Volume 64, Number 2 OBSTETRICAL AND GYNECOLOGICAL SURVEY Copyright 2009 by Lippincott Williams & Wilkins

CME REVIEWARTICLE

CHIEF EDITORS NOTE: This article is part of a series of continuing education activities in this Journal through which a total of 36 AMA/PRA Category 1 CreditsTM can be earned in 2009. Instructions for how CME credits can be earned appear on the last page of the Table of Contents.

Carbetocin for the Prevention of Postpartum Hemorrhage

A Systematic Review
Nina C.J. Peters, MS,* and Johannes J. Duvekot, MD, PhD
*Medical Student, Gynecologist/Perinatologist, Division of Obstetrics and Prenatal Medicine, Department of Obstetrics and Gynecology, Erasmus Medical Centre, University Medical Centre Rotterdam, Rotterdam, The Netherlands The objective of this review was to evaluate the efficacy and safety of carbetocin in the prevention of postpartum hemorrhage. All trials found during a targeted Medline and Cochrane database search were screened for eligibility. Outcome measures were estimated blood loss, uterine tone, amount and type of lochia, fundal position after delivery (number of centimeters above or below the umbilicus), side-effects, adverse effects, vital signs, levels of hemoglobin/hematocrit before delivery compared with 24 or 48 hours postpartum, the need for additional uterotonic therapy, and/or uterine massage and duration of the third stage of labor. The retrieved studies were difficult to compare because of differences in study design and outcome. We conclude that carbetocin probably is as effective as oxytocin or syntometrine in the prophylactic management of the third stage of labor. Also carbetocin has a similar safety profile to oxytocin, which is now used as a standard prophylactic treatment. However, more research on this subject is needed. Target Audience: Obstetricians & Gynecologists, Family Physicians Learning Objectives: After reading this article, the reader should be able to describe the pharmacological and clinical characteristics of carbetocin, outline active management of the third stage of labor to decrease the risk of postpartum hemorrhage, and compare the results of literature on the use of carbetocin to oxytocin for the prevention of postpartum hemorrhage.

Primary postpartum hemorrhage (PPH) was initially defined by the World Health Organization as blood loss of 500 mL or more after delivery (13). A
Dr. Duvekot has disclosed that he was/is a member of the advisory board of Ferring BV, The Netherlands. Dr. Peters has disclosed that she has no financial relationships with or interests in any commercial companies pertaining to this educational activity. The Faculty and Staff in a position to control the content of this CME activity have disclosed that they have no financial relationships with, or financial interests in, any commercial companies pertaining to this educational activity. Lippincott Continuing Educational Institute, Inc. has identified and resolved all faculty conflicts of interest regarding this educational activity. Reprint requests to: Johannes J. Duvekot, MD, PhD, Department of Obstetrics and Gynecology, Division of Obstetrics and Prenatal Medicine, Erasmus MC University Medical Centre Rotterdam, P.O. Box 2040, 3000 CA Rotterdam, The Netherlands. E-mail: j.j. duvekot@erasmusmc.nl.

couple of years later it was redefined as blood loss of 1000 mL or more. PPH occurs in 5% to 15% of all deliveries (4) and is responsible for an estimated 25% to 33% of maternal mortality worldwide (57). It is also an important cause of maternal morbidity (8). Risk factors for PPH include prolonged third stage of labor ( 30 minutes), severe anemia, eclampsia, antepartum hemorrhage, intrapartum blood loss, history of PPH or retained placenta, polyhydramnios, multiple gestation, and difficult instrumental delivery (9,10). To reduce PPH, active management of the third stage of labor is recommended (11). This includes admission of a prophylactic uterotonic drug (typically oxytocin), cutting and clamping of the umbilical cord shortly after birth, and delivery of the placenta by controlled cord traction (12).

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The most frequent cause for PPH is uterine atony ( 50%) (10). Uterotonic drugs administered prophylactically during the third stage of labor have been shown to reduce the occurrence of PPH by about 40% (4). Uterotonics are administered after birth of the child and clamping of the umbilical cord to induce uterine contractions. As a result, excessive blood loss is limited and the total amount of postpartum blood loss reduced. Oxytocin is the most widely used uterotonic agent and has been shown to be effective in reducing the incidence of PPH (12). Syntometrine, a mixture of 5 IU oxytocin and 0.5 mg ergometrine, is associated with a significant reduction of PPH compared with intramuscularly administered oxytocin alone. The use of syntometrine, however, is associated with more adverse effects (12). Another recently registered uterotonic agent is carbetocin. Carbetocin is a synthetic long-lasting oxytocin agonistic analog. Its prolonged uterine activity may theoretically offer advantages over oxytocin in the management of the third stage of labor. The side-effect profile of carbetocin, in comparison with that of syntometrine, may prove to be advantageous (12). Therefore, we performed a systematic review of all studies examining the use of carbetocin as a prophylactic uterotonic for the prevention of PPH. PHARMACOLOGICAL PROPERTIES CARBETOCIN Carbetocin is a long-acting structural analog of the natural human hormone oxytocin, which has uterotonic activity resulting from its binding to oxytocin receptors on the myometrial plasma membranes. A major disadvantage of naturally occurring oxytocin is its short half-life (317 minutes) (13). By modifying the oxytocin molecule, its half-life has been prolonged and its enzymatic degradation reduced. The modified molecule is named carbetocin. Because of these alterations carbetocin has more pronounced pharmacological effects (14). So far, in Europe, carbetocin (as a single intravenous injection) is licensed only for the prevention of uterine atony after cesarean delivery under epidural or spinal anesthesia. Mechanisms of Action Carbetocin binds selectively to oxytocin receptors in the smooth muscle of the uterus. It stimulates rhythmic contractions of the uterus, increasing the frequency of existing contractions and raises the tone of the uterine muscle by releasing Ca . Uteri of

nonpregnant women have very low oxytocin receptor content, but during pregnancy the number of oxytocin receptors increases, peaking at the time of delivery. Therefore carbetocin affects only the pregnant and puerperal uterus. Oxytocin receptors are also located in the myoepithelial cells surrounding the alveoli of the lactating breast. Binding of oxytocin to these receptors stimulates the letdown of milk in breast-feeding mothers. Oxytocin also has moderate antidiuretic effects because of its structural similarity to vasopressin. Therefore, when used in high dosages, oxytocin can result in hyponatremia if not administered as an isotonic solution. As oxytocin can influence the cardiac and vascular tissues, oxytocin may occasionally induce hypotension and tachycardia. Pharmacokinetics Intramuscular Use Carbetocin enters the circulation rapidly, with a peak concentration within 30 minutes. The absolute bioavailability is approximately 80%. The Cmax is 6.35 1.39 g/L at an administered dose of 400 g. Intravenous Use The distribution and elimination half-lives of a 400 g dose are 5.54 1.6 minutes and 41.0 11.9 minutes, respectively. Drug Interaction As carbetocin is in similar chemical structure to oxytocin, the same interactions as with oxytocin may be expected. During clinical studies carbetocin was administered together with analgesics, spasmolytics and anesthetic agents used for spinal or epidural anesthesia, and so far, no specific drug interactions have been reported. Adverse Reactions The adverse reactions of carbetocin were the same as those that occur during the use of oxytocin when administered after cesarean section under epidural or spinal anesthesia. Intravenous carbetocin was frequently associated with nausea (21%27%), abdominal pain (40%), pruritus (10%), flushing (26%), vomiting (7%9%), feeling of warmth (20%), headache (3%14%), and tremor (11%) (15).

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Infrequent adverse events occurring in 1% to 5% of all patients included back pain, dizziness, metallic taste, anemia, sweating, chest pain, dyspnoea, chills, tachycardia, and anxiety. However, most of these effects are more likely to be associated symptoms and signs of surgery or other medications and are probably not directly related to the medication itself. The known contraindications for the use of carbetocin are pregnancy, hypersensitivity to carbetocin or oxytocin, hepatic or renal disease, preeclampsia or eclampsia, serious cardiovascular disorders, and epilepsy (15).

RESULTS Our main search revealed 7 trials, 2 which were excluded because they were published only as abstracts and provided insufficient information and/or could not be retrieved (Fig. 1) (23,24). The remaining 5 trials met the inclusion criteria (Tables 1, 2). They included a total of 1163 women (2529). Three studies compared carbetocin to oxytocin (2527) and 2 compared carbetocin with a mixture of oxytocin and ergometrine (28,29). Carbetocin was administered intramuscularly (27,28) or intravenously (25,26). In 1 study the administration route was not mentioned (29). One study included only women with at least 1 risk factor for PPH (27). All studies used similar exclusion criteria. The method of delivery varied; in 3, it was vaginal (2729) and in 2, cesarean (25,26). Primary outcome measures in the studies varied: blood loss (25), the need for additional uterotonic therapy (26) (and/or uterine massage [27]), the decline in hemoglobin levels 48 hours postpartum (28) and the clinical efficacy in routine settings (29). Assessment of outcome was blinded in 4 studies (2528). One study was performed retrospectively (29). Carbetocin Versus Oxytocin Three trials compared carbetocin with oxytocin (2527). In 2, the effect of an intravenous bolus injection of carbetocin after cesarean delivery under regional anesthesia was assessed (25,26). In the study of Dansereau et al, 317 women received an intravenous bolus injection of carbetocin and 318 oxytocin (5 IU as a bolus injection, followed by continuous infusion of 20 IU in 4 hours) (26). In the other trial in women undergoing cesarean (25), 28 women received carbetocin (100 g as a bolus followed by 3 injections of normal saline) and 26 received oxytocin (a bolus of 2.5 IU followed by 3 boluses of 10 IU). In the third trial, conducted among women who had delivered vaginally, 83 women received intramuscular carbetocin (100 g) and 77 intravenous oxytocin (10 IU). All women had at least 1 risk factor for PPH (27). In all 3 trials, outcome measures were the need for additional oxytocic therapy and/or uterine massage and the type and amount of lochia. In 2 trials, the oxytocin group needed significantly more additional uterotonic therapy and/or uterine massage (26,27). In both trials, this significant difference was driven by an increased rate of uterine massages, not uterotonic administration. Uterine massage performed routinely as part of active management of the third stage of labor was not recorded as an additional uterotonic intervention (27). In the trial by Dansereau, 10.1% of

REVIEW OF LITERATURE Data Sources and Methods of Study Selection A MEDLINE and Cochrane search, which consists of the Cochrane Database of Systematic Reviews, the Cochrane Controlled Trials Register, the York Database of Abstracts of Reviews of Effectiveness, and the Cochrane Review Methodology Database, was performed using the search terms carbetocin, human, and female. All clinical trials executed until April 2008 in English, French, German, and Dutch were considered eligible. The tested intervention was carbetocin administered intravenously or intramuscularly after delivery of the infant as part of active management of the third stage of labor. Carbetocin had to be compared with oxytocin, a mixture of oxytocin and ergometrine, or a placebo. References of the retrieved articles were also screened for eligibility and included if appropriate (110,1620). For the purpose of this review, PPH was defined as blood loss 500 mL and severe PPH was defined as blood loss 1000 mL. Outcome measures were blood loss, uterine tone, amount and type of lochia, fundal position, side or adverse effects, vital signs, hemoglobin/hematocrit levels before delivery compared with those 24 to 48 hours postpartum, the need for additional uterotonic therapy and/or uterine massage, and duration of the third stage of labor. Information was collected about the trial design, number of included women, patient characteristics, type of medication, dosage and administration route, and the primary and secondary outcome measures (Tables 1, 2). We assessed the level of evidence of the included trials according to the Oxford CEBM levels of evidence (21). This review is written according to the QUORUM statement (22).

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TABLE 1 Characteristics of included trials: carbetocin versus oxytocin Boucher et al 1998 (25) Level 1b 160 Vaginal delivery 635 Scheduled caesarean section under regional anesthesia Level 1b Level 1b Dansereau et al 1999 (26) Boucher et al 2004 (27)

Level of evidence (21)

No. women Inclusion criteria

Exclusion criteria

57 Scheduled caesarean section under epidural anesthesia Singleton pregnancy Medical history of heart disease, hypertension, cardiac arrhythmia, liver/renal/endocrine disorders

1 risk factor for PPH Medical history of heart disease, cardiac arrhythmia, chronic liver/renal/endocrine disorders or known/suspected coagulopathy Carbetocin (83) First an IV infusion of saline solution Then an IM bolus of 100 g carbetocin Oxytocin (77) First an IV infusion of 10 IU oxytocin in 500 ml glucose 5%, NaCl 0.45% solution Then an IM bolus of saline solution

Therapy (No. women n) Administration routes and dosages

Carbetocin (28) First an IV bolus injection of 100 g carbetocin Then 3 x an IV bolus injection of normal saline solution during a 16-h infusion

Oxytocin (26) First an IV bolus injection of 2.5 IU oxytocin Then 3 x an IV bolus injection with 10 IU oxytocin during a 16-h infusion

Obstetrical and Gynecological Survey

Primary outcome measure

Blood loss (NS)

Secondary outcome measures

Amount and type lochia, uterine tone, vital signs, adverse events, blood cell count, fundal position, additional uterotonic therapy (NS)

Medical history of heart disease, chronic hypertension that requires treatment, liver/renal/endocrine disorders or known coagulopathy Classic uterine incision Carbetocin (317) Oxytocin (318) First an IV bolus First an IV bolus of 100 g of 5 IU carbetocin oxytocin Then Then an IV an IV infusion infusion of of 20 IU normal saline oxytocin in 1 solution for liter of lactated 8h Ringers solution for 8 h The need for additional uterotonic therapy (n 15 vs. n 32, P .05)* Amount of lochia, uterine tone, vital signs, difference in postpartum chemistry, drop in Hb level, fundal position (NS) Delay between drug administration and adequate uterine contractions/ additional uterotonic therapy (11 vs. 120 min, P 0.001)* 0.05).

The need for additional oxytocic agents (NS) or uterine massage (n 36 vs. n 48, P .02)* Amount and type of lochia, vital signs, adverse events, drop in Hb/Hct level, fundal position, estimated blood loss (NS)

*A significant finding in favor of carbetocin. IM indicates intramuscular; IV, intravenous; NS, no significant difference (P

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TABLE 2 Characteristics of included trials: carbetocin versus oxytocin/ergometrine Leung et al 2006 (28) Level of evidence (21) No. women Inclusion criteria Exclusion criteria Level 1b 300 Vaginal delivery 34 weeks of gestation Singleton pregnancy History of heart disease, hypertension, renal/ liver disorders, preeclampsia, asthma High risk factors for PPH (such as grand multiparity, presence of uterine fibroids, the need for a prophylactic oxytocin infusion after delivery) Carbetocin (150) Syntometrine (150) One IM injection of One IM injection of 100 g 1 ml containing carbetocin 5 IU oxytocin 0.5 mg ergometrine Drop in Hb level compared with 48-h postpartum (NS) Need for additional uterotonic therapy, estimated blood loss, incidence of PPH, number of blood transfusions, duration of third stage (incidence prolonged), need for manual placental removal (NS) Adverse events 60 min after delivery (n 0 vs. n 6, P 0.05)* Ngan et al 2007 (29) Level 2b 118 Vaginal delivery

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History of a clinically relevant disease (not further described)

Therapy (No. women n) Administration routes and dosages

Primary outcome measure Secondary outcome measures

Syntometrine (62) 5 IU oxytocin 0.2 mg ergometrine (administration route unknown) The efficacy in routine clinical settings Amount and type of lochia, uterine tone, vital signs, drop in Hb level, fundal position (NS)

Carbetocin (56) 100 g carbetocin (administration route unknown)

Drop in Hct level (unknown numbers, P .03), estimated blood loss (388 vs. 551 mL, P .01), incidence of PPH (n 1 vs. n 9, P 0.02)*

*A significant finding in favor of carbetocin. Hb indicates hemoglobin; Hct, hematocrit.

group 2 hours (P 0.001). All 3 studies described no differences in side-effects or adverse reactions. Carbetocin Versus Syntometrine In 1 trial of women delivered vaginally, 150 women received 100 g of intramuscular carbetocin and 150 women received 1 mL (5 IU of oxytocin and 0.5 mg of ergometrine) of intramuscular syntometrine (28). Ngan et al performed a retrospective study of women who had delivered vaginally, 56 patients carbetocin and 62 syntometrine (29). The route of drug administration is not described in this study. Both trials reported a variety of outcomes including decline in hemoglobin concentration, estimated blood loss, and incidence of PPH. In the retrospective study of Ngan et al, a significant difference favoring carbocetin was observed for all 3 outcomes (29). The mean estimated blood loss in the carbetocin group was 388 versus 551 mL in the syntometrine group; 21.4% of women who received carbocetin experienced a blood loss of 500 mL versus 43.5% of women who received sytometrine. The respective

Fig. 1. Flowchart search results.

the women in the oxytocin group needed additional uterotonic therapy versus 4.7% of the women in the carbetocin group (P 0.05). In none of the trials, was there a significant difference in type or amount of lochia, mean estimated blood loss, or decline in hemoglobin level. Dansereau et al found a significant difference in the delay between drug administration and the presence of adequate uterine contractions. In the oxytocin group the median time after administration to intervention was 11 minutes, in the carbetocin

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rates of blood loss of at least 1000 mL were 1.8% and 14.5%. The other study found no difference between groups for any of these parameters (28). Both studies report a significant lower incidence of side-effects (eg, nausea, vomiting, and hypertension) in the carbetocin group. In the trial by Leung et al (28), nausea was reported by 1.3% of women in the carbetocin group versus 7.3% in the syntometrine group, and vomiting by 0.7% of the women in the carbetocin group versus 6.7% in the syntometrine group. No women in the carbetocin group experienced hypertension (defined as blood pressure 140/90 mm Hg) 30 or 60 minutes after delivery, whereas in the syntometrine group 5.3% women experienced this level of hypertension at 30 minutes, and 4% experienced it at 60 minutes. Tachycardia (defined as maternal pulse 100 bpm) within 60 minutes after delivery was found in 32% of the women in the carbetocin group, which is significantly higher than the 19% in the syntometrine group (28). DISCUSSION The aim of the present review was to investigate the effectiveness of carbetocin in the management of the third stage of labor compared to other uterotonic agents. Our review showed that, irrespective of delivery mode, carbetocin seems as effective as, but not more effective than oxytocin or syntometrine. However, the design and size of the reviewed trials do not allow firm conclusions to be drawn. In July 2007, a Cochrane review was published on the subject of oxytocin agonists for preventing PPH. In that review, 4 trials were included, 1 of which was described only as an abstract. We decided not to use this trial in our review because of the insufficiency of the data and our inability to retrieve it (23). Since the publication of the Cochrane review, 2 other studies (28,29) with a total of 418 women were published on this subject and are included in our review. Our review describes the use of carbetocin in 692 women after cesarean section and 579 women after vaginal delivery (2 studies on cesarean delivery and 3 on vaginal delivery). The number of women in these 5 studies ranged from 57 to 635. The eligible studies are difficult to compare because there are great differences in inclusion criteria of the subjects, the different dosages, and administration routes of the medication and the variety of outcome measures (Tables 1, 2). Four of the studies were prospective, randomized, and double-blinded (2528), 1 was a nonrandomized cohort study (29). It included only 118 women and is

the only one in which carbetocin showed benefit in terms of diminished estimated blood loss. It was not blinded and treatment allocation was not random, and thus its results are more subject to bias than the other 4 studies. Carbetocin was administered as an intravenous or intramuscular bolus of 100 g in all studies. However, oxytocin was dosed variously as an intravenous or intramuscular bolus of 2.5, 5, or 10 IU. In 2 of the 3 studies comparing carbetocin with oxytocin after a bolus, a continuous dose of oxytocin was administered for the subsequent 4 hours, likely improving effectiveness beyond that of a bolus alone. In 2 of the studies, carbetocin was administered intravenously in 2 intramuscularly. Hunter et al examined the relative effectiveness of carbetocin given by these 2 routes (8). Carbetocin was administered within 24 to 48 hours postpartum. After measuring the mean interval from injection to uterine contractions and the median duration of tetany, they concluded that the effect of carbetocin lasted twice as long when given intramuscularly. Preventive measures during the third stage of labor and during cesarean section are all meant primarily to reduce maternal blood loss. This is the most important cause of maternal morbidity and mortality worldwide. It is therefore surprising that most of the reviewed trials did not use blood loss (or at least an estimate thereof) as a primary outcome. Blood loss during delivery can be inferred by the following parameters: estimated blood loss during delivery and postdelivery hemoglobin decline. Need for transfusion is a meaningful surrogate. With some effort, blood loss can also be directly measured (9). Only 3 studies mention side-effects. Two studies showed no difference (25,27) and 1 showed a decreased incidence of side-effects in the carbetocin group compared with the syntometrine group. The latter study describes fewer patients with nausea, vomiting and hypertension, side-effects probably because of the presence of ergometrine in syntometrine. However, the study describes more patients with tachycardia after carbetocin use. It is not clear whether this is a dose-related effect as seen in oxytocin (30). SUMMARY Carbetocin is an oxytocin agonist whose effectiveness for the prevention of PPH, both in vaginal deliveries and in cesarean section, is not yet proven to be superior over currently available uterotonic agents. On theoretical grounds, this medication is

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more potent and has a longer lasting effect since it produces a prolonged uterine response, in terms of both amplitude and frequency of contractions (8). Since the present studies cannot be compared properly and lack consistently meaningful outcome measures, more clinical studies are needed. These studies should have relevant primary outcome measures concerning PPH prevention. To provide compelling evidence of a reduction in the incidence of PPH these trials should be larger than any of the already completed trials. Future clinical studies should address also the subject of potential cardiac side-effects. Target Audience: Obstetricians & Gynecologists, Midwives. Leaning Objectives: After completion of this article, the reader should be able to understand the working mechanisms of both carbetocin and oxytocin. They also should be able to evaluate which therapy is the most efficient and effective in the clinical setting. REFERENCES
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