Postpartum hemorrhage, the most common form of major obstetric hemorrhage, remains a leading cause of maternal morbidity and mortality worldwide, even in high-income countries.1–5 Postpartum hemorrhage results from various causes, especially uterine atony.6–9 One form of postpartum hemorrhage prevention involves a package of interventions known as active management of the third stage of labor.10–15 This approach commonly includes prophylactic injection of 5 or 10 international units of oxytocin after delivery of the anterior shoulder in vaginal births or immediately after birth in cesarean deliveries, early clamping of the umbilical cord, and controlled cord traction. Evidence indicates that routine active management of the third stage of labor is effective in reducing the risk of postpartum hemorrhage.16 Oxytocin is the first-choice agent as a result of its high efficacy and low incidence of adverse effects.17
Prostaglandins also have uterotonic effects and are widely used in obstetric practice for the prevention and especially the treatment of postpartum hemorrhage.18,19 Misoprostol, a prostaglandin E1 analog, is the most common prostaglandin used off-label for postpartum hemorrhage prevention as a result of advantages including low cost, ease and multiple routes of administration, and thermal stability (easy storage).19 A large multicenter double-blind, randomized trial compared misoprostol and oxytocin for the management of the third stage of labor and showed that oxytocin provides the best prophylaxis for postpartum hemorrhage.20 Nonetheless, shortly afterward, Caliskan et al21 suggested that misoprostol might interact synergistically with oxytocin to improve prevention. We hypothesized that a combination of routine oxytocin and misoprostol, compared with oxytocin alone, both as part of active management of the third stage of labor, would decrease the postpartum hemorrhage rate.
MATERIALS AND METHODS
This double-blind multicenter, randomized controlled trial took place in three French university hospitals (Poissy-Saint-Germain, Necker-Enfants Malades, and Port Royal) in and around Paris from April 2010 to September 2013. An independent data and safety monitoring board monitored unblinded trial results and safety events. The Ethics Committee of Poissy Saint-Germain Hospital (Comité de Protection des Personnes Ile de France XI) approved the study protocol for all centers. The trial was registered at ClinicalTrials.gov NCT01113229 and is reported according to the Consolidated Standards of Reporting Trials (CONSORT) 2010 statement.22
Women for whom a vaginal delivery was expected and who received information about the trial were invited to participate. Enrolment was offered to women who were at least 18 years old, in the first stage of labor, at 36–42 weeks of gestation, had epidural anesthesia, and provided written informed consent. Exclusion criteria were multiple pregnancies, known hypersensitivity to prostaglandins, cesarean delivery, or participation in any other treatment trial.
After verification of the inclusion and exclusion criteria, eligible consenting women were randomly assigned during the first stage of labor in a one-to-one ratio to receive two tablets of 200 micrograms misoprostol (ie, a total dose of 400 micrograms) or two tablets of placebo orally immediately after delivery of the newborn. An independent, centralized, computer-generated randomization sequence (CleanWeb; Télémedecine Technologies, Boulogne, France) was used for this allocation based on a randomization list established by an independent statistician according to a permuted block method balanced and stratified by center.
To conceal allocation, treatment boxes were sealed and numbered sequentially according to the randomization sequence and were stored in the predelivery unit of each maternity ward. The misoprostol used in our trial was Cytotec. The placebo tablets were provided by the pharmacy of the Assistance Publique-Hôpitaux de Paris. They were identical to misoprostol tablets in color but their shape was slightly different. Therefore, the treatment was administered by a research midwife who did not otherwise participate in this trial, to maintain the treatment blind of patients and staff, before or after randomization.
All eligible women had active management of the third stage of labor, including a prophylactic intravenous injection of 10 international units oxytocin after delivery of the fetal anterior shoulder, early clamping of the umbilical cord, and controlled cord traction. Monitoring of blood loss started as soon as the neonate was born and before delivery of the placenta. Blood loss was collected into a calibrated plastic bag placed under the mother's pelvis. The transparent, graduated bag allowed continuous monitoring of blood loss and was maintained in place for at least 2 hours after the neonate’s delivery. It did not require sterilization and could be used in a dorsal, lateral, or lithotomy position. Blood from blood-soaked gauze swabs was also transferred into the plastic bag.
Additional management in both arms was left to the discretion of the attending obstetrician or midwife, notably the implementation of a continuous infusion of oxytocin (10 international units) in the intravenous maintenance bag. However, no misoprostol could be given in either group after administration of the study medication. If bleeding occurred despite the active management of the third stage of labor, physicians immediately provided standard care for postpartum hemorrhage, including manual removal of any uterine-retained products, systematic examination of the lower vaginal tract, placement of a bladder catheter, infusion of another bolus of 5 international units of oxytocin supplemented by an additional 10 international units administered by slow infusion, and uterine massage. If bleeding persisted, a second-line uterotonic drug (intravenous sulprostone, a prostaglandin E2 analog) was administered with circulatory support and prophylactic antibiotic treatment. If this infusion did not control the bleeding, intrauterine balloon tamponade, an invasive procedure, or both, including pelvic embolization or surgery, was performed. Transfusion decisions were left to the clinician's discretion.
The primary outcome was the rate of postpartum hemorrhage, defined as blood loss 500 mL or greater in the 2 hours after administration of the trial medication. Secondary outcome measures were: 1) clinical criteria: total blood loss, blood loss 1,000 mL or greater, time to placental delivery, need for a second-line uterotonic drug, a blood transfusion, or surgery or pelvic embolization; 2) laboratory criteria: difference between hemoglobin and hematocrit before and 2 days after delivery, in the absence of transfusion; and 3) adverse maternal events: maternal fever greater than 38°C, shivering, nausea, vomiting, diarrhea, or any severe adverse maternal reaction attributed to the trial medication.
Details of the procedures used to manage the third stage and all clinical outcomes identified during the immediate postpartum period were prospectively collected by the midwife or obstetrician in charge of the delivery and recorded in the woman's electronic case report form in the delivery room. Other data were collected by a research assistant, independent of the local medical team. An independent Data Safety and Monitoring Board was responsible for reviewing adherence to the trial procedures, recruitment, and safety data; the quality of collected outcome data was checked in each center for 10% of the included women, randomly selected, and in all cases of postpartum hemorrhage. The protocol called for an interim analysis to be performed by the Data Safety and Monitoring Board after inclusion of half the number of planned participants.
We assumed a 7.5% incidence of postpartum hemorrhage in the control group based on the rate found in the overall cohort in the Pithagore6 trial.23 The study sample size was planned to detect a decrease in the primary outcome from 7.5% in the placebo group to 5.0% in the misoprostol group. We calculated that 1,550 women per group (3,100 total) would yield 80% power to detect this difference with the use of a two-tailed α at 0.05. To preserve the overall type I error, the critical values for the planned interim analysis after the completion of 50% of the case report forms and for the final analysis were determined by applying the O'Brien-Fleming function. The Data Safety and Monitoring Board was to perform that interim analysis and recommend stopping the trial if there was a significant difference between groups in the primary outcome, if there was a safety signal that suggested an increased risk of adverse events in the misoprostol group, or if analysis of the observed trends indicated a low conditional power to show a significant difference between groups in the primary outcome.
The treatment groups were compared for baseline characteristics and outcomes, the continuous variables by the Mann-Whitney test, and the categorical variables by the χ2 or Fisher exact test, as appropriate. We calculated the absolute differences between groups and their 95% confidence intervals (CIs) for all outcomes. The Cochran Mantel-Haenzel test was used for stratified analyses to take potential differences across hospitals into account and to assess the homogeneity of the treatment effect. The primary analysis was conducted for both the intention-to-treat and per-protocol sets. All patients who underwent randomization were included in intention-to-treat analysis, except the women who had cesarean deliveries during labor and those who dropped out early. The per-protocol population comprised all women from the intention-to-treat population who received either misoprostol or placebo tablets.
We also performed a post hoc analysis in a high-risk population, which included all women with at least one of the following risk factors: grand multiparity (parity greater than four), polyhydramnios, induction of labor, or fever during labor. We used R 3.1 to perform the analyses.
The planned interim analysis was performed after the enrolment of 1,721 patients from April 2010 to September 2013 (Fig. 1). Its results showed that the lack of efficacy of the combination of misoprostol and oxytocin in reducing the postpartum hemorrhage rate made continuation of the trial futile. They also showed that misoprostol was associated with an unexpectedly high rate of adverse events. The Data Safety and Monitoring Board therefore recommended discontinuation of the trial. All further enrollment stopped, but patients who were already enrolled were included in the analysis.
The study groups were similar at baseline (Table 1). Furthermore, birth weight of the newborns was also similar (3,405±425 g in the misoprostol group compared with 3,402±448 g in the placebo group, P=.89), and there was no difference in the rate of macrosomia defined as birth weight greater than 4,000 g (7.8% in the misoprostol group compared with 8.8% in the placebo group, P=.54). Analysis of the primary outcome showed no significant difference in blood loss 500 mL or greater between the two groups in the 2 hours after the neonate’s delivery (8.4% in the misoprostol and 8.3% in the placebo group, P=.98; Table 2). This result was consistent in all three hospitals. Similarly, most secondary outcomes did not differ significantly between the treatment groups: blood loss 1,000 mL or greater, mean blood loss, transfusion rate, use of additional oxytocin, need for sulprostone, or emergency surgery or pelvic embolization. However, changes in the concentrations of both hemoglobin (1.0±1.2 g/dL in the misoprostol group compared with 1.1±1.3 g/dL in the placebo group, P<.005) and hematocrit (2.5±3.8 compared with 3.1±3.8, respectively, P=.001) from before to 2 days after delivery in the women without transfusions was statistically different between the two groups (Table 2). The post hoc comparison of a high-risk population showed no significant differences between the groups in postpartum hemorrhage or severe postpartum hemorrhage rates (Table 3).
The most common side effects strongly associated with misoprostol were temperature greater than 38°C (30.4% compared with 6.3% in the placebo group, P<.001) and shivering (10.8% compared with 0.6% in the placebo group, P<.001). Reports of diarrhea and vomiting were infrequent but nonetheless significantly more common in the misoprostol group (Table 4).
The per-protocol analysis included 780 of 806 (97%) of the women in the misoprostol group and 766 of 797 (95%) of those in the placebo group. The proportion of women with a measured postpartum blood loss 500 mL or greater did not differ between the misoprostol and placebo groups (8.6% [67/780] compared with 8.2% [63/766], respectively, P=.81).
Prophylactic misoprostol at a dose of 400 micrograms, added to oxytocin for active management of the third stage of labor, did not reduce the rate of postpartum hemorrhage, severe postpartum hemorrhage, or second-line procedures. However, frequent adverse events were strongly associated with misoprostol.
The similar incidence of the primary and secondary outcomes in both groups in our study suggests that misoprostol will produce no further uterotonic effects after a prophylactic infusion of 10 international units of oxytocin.
Our trial is not the first to demonstrate a lack of effectiveness of adjunctive misoprostol. In a double-blind multicenter randomized controlled trial, Widmer et al24 assessed the effectiveness of misoprostol (600 micrograms sublingually) as an adjuvant to standard uterotonics compared with standard uterotonics alone for treatment of postpartum hemorrhage. The proportion of women with blood loss 500 mL or greater within 60 minutes was similar in the groups receiving misoprostol (14%) and placebo (14%; relative risk 1.02, 95% CI 0.79–1.32).
These findings and ours highlight the major role of oxytocin in both prophylaxis and first-line treatment of postpartum hemorrhage and the absence of any additional benefit from misoprostol as adjuvant treatment for women receiving oxytocin. Although misoprostol may be useful in settings with poor health services where availability of both refrigerators and skilled birth attendants is scarce,25 its use should be infrequent in high-income countries, especially combined with oxytocin. This is especially true in that misoprostol induces numerous and frequent maternal side effects.24,26 Given that misoprostol is routinely used prophylactically among a very large number of healthy women, the greatest emphasis should be placed on limiting its use in high-income countries. Continued monitoring for adverse effects is essential.
The 400-microgram dose of misoprostol used in our study was determined by our review of previous studies showing that use of 600 or 800 micrograms of misoprostol did not improve its efficacy against blood loss, but resulted in higher proportions of women with side effects.26,27 The oral route was chosen based on the findings of Caliskan et al.21
Three randomized trials have evaluated the effect of prophylactic uterotonic drugs used alone or with oral or sublingual misoprostol for the prevention of postpartum hemorrhage.21,28,29 The first study was published before our trial was planned24 and the last two while our study was underway.28,29 In 2003, Caliskan et al24 showed a significant decrease in the occurrence of postpartum hemorrhage 500 mL or greater when 10 international units oxytocin was administered intravenously for 30 minutes after cord clamping together with 400 micrograms oral misoprostol followed by two doses of 100 micrograms oral misoprostol 4 hours apart (3.2%) compared with oxytocin alone (7.3%, P<.01). In 2011, Fawole et al28 and Hofmeyr et al29 reported a nonsignificant decrease in postpartum hemorrhage when 400 micrograms misoprostol was added to a standard prophylactic uterotonic drug.
Our study has several strengths. It was large, blind, and analyzed by the intent-to-treat principle. The use of a calibrated collecting bag enabled an objective measurement of postpartum blood loss and enhanced the quality of the study.
Our study also has several limitations. First, the exclusion of 118 women (6.9%) after treatment allocation in our trial might have induced a potential attrition bias. Second, the trial was halted before the target sample size was accrued. However, there is little reason to postulate that continued recruitment would have led to different results.
All in all, the findings of this trial do not support the use of misoprostol in addition to oxytocin for the prevention of postpartum hemorrhage. As Gibbins et al30 have pointed out, despite misoprostol's ready availability, easy use, and utility for other pregnancy indications, oxytocin should remain the mainstay of prophylaxis of postpartum hemorrhage in high-income countries, and misoprostol should be used infrequently for this indication.
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