The Journal of Maternal-Fetal & Neonatal Medicine

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Carbetocin versus syntometrine for prevention of

postpartum hemorrhage after cesarean section

Ahmed Mohamed Maged, Ahmed Shaker Ragab, Noura Elnassery, Walaa AI

Mostafa, Sherif Dahab & Amal Kotb

To cite this article: Ahmed Mohamed Maged, Ahmed Shaker Ragab, Noura Elnassery, Walaa
AI Mostafa, Sherif Dahab & Amal Kotb (2016): Carbetocin versus syntometrine for prevention
of postpartum hemorrhage after cesarean section, The Journal of Maternal-Fetal & Neonatal
Medicine, DOI: 10.1080/14767058.2016.1192601

To link to this article: http://dx.doi.org/10.1080/14767058.2016.1192601

Published online: 08 Jun 2016.

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ISSN: 1476-7058 (print), 1476-4954 (electronic)

J Matern Fetal Neonatal Med, Early Online: 1–5

! 2016 Informa UK Limited, trading as Taylor & Francis Group. DOI: 10.1080/14767058.2016.1192601

ORIGINAL ARTICLE

Carbetocin versus syntometrine for prevention of postpartum

hemorrhage after cesarean section
Ahmed Mohamed Maged1, Ahmed Shaker Ragab2, Noura Elnassery1, Walaa AI Mostafa1, Sherif Dahab1, and
Amal Kotb3
1
Obstetrics and Gynecology Department, Kasr Aini Hospital, Cairo University, Cairo, Egypt, 2Anaesthesia and Pain Department, National Cancer
Institute, Cairo University, Cairo, Egypt, and 3Obstetrics and Gynecology Department, Beni-Suef Hospital, Beni-Suef University, Cairo, Egypt
Downloaded by [University of Lethbridge] at 19:47 19 June 2016

Abstract Keywords
Objective: To compare effectiveness and tolerability of carbetocin versus syntometrine in Carbetocin, cesarean section, postpartum
prevention of postpartum hemorrhage (PPH) after cesarean section (CS). hemorrhage, syntometrine
Methods: A double-blind randomized study conducted on 300 pregnant subjected randomly
either to single 100 mg IV dose of carbetocin (150 women) or combination of 5 IU oxytocin and History
0.2 mg ergometrine (150 women) after fetal extraction and before placental removal. Primary
outcome parameter was the occurrence of PPH. Other parameters were hemoglobin and Received 12 February 2016
hematocrit changes, the need of additional oxytocic, hemodynamic changes and occurrence of Revised 15 May 2016
side effects. Accepted 18 May 2016
Results: There was no significant difference between the two study groups regarding Published online 6 June 2016
hemoglobin and hematocrit at start of CS and after 2 days of surgery and mean blood loss
during the operation (p40.05). There was a highly significant difference between the two study
groups regarding incidence of primary PPH (2.7% versus10%) and the need of additional
oxytocic (3.3% versus17.3%). Women in oxytocin group showed a statistically significant lower
systolic and diastolic blood pressure at 1, 5 and 30 min than women in carbetocin group.
Women in carbetocin group experienced more metallic taste, flushing, headache, dizziness,
dyspnea and itching, while women in oxytocin methergine group experienced more
palpitations.
Conclusions: Carbetocin is a reasonable effective alternative to syntometrine in prevention of
PPH after cesarean delivery.

Introduction Stage Labor (AMTSL), recommended by WHO to prevent

postpartum blood loss [9]. Prophylactic use of oxytocin after
World Health Organization (WHO) defines primary postpar-
delivery of the infant has been shown to reduce the incidence of
tum hemorrhage (PPH) as blood loss of 1000 ml following
PPH by about 60% [10]. Oxytocin has a half-life of only 4–
cesarean section (CS) [1]. It accounts for one-quarter of the
10 min [11] that is why it is better administered as a continuous
major direct causes of maternal deaths globally [2], while it
intravenous infusion to achieve sustained uterotonic activity
rises up to nearly one-third of mortalities in Africa and Asia
[12]. Carbetocin is a synthetic long-lasting oxytocin agonistic
[3]. The risk of postpartum complications in women who
analog with prolonged half-life [13]. Its prolonged uterine
received a CS was higher than that in women who underwent a
activity may theoretically offer advantages over oxytocin in the
vaginal delivery (VD) and vaginal birth after cesarean section
management of the third stage of labor [14]. Carbetocin is
(VBAC) [4,5]. The incidence of PPH has been reported to be
superior to oxytocin in prevention of PPH after VD in women
3.9% in women delivered vaginally and reaches 7.9% after CS
with at least two risk factors for developing atonic PPH [15].
[6]. The Millennium Development Goal of reducing the
The side-effect profile of carbetocin was not found to be
maternal mortality ratio by 75% by 2015 will remain beyond
different from that of oxytocin [16,25].
our reach unless we prioritize the prevention and treatment of
The aim of our study is to evaluate efficiency and
PPH in low-resource countries [7]. Failure of the uterus to
tolerability to carbetocin versus combination of Oxytocin
contract properly following delivery is the most common cause
and Methergine in prevention of primary postpartum hemor-
of obstetrical hemorrhage [8] .Currently, oxytocin is the
rhage after CS.
uterotonic of first choice for the Active Management of Third
Material and methods
This study is a double-blind randomized study conducted on
Address for correspondence: Ahmed Mohamed Maged, 135 King Faisal
Street, Haram, Giza, Egypt. Tel: +20 0105227404. Fax: +20 35873103. 400 pregnant women attending Kasr Al Ainy maternity
E-mail: prof.ahmedmaged@gmail.com hospital during the period from June 2014 to December 2015.
 2 A. M. Maged et al. J Matern Fetal Neonatal Med, Early Online: 1–5

Power analysis Group 1 included 150 women received single 100 mg IV

dose of carbetocin (Pabal, Ferring Pharmaceuticals Ltd, West
As the primary outcome in the study, power analysis was done
Drayton, UK). Group 2 included 150 women received
on the occurrence of primary PPH. Fisher exact test was
combination of 5 IU oxytocin (SyntocinonÕ , Novartis,
chosen to perform the power analysis, the a-error level was
Basel, Switzerland) and 0.2 mg ergometrine (MetherginÕ ,
fixed at 0.05 and the sample size was entered to be 300
Novartis). Both groups received their drug after fetal extrac-
participants divided equally into two groups. Primary PPH
tion and before placental removal.
had occurred in 2.7% of cases of group I and 10% in group 2
The procedure is then completed using traction on cord to
(overall incidence 6.33%). According to this effect size, the
deliver the placenta, exteriorization of uterus, closure of
calculated statistical power was 499.9%. Calculations were
uterine incision in two layers, closure of both visceral and
done using PS Power and Sample Size Calculations Software,
parietal peritoneum, then abdominal wall closure. Follow up
version 3.0.11 for MS Windows (William D. Dupont and
for all cases was 48 h. Primary outcome parameter was the
Walton D. Vanderbilt).
occurrence of PPH. Other parameters were hemoglobin and
The study was approved by local ethics committee and
hematocrit changes, the need of additional oxytocic, hemo-
informed consents about the study and expected value and
dynamic changes and occurrence of side effects.
outcome were obtained. All participants were at 37–40 weeks
Calculated estimated blood loss ¼ estimated blood vol-
of gestational age with noncomplicated pregnancy.
ume  [preoperative packed cell volume (PCV) – post-
Participants with placenta previa, coagulopathy, preeclamptic
operative PCV]/preoperative PCV [where estimated blood
or known sensitivity to oxytocin or methergine were excluded
volume ¼ booking weight (kg)  85] [19]. We chose this
(Figure 1).
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calculation as a quantitative objective measure to estimate

The patients were subjected to history taking, including
hemorrhage because it is widely accepted that clinicians
age, parity, menstrual history for verification of gestational
underestimate blood loss and that gravimetric methods
age, medical history and risk factors for PPH. Full examin-
include amniotic liquid in addition to blood, which limits
ation including general and abdominal obstetric examination
accuracy [19].
was done. Investigations including complete blood picture,
Adverse effects of uterotonics and their intensity were
liver functions and coagulation profile to exclude those not
tested using Likert-type scales. Attitude of the awake patient
fitting with the above listed criteria. Ultrasound was done to
postinjection was applied to an even numbered Likert-type
assess gestational age, fetal weight estimation, placental site
scale with four answers: ‘‘NO, YES, ANNOYING,
and grading.
UNBEARABLE’’, which was transformed into 1, 2, 3, 4
CSs were a mixture of planned and emergency interven-
numbers, respectively [20]. These answers refer to the feeling
tions performed by obstetric surgeons with close surgical
of palpitations, flushing, headache, and nausea and vomiting.
skills. Regional anesthetic techniques are standard at elective
Data were collected, verified and revised. Continuous data
CS in developed countries. General anesthesia is known to
were expressed as means ± standard deviation. Categorical
increase blood loss at the time of CS as inhalational agents
data were presented in the form of number and percentage.
can reduce uterine contractility and increase atony [17].
Comparison between the two groups was performed using
Patients were checked for coagulation abnormalities. Large
student unpaired t test. The data were considered significant if
gauge (18G) cannula was inserted in cephalic or antecubital
p values was 0.05, highly significant if p50.01. Statistical
veins. Patients were preloaded with HAES-steril 6% (hydro-
analysis was performed with the aid of the SPSS computer
xyl ethyl starch) or with ringer’s lactate 20 ml/kg [13]. L3–L4
program (version 12 windows, Chicago, IL).
space was determined for the insertion of spinal needle. Then,
25G spinal needle was used to perform a single shot spinal
anesthesia using 10 mg of 0.5% hyperbaric bupivicaine and Results
fentanyl 20 mg [18]. All surgeons used the same technique
The 300 patients admitted to Kasr Aini causality were
transverse lower segment incision. The participants were
classified into two groups: group 1 (150 patients) received
randomized using automated web based randomization
carbetocin and group 2 (150 patients) received oxytocin and
system ensuring allocation concealment into two groups.
methergine.

• 5 with placenta previa

• 12 had preeclampsia Table 1. Demographic characteristics of the study population.
323 women • 1 with sen
• 15 with coagulopathy Mean ± SD GI (n ¼ 150) GII (n ¼ 150)
enrolled
Age (years) 24.6 ± 5.2 26.4 ± 6.1
Parity 1.2 ± 2.2 1.6 ± 2.3
• 150 women recived carbetocin BMI (kg/m2) 28.2 ± 2.5 26.3 ± 3.1
GA at CS (weeks) 38.7 ± 1.8 39.2 ± 1.7
300 women • 150 women recived syntometrine FBW (g) 3340 ± 454 3274 ± 465
randomized Duration of CS (min) 39.4 ± 11.3 41.2 ± 14.2
Time between induction till 4.1 ± 1.1 4.2 ± 1.6
fetal extraction (min)

Data are presented as mean ± SD. BMI, body mass index; GA,
Figure 1. Flow chart of participants. gestational age; FBW, fetal birth weight. p values40.05 nonsignificant.
 DOI: 10.1080/14767058.2016.1192601 Postcesarean section hemorrhage prevention 3
Table 2. Risk factors for PPH and indications for CS. regarding hemoglobin and hematocrit at start of CS and after
2 days of surgery (Table 3). The mean fall of hemoglobin and
No. (%) GI (n ¼ 150) GII (n ¼ 150)
mean blood loss during the operation was not different
Risk factors between both groups (Table 3). There was a highly significant
Previous PPH 16 (10.7) 14 (9.3) difference between the two study groups regarding incidence
Antepartum hemorrhage 5 (3.3) 4 (2.7)
Anemia 41 (27.3) 34 (22.7) of primary PPH and the need of additional oxytocic (Table 3).
Chronic hypertension 24 (16) 19 (12.7) Women in oxytocin group showed a statistically significant
Over distended uterus* 39 (26) 36 (24) lower systolic and diastolic blood pressure at 1, 5 and 30 min
Indications for CS
than women in carbetocin group. There was no significant
Previous CS 43 (22.66) 36 (24)
Antepartum hemorrhage 3 (2) 2 (1.3) difference between the two study groups regarding pulse and
Malpresentations 41 (27.3) 40 (26.7) respiratory rate measured preoperatively and at 1, 5, 30,
Cephalopelvic disproportion 18 (12) 6 (4) 60 min and 24 h postoperatively (Figures 2–5).
Abnormal FHR 30 (20) 19 (12.7)
CS on demand 7 (4.66) 3 (2)
Regarding side effects, there was no significant difference
Others 8 (5.3) 28 (18.7) between the two study groups regarding occurrence of nausea,
vomiting and shivering. Women in carbetocin group experi-
Data are presented as number (%). PPH, postpartum hemorrhage; CS, enced metallic taste, flushing, headache, dizziness, dyspnea
cesarean section; FHR, fetal heart rate. p values40.05 nonsignificant.
and itching more than women in oxytocin methergine group,
*Over distended uterus include large fetus, hydramnios and twins.
while women in oxytocin methergine group experienced more
palpitations than women in carbetocin group (Table 4).
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Table 3. Outcome parameters.

Discussion
GI (n ¼ 150) GII (n ¼ 150) p values
The major cause of maternal death worldwide is hemorrhage.
Hb at onset of labor (g/dl) 11.21 ± 1.2 11.51 ± 1.31 0.758 The WHO estimated that 25% of 585 000 maternal deaths
Hb on postpartum day 2 (g/dl) 10.1 ± 1.5 10.3 ± 1.6 0.897 in 1990 worldwide were due to severe peripartum
Hct at onset of labor 33.1 ± 4.6 34.9 ± 5.1 0.788
Hct on postpartum day 2 29.8 ± 4.5 30.2 ± 4.9 0.843 hemorrhage [21].
Mean fall in Hb (g/dl) 1.1 ± 1.2 1.2 ± 1.3 0.988 The results of the present randomized, open-label trial
Mean blood loss intraoperative 578 ± 178 602 ± 213 0.241 demonstrate that carbetocin is a reasonable effective alterna-
Primary postpartum hemorrhage* 4 (2.7) 15 (10) 50.001 tive to syntometrine in prevention of PPH after cesarean
Need for additional oxytocic* 5 (3.3) 26 (17.3) 50.001
delivery.
Hb, hemoglobin; Hct, hematocrit. Data are presented as mean ± SD. Although the risk factors for PPH and indications of CS
*Data are presented as number (%). showed a nonsignificant difference between the two study
groups, there was a highly significant difference between the
two study groups regarding incidence of primary PPH (2.7%
There was no significant difference between the two study versus 10%, respectively) and the need of additional oxytocic
groups regarding age, parity, BMI, GA at delivery, EFW, (3.3% versus 17%, respectively).
duration of CS, the time elapsed between induction of Borruto et al. performed a randomized study involving 104
anesthesia and fetal extraction and coagulation measured pregnant women with at least one risk factor for PPH
parameters (Table 1). undergoing CS to compare the effectiveness of a single
Risk factors for PPH was similar in the two groups intravenous (IV) injection of carbetocin with that of a
(Table 2). There was no significant difference between the standard 2-h oxytocin IV infusion with respect to intraopera-
two study groups regarding indications of CS (Table 2). There tive blood loss in the prevention of uterine atony after CS.
was no significant difference between the two study groups They found that a single 100 mg IV injection of carbetocin was

Figure 2. Systolic blood pressure changes in

both groups.
 4 A. M. Maged et al. J Matern Fetal Neonatal Med, Early Online: 1–5

Figure 3. Diastolic blood pressure changes in

both groups.

Figure 4. Pulse changes in both groups.

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Figure 5. Respiratory rate changes in both

groups.

Table 4. Adverse effects.

as effective as a continuous 2-h infusion of oxytocin in
GI (n ¼ 150) GII (n ¼ 150) p values controlling intraoperative blood loss after placental delivery.
Carbetocin enhanced early postpartum uterine involution.
Nausea 5 (3.3) 11 (7.66) 0.08
Vomiting 4 (2.66) 10 (7.33) 0.05 They concluded that carbetocin with a single IV injection,
Metallic taste 8 (5.3) 0 (0) 50.01 results equivalent to those of oxytocin on the maintenance of
Flushing 22 (14.66) 4 (2.66) 50.01 uterine tonicity and the limitation of blood losses, in the peri-
Headache 17 (11.3) 2 (1.33) 50.01
and in the postoperative period, during a delivery by CS [22].
Dizziness 6 (4) 1 (0.66) 50.01
Dyspnea 14 (9.3) 1 (0.66) 50.01 Four studies (1037 women) were included in meta-analysis
Shivering 3 (2) 3 (2) 0.796 by Su et al. (three studies on CS and one study on VD).
Palpitations 3 (2) 10 (6.66) 50.01 Carbetocin is associated with a reduced need for uterine
Itching 16 (10.66) 1 (0.66) 50.01
massage in both CS and VDs (RR 0.38, 95% CI 0.18–0.80;
Data are presented as number (%). RR 0.70, 95% CI 0.51–0.94), respectively [23].
 DOI: 10.1080/14767058.2016.1192601
Our study found that women received carbetocin had more
metallic taste (8 versus 0), flushing (22 versus 9), headache
(17 versus 5), dizziness (6 versus 2), dyspnea (14 versus 1)
and itching (16 versus 2), while women received syntometrine
experienced more vomiting (20 versus 4) and palpitation
(20 versus 3).
Leung et al. compared the efficacy and safety of
intramuscular (IM) carbetocin with IM syntometrine in
preventing primary PPH in a prospective, double-blinded,
randomized controlled trial. They found that intramuscular
carbetocin was as effective as IM syntometrine in preventing
primary PPH after VD. It was less likely to induce hyperten-
sion and had a low incidence of adverse effect. So, it should
be considered as a good alternative to conventional uterotonic
agents used in managing the third stage of labor [24].
Moertl et al. found no significant difference in the side
effect between carbetocin and oxytocin groups. The difference
with our study is that side effects started to be more noticeable
at 30 min after the administration of the two drugs, whereas
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Moertl et al. study was for 500 s after administration of the
drugs [25]. Our study concluded that women received
carbetocin had better hemodynamic stability regarding systolic
and diastolic blood pressure stability during first 24 h after
surgery.
Samimi et al. in a comparison between carbetocin and
syntometrine found that there was a significant difference
between the two groups concerning the systolic BP at 0, 30,
60 min after drug intake. Syntometrine group was higher in
systolic BP [26].
In our study, there was significantly lower in BP with the
syntometrine group but this may be due to the difference in
the anesthesia technique as we used spinal anesthesia.
Although the recommended preload was given but still
some hypotension is expected. Also, in this study, CS was
done with more expected blood loss than normal deliveries.
To the best of our knowledge, our study is the first study
comparing carbetocin effectiveness, safety and hemodynamic
stability with the standard syntometrine during CS.
We concluded that carbetocin is a good alternative to
traditional syntometrine in prevention of PPH following CS
with better tolerance and less hemodynamic changes and
could be routinely used to prevent PPH, which represents the
main deaths among parturient women.
Declaration of interest
Authors have no conflict of interest.
References
1. Gülmezoglu AM, Souza JP, Chou D, et al. WHO guidelines for the
management of postpartum haemorrhage and retained placenta
[Internet]. Geneva: World Health Organization; 2009.
2. Van Lerberghe W, Manuel A, Matthews Z, Cathy W. The World
Health Report 2005 – make every mother and child count. Geneva:
World Health Organization; 2005.
3. Khan KS, Wojdyla D, Say L, et al WHO analysis of causes of
maternal death: a systematic review. Lancet 2006;367:1066–74.
Postcesarean section hemorrhage prevention 5
4. Farchi S, Polo A, Franco F, et al Severe postpartum morbidity and
mode of delivery: a retrospective cohort study. Acta Obstet Gynecol
Scand 2010;89:1600–3.
5. Leth RA, Møller JK, Thomsen RW, et al. Risk of selected
postpartum infections after cesarean section compared with vaginal
birth: a five-year cohort study of 32,468 women. Acta Obstet
Gynecol Scand 2009;88:976–83.
6. Naef III RW, Chauhan SP, Chevalier SP, et al Prediction of
hemorrhage at cesarean delivery. Obstet Gynecol 1994;83:923–6.
7. United Nations. United Nations Millennium Development Goals.
2000. Available from: http://www.un.org/millenniumgoals [last
accessed 15 Sep 2011].
8. Cunningham FG, Leveno KJ, Bloom SL, et al. Obstetric hemor-
rhage. In: Cunningham FG, Williams JW, eds. William’s obstetrics.
23rd ed. New York, NY: McGraw-Hill; 2010:809–54. Chapter 35.
9. WHO. Mother–baby package: implementing safe motherhood in
countries. Geneva: World Health Organization; 1994.
10. El-Refaey H, Rodeck C. Post-partum haemorrhage: definitions,
medical and surgical management. A time for change. Br Med Bull
2003;67:205–17.
11. Chard T, Boyd N, Forsling M. The development of a radio-
immunoassay for oxytocin: the extraction of oxytocin from plasma,
and its measurement during parturition in human and goat blood.
J Endocrinol 1970;48:223–34.
12. Liabsuetrakul T, Choobun T, Peeyanajarassri K, Islam QM.
Prophylactic use of ergot alkaloids in the third stage of labour.
Cochrane Database Syst Rev 2007;18:CD005456.
13. Hunter DJ, Schulz P, Wassenaar W. Effect of carbetocin, a long
acting oxytocin analog on the postpartum uterus. Clin Pharmacol
Ther 1992;52:60–7.
14. Maged AM, Hassan AM, Shehata NA. Carbetocin versus oxytocin
in the management of atonic post partum haemorrhage (PPH) after
vaginal delivery: a randomised controlled trial. Arch Gynecol
Obstet 2016;293:993–9.
15. Maged AM, Hassan AM, Shehata NA. Carbetocin versus oxytocin
for prevention of postpartum hemorrhage after vaginal delivery in
high risk women. J Matern Fetal Neonatal Med 2016;29:532–6.
16. Attilakos G, Psaroudakis D, Ash J, et al Carbetocin versus oxytocin
for the prevention of postpartum haemorrhage following caesarean
section: the results of a double-blind randomised trial. BJOG 2010;
117:929–36.
17. Combs CA, Murphy EL, Laros Jr. RK, Factors associated with
postpartum hemorrhage with vaginal birth. Obstet Gynecol 1991;
77:69–76.
18. Ko JS, Kim CS, Cho HS, Choi DH. A randomized trial of
crystalloid versus colloid solution for prevention of hypotension
during spinal or low-dose combined spinal-epidural anesthesia for
elective cesarean delivery. Int J Obstet Anesth 2007;16:8–12.
19. Bose P, Regan F, Paterson-Brown S. Improving the accuracy of
estimated blood loss at obstetric haemorrhage using clinical
reconstructions. BJOG 2006;113:919–24.
20. Sullivan GM, Artino Jr. AR Analyzing and interpreting data from
Likert-type scales. J Grad Med Educ 2013;5:541–2.
21. Revised 1990 estimates of maternal mortality: a new approach by
WHO and UNICEF. Geneva: World Health Organization; 1996.
22. Borruto F, Treisser A, Comparetto C. Utilization of carbetocin for
prevention of postpartum hemorrhage after cesarean section: a
randomized clinical trial. Arch Gynecol Obstet 2009;280:707–12.
23. Su LL, Chong YS, Samuel M. Oxytocin agonists for preventing
postpartum haemorrhage. Cochrane Database Syst Rev 2007;
3:CD005457.
24. Leung SW, Ng PS, Wong WY, Cheung TH. A randomised trial of
carbetocin versus syntometrine in the management of the third
stage of labour. BJOG 2006;113:1459–64.
25. Moertl MG, Friedrich S, Kraschl J, et al haemodynamic effects of
carbetocin and oxytocin given as IV bolus on women undergoing
CS. BJOG 2011;118.
26. Samimi M, Harsini AI, Kalahroudi M. Carbetocin vs syntometrine
in prevention of post partum haemorrhage. Iranian Red Crescent
Med J 2013;15:817–22.