individually assigned by the hospital’s pharmacy during labor to receive misoprostol or placebo. In the third stage of labor, immediately after cord clamping, subjects received oral misoprostol (600 µg) or placebo. For proper masking, the study drugs were prepared by the hospital pharmacy as three identical gelatine capsules, each containing misoprostol (200 µg) (Cytotec; Searle, Chicago, IL) or placebo. If intravenous oxytocin was used during the second stage of labor, it was stopped immediately after delivery. The third stage of labor was managed actively by using early cord clamping and cord traction. No additional oxytocic drugs except the study medication were administered routinely. Uterine bleeding was observed closely; if it was more than normal, or if the placental separation did not occur until 30 minutes after delivery, additional oxytocin was administered intravenously in boluses of 5 IU, repeated as necessary.

Postpartum blood loss was estimated by delivering physicians. Maternal hemoglobin and hematocrit values were measured prenatally and 24 and 48 hours postpartum. Postpartum hemorrhage was defined as estimated blood loss of at least 500 mL. Length of the third stage of labor, oxytocics used postpartum other than the allocated study drug, side effects including nausea and vomiting, diarrhea, shivering, and hypotension were recorded prospectively. To assess pain during the third stage of labor, women who did not have epidural analgesia were asked to judge their pain on a visual analog scale ranging from 1 (no pain) to 10 (worst possible pain). The randomization code was not broken until study completion.

The primary outcome was postpartum blood loss as estimated by physicians, and by antepartum and postpartum hematocrit values. A sample of 60 was calculated to detect a 20% difference in estimated blood loss between groups with a power of 80%, at a significance level of .05. Entry characteristics and outcomes of subjects in the misoprostol and placebo groups were compared using ² or Fisher exact test for categoric data and Mann-Whitney U test for continuous data. A two-tailed P < .05 was considered statistically significant.

	Results

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A total of 65 women completed the study; there were no withdrawals after randomization. In Tables 1 and 2, demographic characteristics of mothers and fetuses and intrapartum data are summarized. There were no statistically significant differences between groups. Fetal outcome was favorable in all women, no transfers to neonatal intensive care unit were necessary, and there were no significant differences in Apgar scores at 5 minutes or umbilical artery pH values between groups (data not shown).

	Discussion

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To date, few data are available on the effects of postpartum misoprostol. El-Rafaey et al¹¹ reported a prospective observational study in which 600 µg of misoprostol was given orally after delivery. They had a postpartum hemorrhage rate of 6%, and shivering occurred in 60%. In a randomized trial, rectal misoprostol (400 µg) was compared with intramuscular syntometrine (a combination of oxytocin plus ergometrine), and no differences in blood loss or postpartum hemorrhage were found.¹² Most recently, two randomized, placebo-controlled studies by the same group^13,14 used 400 µg of misoprostol and nonidentical placebo, one orally administered and one rectally administered. In the first study, postpartum hemorrhage (defined as measured blood loss of at least 1 L) was not significantly different after misoprostol compared with placebo (6% versus 9%), but more women in the placebo group needed conventional oxytocics; 19% in the misoprostol group had shivering. In the second study, the difference in postpartum hemorrhage between misoprostol (4.8%) and placebo (7%) was not statistically significant, and there was no difference in need for additional oxytocics.

In our randomized controlled trial with a smaller sample, we showed a significant difference in blood loss and need for additional oxytocics, although there was no significant difference in incidence of postpartum hemorrhage, probably due to lack of power. We speculate that a dose of 600 µg, chosen on the basis of the initial report,¹¹ might be more effective in reducing blood loss and probably postpartum hemorrhage than the 400-µg dose, with a similar rate of unwarranted side effects. In an uncontrolled study in which a single dose of 1000 µg of misoprostol was prescribed for postpartum hemorrhage, no severe side effects were reported.¹⁵

A weak point in our study was that blood loss was estimated and not measured. Visual estimation has been shown to underestimate actual blood loss by 30–50%. Besides measuring hematocrit and hemoglobin differences before and after delivery, we excluded potential examiner bias in blood loss estimation by masking both women and physicians who attended deliveries as to whether the woman received misoprostol or placebo.

The reduction of blood loss in our study was rather small (mean 70 mL), a difference that might have been larger without additional oxytocin because more than twice as many women in the placebo group received oxytocin postpartum. In countries where many women have severe anemia during pregnancy because of nutritional, genetic, or environmental factors, even a relatively small reduction of postpartum blood loss could be clinically relevant.

The optimal route of misoprostol administration during third stage of labor is unknown. We chose the oral route because rapid absorption and systemic bioavailability are known,⁹ and the simplest route is desirable in developing countries where many deliveries in rural areas are not attended by medically trained staff.

	Footnotes

 
PII S0029-7844(99)00271-9

Received November 4, 1998. Received in revised form January 22, 1999. Accepted February 10, 1999.

	References

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