Original Research

Active Management of the Third Stage of Labor With a Combination of Oxytocin and Misoprostol to Prevent Postpartum Hemorrhage A Randomized Controlled Trial Thibaud Quibel, MD, Idir Ghout, MSc, François Goffinet, MD, Laurent J. Salomon, MD, Julie Fort, MSc, Sophie Javoise, Laurence Bussieres, MD, Philippe Aegerter, MD, and Patrick Rozenberg, MD, for the Groupe de Recherche en Obstétrique et Gynécologie (GROG) OBJECTIVE: To evaluate the effectiveness and safety of misoprostol administered simultaneously with oxytocin as part of the active management of the third stage of labor. METHODS: This multicenter, double-blind, randomized, placebo-controlled trial recruited women in the first stage of labor with expected vaginal deliveries at 36–42 weeks of gestation. Exclusion criteria were multiple pregnancies, hypersensitivity to misoprostol, and cesarean delivery. Participants received routine intravenous oxytocin and were randomly allocated to receive 400 micrograms misoprostol or placebo orally immediately after delivery of the newborn. The primary outcome was postpartum hemorrhage (500 mL or greater within 2 hours of birth). Secondary outcomes included severe postpartum hemorrhage (1,000 mL or greater) and adverse maternal events such as fever, From the Department of Obstetrics and Gynecology, Poissy-Saint Germain Hospital, Versailles-Saint Quentin University, research unit EA 7285, Versailles, the Department of Clinical Research Paris Ouest, Ambroise Paré Hospital, Assistance Publique-Hôpitaux de Paris, Boulogne, the Departments of Obstetrics and Gynecology, Port-Royal Cochin Hospital and Necker Hospital, Assistance Publique-Hôpitaux de Paris, Descartes University, Paris, and the Department of Clinical Research Necker-Cochin, Necker-Cochin Hospital, Assistance Publique-Hôpitaux de Paris, Paris, France. Supported by a grant from Programme Hospitalier de Recherche Clinique Clinique—PHRC 2009 (Ministère de la Santé N° AOR 09010). Presented at the 35th annual meeting of the Society for Maternal-Fetal Medicine, February 2–7, 2015, San Diego, California. Corresponding author: Thibaud Quibel, MD, Service de Gynécologie-Obstétrique, Centre Hospitalier Poissy Saint-Germain, 10 rue du champ Gaillard, 78300 Poissy, France; e-mail: [email protected]. Financial Disclosure The authors did not report any potential conflicts of interest. © 2016 by The American College of Obstetricians and Gynecologists. Published by Wolters Kluwer Health, Inc. All rights reserved. ISSN: 0029-7844/16

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shivering, and nausea. Two groups of 1,550 women were required to demonstrate a 33% decrease of postpartum hemorrhage according to a two-tailed a at 0.05 with 80% power. An interim analysis was planned after 50% enrollment. RESULTS: Participant enrollment occurred from April 2010 to September 2013. Baseline characteristics were similar in the two groups. The study was discontinued after the planned interim analysis including 1,721 patients showed that misoprostol was not effective and was associated with significantly more adverse effects. The rate of postpartum hemorrhage was 8.4% (68/806) in the misoprostol and 8.3% (66/797) in the placebo group (P5.98), and rates of severe postpartum hemorrhage were 1.8% and 2.4%, respectively (P5.57). Maternal adverse events occurred significantly more frequently in the misoprostol group (for fever 30.4% in the misoprostol group compared with 6.3% in the placebo group, P,.001; for shivering 10.8% in the misoprostol group compared with 0.6% in the placebo group, P,.001). CONCLUSION: Misoprostol administered with prophylactic routine oxytocin did not reduce the rate of postpartum hemorrhage risk and increased the rate of adverse events. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov, https:// clinicaltrials.gov, NCT01113229. (Obstet Gynecol 2016;128:805–11) DOI: 10.1097/AOG.0000000000001626

P

ostpartum 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

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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 SaintGermain 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

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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

Misoprostol for Prevention of Postpartum Hemorrhage

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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

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of a two-tailed a 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 x2 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 perprotocol 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 intentionto-treat population who received either misoprostol or placebo tablets. We also performed a post hoc analysis in a highrisk 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.

RESULTS 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

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Fig. 1. Trial profile. Quibel. Misoprostol for Prevention of Postpartum Hemorrhage. Obstet Gynecol 2016.

was also similar (3,4056425 g in the misoprostol group compared with 3,4026448 g in the placebo group, P5.89), 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, P5.54). 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, P5.98; 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 (1.061.2 g/dL in the misoprostol group compared

Table 1. Baseline Characteristics of Study Participants and Their Neonates Characteristic

Misoprostol+AMTSL (n5806)

Placebo+AMTSL (n5797)

3164.8 27.9612.2 431 (53.5) 33 (4.1) 29/803 (3.6) 4061.1 173 (21.5) 173 (21.5) 3246102 110668 257/803 (32.0) 14 (1.7) 56/807 (6.9) 37.260.5

3164.8 27.8610.2 433 (54.3) 49 (6.1) 33/795 (4.2) 4061.2 141 (17.7) 185 (23.2) 3266120 114670 246/796 (30.9) 21 (2.6) 48/796 (6.1) 37.260.5

Maternal age (y) BMI (kg/m2) Primiparous Previous cesarean delivery History of postpartum hemorrhage Gestational age at delivery (wk) Induction of labor Operative vaginal delivery 1st stage of labor (min) 2nd stage of labor (min) Episiotomy 3rd- or 4th-degree perineal tear Temperature greater than 38˚C during labor Maternal temperature (˚C) before administration of the study tablets AMTSL, active management of the third stage of labor; BMI, body mass index. Data are mean6standard deviation, n (%), or n/N (%).

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Table 2. Main, Secondary, and Other Maternal Outcomes Misoprostol+AMTSL (n5806)

Placebo+AMTSL (n5797)

P

68 (8.4)

66 (8.3)

.98

67/780 (8.6)

63/766 (8.2)

.81

13 (1.8) 150 (100–265) 19 (2.4) 5 (0.6) 5 (0.6) 2.0 (2.0–2.2) 1.0 (1.2) 2.5 (3.8) 50 (6.2)

17 (2.4) 150 (100–250) 25 (3.1) 9 (1.1) 9 (1.1) 2.5 (2.0–4.0) 1.1 (1.3) 3.1 (3.8) 50 (6.3)

.57 .52 .42 .41 .41 .48 .005 .001 .98

Primary outcome Intention-to-treat analysis of postpartum hemorrhage greater than 500 mL Per-protocol analysis greater than 500 mL Secondary outcomes Postpartum hemorrhage greater than 1,000 mL Total blood loss (mL) Sulprostone Pelvic embolization or surgery Blood transfusion No. of red cell units required among women transfused Delta hemoglobin (g/dL) Delta hematocrit Placental removal

AMTSL, active management of the third stage of labor; IQR, interquartile range. Data are n (%), n/N (%), or median (interquartile range) unless otherwise specified.

with 1.161.3 g/dL in the placebo group, P,.005) and hematocrit (2.563.8 compared with 3.163.8, respectively, P5.001) 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, P5.81).

DISCUSSION 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 doubleblind 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).

Table 3. Postpartum Hemorrhage and Severe Postpartum Hemorrhage in High-Risk Pregnancies Misoprostol+AMTSL (n5234)

Placebo+AMTSL (n5202)

P

27 (11.5) 5/208 (2.4)

23 (11.4) 4/173 (2.3)

.95 .96

Postpartum hemorrhage greater than 500 mL Postpartum hemorrhage greater than 1,000 mL

AMTSL, active management of the third stage of labor. Data are n (%) or n/N (%) unless otherwise specified. High-risk pregnancies include any woman with at least one of the following risk factors: grand multiparity (parity greater than four), polyhydramnios, fever during labor greater than 38˚C, induction of labor.

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Table 4. Adverse Events Associated With the Trial Medication Adverse Event Fever Shivering Nausea Vomiting Diarrhea Any

Misoprostol +AMTSL (n5806) 245 87 22 18 6 518

(30.4) (10.8) (2.7) (2.2) (0.7) (64.3)

Placebo +AMTSL (n5806) 50 5 8 6 0 729

(6.3) (0.6) (1.0) (0.8) (0) (91.5)

P ,.001 ,.001 .01 .02 .03 ,.001

AMTSL, active management of the third stage of labor. Data are n (%) unless otherwise specified.

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

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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 highincome countries, and misoprostol should be used infrequently for this indication. REFERENCES 1. Khan KS, Wojdyla D, Say L, Gülmezoglu AM, Van Look PF. WHO analysis of causes of maternal death: a systematic review. Lancet 2006;367:1066–74. 2. Say L, Chou D, Gemmill A, Tunçalp Ö, Moller AB, Daniels J, et al. Global causes of maternal death: a WHO systematic analysis. Lancet Glob Health 2014;2:e323–33. 3. Souza JP, Gülmezoglu AM, Vogel J, Carroli G, Lumbiganon P, Qureshi Z, et al. Moving beyond essential interventions for reduction of maternal mortality (the WHO Multicountry Survey on Maternal and Newborn Health): a cross-sectional study. Lancet 2013;381:1747–55. 4. Carroli G, Cuesta C, Abalos E, Gulmezoglu AM. Epidemiology of postpartum haemorrhage: a systematic review. Best Pract Res Clin Obstet Gynaecol 2008;22:999–1012. 5. Saucedo M, Deneux-Tharaux C, Bouvier-Colle MH; Le Comité national d’experts sur la mortalité maternelle. Maternal mortality in France, 2007–2009 [in French]. J Gynecol Obstet Biol Reprod (Paris) 2013;42:613–27. 6. Bateman BT, Berman MF, Riley LE, Leffert LR. The epidemiology of postpartum hemorrhage in a large, nationwide sample of deliveries. Anesth Analg 2010;110:1368–73. 7. Callaghan WM, Kuklina EV, Berg CJ. Trends in postpartum hemorrhage: United States 1994–2006. Am J Obstet Gynecol 2010;202:353.e1–6. 8. Al-Zirqi I, Vangen S, Forsen L, Stray-Pedersen B. Prevalence and risk factors of severe obstetric hemorrhage. BJOG 2008; 115:1265–72. 9. Joseph KS, Rouleau J, Kramer MS, Young DC, Liston RM, Baskett TF, et al. Investigation of an increase in postpartum hemorrhage in Canada. BJOG 2007;114:751–9. 10. Sentilhes L, Vayssière C, Mercier F, Aya AG, Bayoumeu F, Bonnet MP. Postpartum hemorrhage: guidelines for clinical

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practice—text of the guidelines (short text) [in French]. J Gynecol Obstet Biol Reprod (Paris) 2014;43:1170–9.

tol in the management of the third stage of labour. Lancet 2001; 358:689–95.

11. Tunçalp O, Souza JP, Gülmezoglu M; World Health Organization. New WHO recommendations on prevention and treatment of postpartum hemorrhage. Int J Gynaecol Obstet 2013; 123:254–6.

21. Caliskan E, Dilbaz B, Meydanli MM, Oztürk N, Narin MA, Haberal A. Oral misoprostol for the third stage of labor: a randomized controlled trial. Obstet Gynecol 2003;101:921–8.

12. Postpartum hemorrhage. ACOG Practice Bulletin No. 76. American College of Obstetricians and Gynecologists. Obstet Gynecol 2006;108:1039–47. 13. Royal College of Obstetricians & Gynaecologists. Postpartum hemorrhage: prevention and management. 2011. Available at: http:// www.rcog.org.uk/womens-health/clinical-guidance/preventionand-management-postpartum-haemorrhage-green-top-52. Retrieved August 17, 2016. 14. Clinical Practice Obstetrics Committee. Active management of the third stage of labour: prevention and treatment of postpartum hemorrhage: No. 235 October 2009 (Replaces No. 88, April 2000). Int J Gynaecol Obstet 2010;108:258–67. 15. Royal Australian and New Zealand College of Obstetricians and Gynaecologists. Management of postpartum hemorrhage. 2011. Available at: http://www.ranzcog.edu.au/college-statements-guidelines.html#obstetrics. Retrieved August 17, 2016. 16. Begley CM, Gyte GM, Devane D, McGuire W, Weeks A. Active versus expectant management for women in the third stage of labour. The Cochrane Database of Systematic Reviews 2015, Issue 3. Art. No.: CD007412. DOI: 10.1002/14651858. CD007412.pub4. 17. Westhoff G, Cotter AM, Tolosa JE. Prophylactic oxytocin for the third stage of labour to prevent postpartum haemorrhage. The Cochrane Database of Systematic Reviews 2013, Issue 10. Art. No.: CD001808. DOI: 10.1002/14651858.CD001808.pub2. 18. Chong YS, Chua S, El Refaey H, Choo WL, Chanrachakul B, Tai BC, et al. Postpartum intrauterine pressure studies of the uterotonic effect of oral misoprostol and intramuscular syntometrine. BJOG 2001;108:41–7. 19. Tunçalp Ö, Hofmeyr GJ, Gülmezoglu AM. Prostaglandins for preventing postpartum haemorrhage. The Cochrane Database of Systematic Reviews 2012, Issue 8. Art. No.: CD000494. DOI: 10.1002/14651858.CD000494.pub4. 20. Gülmezoglu AM, Villar J, Ngoc NT, Piaggio G, Carroli G, Adetoro L, et al. WHO multicentre randomised trial of misopros-

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22. Schulz KF, Altman DG, Moher D; CONSORT Group. CONSORT 2010 statement: updated guidelines for reporting parallel group randomized trials. Obstet Gynecol 2010;115: 1063–70. 23. Deneux-Tharaux C, Dupont C, Colin C, Rabilloud M, Touzet S, Lansac J, et al. Multifaceted intervention to decrease the rate of severe postpartum haemorrhage: the PITHAGORE6 cluster-randomised controlled trial. BJOG 2010;117:1278–87. 24. Widmer M, Blum J, Hofmeyr GJ, Carroli G, Abdel-Aleem H, Lumbiganon P, et al. Misoprostol as an adjunct to standard uterotonics for treatment of post-partum haemorrhage: a multicentre, double-blind randomised trial. Lancet 2010;375:1808–13. 25. Derman RJ, Kodkany BS, Goudar SS, Geller SE, Naik VA, Bellad MB, et al. Oral misoprostol in preventing postpartum haemorrhage in resource-poor communities: a randomised controlled trial. Lancet 2006;368:1248–53. 26. Elati A, Weeks A. Risk of fever after misoprostol for the prevention of postpartum hemorrhage: a meta-analysis. Obstet Gynecol 2012;120:1140–8. 27. Lumbiganon P, Hofmeyr J, Gülmezoglu AM, Pinol A, Villar J. Misoprostol dose-related shivering and pyrexia in the third stage of labour. WHO Collaborative Trial of Misoprostol in the Management of the Third Stage of Labour. Br J Obstet Gynaecol 1999;106:304–8. 28. Fawole AO, Sotiloye OS, Hunyinbo KI, Umezulike AC, Okunlola MA, Adekanle DA, et al. A double-blind, randomized, placebo-controlled trial of misoprostol and routine uterotonics for the prevention of postpartum hemorrhage. Int J Gynaecol Obstet 2011;112:107–11. 29. Hofmeyr GJ, Fawole B, Mugerwa K, Godi NP, Blignaut Q, Mangesi L, et al. Administration of 400 mg of misoprostol to augment routine active management of the third stage of labor. Int J Gynaecol Obstet 2011;112:98–102. 30. Gibbins KJ, Albright CM, Rouse DJ. Postpartum hemorrhage in the developed world: whither misoprostol? Am J Obstet Gynecol 2013;208:181–3.

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