Hypertension in Pregnancy

ISSN: (Print) (Online) Journal homepage: https://www.tandfonline.com/loi/ihip20

Carbetocin versus oxytocin for prevention of

postpartum hemorrhage in hypertensive women
undergoing elective cesarean section

Zakia M. Ibrahim , Waleed A. Sayed Ahmed , Eman M. Abd El-Hamid , Omima

T. Taha & Amira M. Elbahie

To cite this article: Zakia M. Ibrahim , Waleed A. Sayed Ahmed , Eman M. Abd El-Hamid , Omima
T. Taha & Amira M. Elbahie (2020) Carbetocin versus oxytocin for prevention of postpartum
hemorrhage in hypertensive women undergoing elective cesarean section, Hypertension in
Pregnancy, 39:3, 319-325, DOI: 10.1080/10641955.2020.1768268

To link to this article: https://doi.org/10.1080/10641955.2020.1768268

Published online: 18 May 2020.

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HYPERTENSION IN PREGNANCY
2020, VOL. 39, NO. 3, 319–325
https://doi.org/10.1080/10641955.2020.1768268

Carbetocin versus oxytocin for prevention of postpartum hemorrhage in

hypertensive women undergoing elective cesarean section
Zakia M. Ibrahima, Waleed A. Sayed Ahmeda, Eman M. Abd El-Hamida, Omima T. Tahaa, and Amira M. Elbahiea
a
Obstetrics and Gynecology Department, Faculty of Medicine, Suez Canal University, Ismailia, Egypt

ABSTRACT ARTICLE HISTORY

Objective: Assess the efficacy and safety of carbetocin, versus oxytocin in the prevention of Received 18 March 2020
postpartum hemorrhage in hypertensive women. Accepted 7 May 2020
Study design: A randomized clinical trial. KEYWORDS
Setting: Obstetrics and Gynecology Department of Suez Canal University Hospital. Postpartum hemorrhage;
Patients: One hundred and sixty hypertensive pregnant women who underwent CS. carbetocin; oxytocin; elective
Interventions: Patients were randomized to receive either 10 IU oxytocin or 100 μg carbetocin. cesarean section
Primary outcomes included estimated blood loss, blood transfusion, hemoglobin (HB), and
hematocrit changes pre- and post-delivery and the use of additional uterotonics.
Results: The postoperative HB was not different from preoperative HB in the carbetocin group
(11.8 ± 1.2 vs. 11.2 ± 1.2 g/dL) while it decreased significantly in the oxytocin group (12.1 ± 3.8 vs.
10.4 ± 1.1 g/dL, p < 0.001). Blood loss was significantly more among the oxytocin group
(679.5 ± 200.25 vs. 424.75 ± 182.59 ml) in the carbetocin group (p < 0.001). Nausea, vomiting,
and sweating were reported more significantly in oxytocin group patients.
Conclusion: Carbetocin was more effective than oxytocin in reducing intraoperative and post-
operative blood loss.

Introduction its minimal effect on the hemodynamic state of the

patients, it was recommended to evaluate this drug in
Hemorrhage is a leading contributor to maternal mor-
women with hypertensive disorders during pregnancy
tality, especially in developing countries, accounting for
(11). Therefore, the current study was conducted to eval-
more than 30% of direct causes (1,2). Other risk factors
uate the effectiveness of carbetocin versus oxytocin for the
include a cesarean section (CS) as well as hypertensive
prevention of PPH in hypertensive women undergoing
disorders (3). The most commonly used uterotonic
elective CS.
agent is oxytocin. It is characterized by a short half-
life of only 4–10 min, which mandates continuous
intravenous infusion to guarantee sustained uterotonic Materials and methods
activity (4). The recently introduced analogue to oxyto-
After approval of the institutional ethical committee on
cin, carbetocin, is a long-acting synthetic octapeptide
the study protocol, this randomized, double-blind clinical
(5) that binds to oxytocin receptors on the smooth
study has been carried out in the labor word at Suez Canal
muscles of the uterus, resulting in more robust and
University hospitals from 1/1/2014 to 31/12 /2018.
regular uterine contractions (6). Accordingly, it is
We recruited women according to the following
more advantageous over oxytocin in the management
inclusion and exclusion criteria. Inclusion criteria
of the third stage of labor (7), especially with a similar
included a) women aged 18–35 years, b) singleton
side effect profile (8).
pregnancy, c) scheduled for elective (with no evidence
Many studies evaluated different obstetrician’s arsenal
of labor pain) lower segment CS, d) gestational age of
in postpartum hemorrhage (PPH), but those evaluating
≥37 weeks, and e) have one of the hypertensive disor-
the effectiveness of carbetocin in hypertensive patients are
ders in pregnancy. These included: 1) chronic hyper-
scarce. The strides made for the management of PPH are
tension defined as high blood pressure that precedes
so clear considering uterotonic agents as an essential item
pregnancy, is diagnosed within the first 20 weeks of
in the care bundle in the third stage of labor (9).
pregnancy, or does not resolve by the 12-week
Carbetocin has advantages over oxytocin (10). Besides

CONTACT Omima T. Taha Omimatharwat@yahoo.com Obstetrics and Gynecology Department, Faculty of Medicine, Suez Canal University, Ismailia,
Egypt
© 2020 Informa UK Limited, trading as Taylor & Francis Group
320 Z. M. IBRAHIM ET AL.

Enrollment

- 170 patients were eligible for the study.

- 10 patients declined to participate.
- 160 patients were recruited

Allocation
Control group (n=80) Study group (n=80)
Received treatment (n=80) Received treatment (n=80)
Refused treatment (n=0) Refused treatment (n=0)

80 patients completed the study Analysis 80 patients completed the study

Data analysis included 80 Data analysis included 80
patients patients
No case was excluded No case was excluded.

Figure 1. The study flow chart.

postpartum checkup. 2) Gestational hypertension
defined as the new onset of hypertension after
20 weeks of gestation. The diagnosis requires that the
patient has elevated blood pressure (systolic ≥140 or
diastolic ≥90 mm Hg) and no protein in the urine. 3)
Preeclampsia characterized by the development of
hypertension and proteinuria after 20 weeks of gesta-
tion (12).
The exclusion criteria were a) history of risk factors for
excessive blood loss during the surgery (placenta previa,
twin pregnancy, or presence of uterine fibroid), b) history
of thromboembolic disorders, c) cases suffering from
chronic medical diseases (cardiac, hepatic, renal), d)
maternal request for CS (associated with a risk of PPH
of 3.1%(13)), and e) CS performed under general anesthe-
sia. The required sample size was calculated using a-error
of 0.05 (14) and study power 80%.
We followed the methods of El Behery et al., 2015 (15).
Women allowed for the study (160 women) were divided
into study and control groups. Each group included 80
pregnant women, fulfilling the selection criteria and
designated to deliver by elective CS for different obstetric
indications. Randomization of women was performed by
a simple randomization method by computer-generated
random tables, divided into two groups (study and con-
trol) in a 1:1 manner.
The recruited women received an explanation of the
study and signed a consent form. All patients received
regional anesthesia. Patients were then randomized to
receive either one ampoule 10 IU oxytocin (Syntocinon;
Alliance, Chippenham, UK) in 1000 ringer lactate as IV
drip at a rate of 125 ml/h or 100 µg carbetocin diluted in
10 ml of Ringer’s lactate solution injected directly into the
vein over 2 min (Pabal; Ferring, Langley, UK). The study
medication was administered by the anesthesia team after
delivery of the fetus and before placental removal. CS was
performed by two of the research investigators. Another
investigator performed the follow-up. Diclofenac sodium
75 mg (Voltaren®; Novartis Pharma, Berne, Switzerland)
was used as an analgesic on request as an intravenous
infusion in dextrose 5% solution for all patients.
This was a single-blinded trial (patients only). The
codes were broken only after the study was finished,
and all the data were tabulated and analyzed, thus
avoiding detection bias.
The primary outcome measure was the occurrence
of major primary PPH defined as blood loss >1000 ml
within 24 h of delivery (16). Blood loss was estimated
by the surgeon through visual estimation, number of
used swabs, and amount of aspirated blood (17).
Secondary outcomes were the change in vital signs,
the need for blood transfusion, preoperative hemoglo-
bin, and hematocrit levels compared to those obtained
at 24 h after delivery and the use of additional utero-
tonics during the first 24 h after delivery.
The uterine tone was evaluated by palpation.
Administration of further uterotonics (two rectal sup-
positories of misoprostol) was the choice of the inves-
tigators according to the clinical situation, whether
there is excessive blood loss associated with hypoten-
sion, tachycardia, or decreased uterine contractility or
tone during the operation or up to 24 h afterward.
 HYPERTENSION IN PREGNANCY 321

Ethical approval conducted and analyzed. A probability value (p-value)

This study was carried out after obtaining ethical approval
on 18/9/2013 with a research number 926#. Trial regis-
tration number is PACTR201909807831604.
Statistical analysis
Gathered data were processed using Statistical Package of
Social Sciences version 22.0 (SPSS version 22.0 Inc.,
Chicago, IL, USA). Qualitative data (categorical variables)
were expressed as frequency (numbers) and percentages in
the form of rates (%). Simple group comparisons were
processed using chi-square tests (with continuity correc-
tions in the case of 2 × 2 tables). Chi Squares and Fishers
Exact tests were used to test the significance of difference for
qualitative variables. Quantitative data were expressed as
median or means ± standard deviation (SD) as appropriate.
The student t-test was used to test the significance of
difference for quantitative variables that follow a normal
distribution.
Mann–Whitney U tests were used for variables that
are not normally distributed. Blood pressure and pulse
rates up to 40 minutes after the administration of the
study drug were measured every 10 minutes and com-
pared with repeated measures Analyses of Variance
(ANOVA). The independent data of the study were
<0.05 was considered statistically significant.
Results
We had 170 women eligible for the study. Ten women
declined to participate leaving 160 women allocated to
either group (Figure 1).There was no statistically sig-
nificant difference between both groups regarding age,
gestational age, gravidity, type of hypertension, and
indications of CS (Table 1).
Both groups were matched regarding baseline vital
signs including heart rate, blood pressure, and respiratory
rate. Post-operatively, still there was no significant differ-
ence between both groups regarding vital signs while
hemoglobin and hematocrit were lower in oxytocin
group compared to carbetocin group (p < 0.001). Data
showed that carbetocin group patients have a significant
decrease in systolic and diastolic blood pressure with no
significant change of heart rate while oxytocin group
patients showed a significant decrease in systolic and
diastolic blood pressure and significant increase of post-
partum heart rate (Table 2).
Regarding the postoperative weight of gauze, drapes,
and gowns, there was a significant difference between
both groups as they were heavier among oxytocin
group patients denoting more blood loss. (NB:

Table 1. Demographic characteristics of the study groups.

Variables Study group (Carbetocin) (n = 80) Control group (Oxytocin) (n = 80) p-value
Age (years) ≤ 30 38 47.5% 30 37.5% 0.11 (NS)
> 30 42 52.5% 50 62.5%
Gestational age (weeks) 38.15 ± 1.2 38.18 ± 0.8 0.9 (NS)
Mean ± SD
Gravidity PG 20 25% 20 25% 1 (NS)
G 2–3 44 55% 44 55%
> G3 16 20% 16 20%
Types of hypertension Chronic 10 12.5% 16 20% 0.5 (NS)
Pregnancy-induced 70 87.5% 64 80%
Indications of elective CS:
Repeat CS 58 72.5% 55 68.75% 0.37 (NS)
Malpresentation 16 20% 12 15%
Cephalopelvic disproportion 6 7.5% 13 16.25%
CS, cesarean section; NS, non-significant.

Table 2. Pre and postoperative vital signs and laboratory findings among study groups.
Study group (Carbetocin) (n = 80) Control group (oxytocin) (n = 80)
Pre op Postop Pre op Post op
HR (beat/min) 92.9 ± 7.5 95.6 ± 6.8 91.5 ± 5.5 96 ± 5.4*
SBP (mmHg) 154.5 ± 5.9 144.7 ± 6.1* 156.3 ± 7.1 146.5 ± 6.6*
DBP (mmHg) 97.8 ± 6.2 94.9 ± 5.1* 99.5 ± 3.2 96.8 ± 4.8*
RR (cycle/min) 13 ± 0.8 13.3 ± 0.6 13.1 ± 0.9 13.2 ± 0.9
HB (g/dl) 11.8 ± 1.2 11.2 ± 1.2 12.1 ± 2.8 10.4 ± 1.1#*
HCT (%) 35.2 ± 2.5 33.6 ± 2.4* 36.1 ± 3.1 29.8 ± 4.8#*
HR, heart rate; SBP, systolic blood pressure; DBP, diastolic blood pressure; RR, respiratory rate; HB, hemoglobin; HCT, Hematocrit.
*Statistically significant difference versus the preoperative value of the same group.
#
Statistically significant difference between postoperative values of both groups.
322 Z. M. IBRAHIM ET AL.
preoperative gauze weight was 150 g, and drapes and
gowns were 850 g). The amount of blood at the suction
unit was significantly larger among women treated with
oxytocin than those treated with carbetocin. Total
blood loss was significantly higher among the oxytocin
group compared to the carbetocin group.
None of carbetocin group patients required blood
transfusion versus 8 (10%) of oxytocin group patients
with no statistically significant difference. Also, none of
the carbetocin group patients required additional
uterotonic, while 85% of oxytocin group patients
received two rectal misoprostol with a statistically sig-
nificant difference (Table 3).
Discussion
Principle findings
Carbetocin was superior to oxytocin in the prevention
of PPH in hypertensive women. Postpartum hemoglo-
bin and hematocrit were significantly decreased 24 h
postpartum in the oxytocin group compared to preo-
perative values. None of the patients in the carbetocin
group required additional uterotonic compared to 85%
of women in the oxytocin group. Drug-related adverse
effects included nausea and vomiting, which were
higher among the oxytocin group, with incidence
rates ranged from 42.5% to 67.5%.
Results and clinical implications
The current study has shown that carbetocin was
superior to oxytocin in the prevention of PPH in hyper-
tensive women. The longer half-life of carbetocin can
explain this compared to oxytocin, which results in
more uterine contractility (18).
Postpartum hemoglobin and hematocrit were signif-
icantly decreased 24-h after delivery in the oxytocin
group compared to preoperative values, denoting
more blood loss among the oxytocin group. An earlier
studies15 reported similar results. Also, Uy et al., 2013
reported a significantly higher level of postoperative
hemoglobin in the carbetocin group versus the oxytocin
Table 3. Blood loss and need additional uterotonic among study groups.
Study group (Carbetocin) (n = 80)
Gauze, drapes and gowns weight (g)
Amount of blood at the suction unit (ml)
Total blood loss
Need blood transfusion No
Yes
Need additional uterotonics No
Yes
*Statistically significant differenceNS: non-significant.
group; however, they recruited women with uncompli-
cated pregnancies undergoing elective CS (19).
These findings were inconsistent with Reyes and
Gonzalez (20) as they have reported no statistically sig-
nificant difference between both carbetocin and oxytocin
regarding the mean fall of postoperative hemoglobin. This
would be explained by the fact that they recruited patients
who had vaginal delivery in their study while ours did not.
Also, another study reported no significant difference in
the mean HB level before and after delivery in their
studied population. However, carbetocin was compared
with the combined use of oxytocin and ergometrine (HB
difference of 0.51 ± 0.26 and 0.54 ± 0.30, respectively,
p = 0.50) (21). Additionally, another study reported no
change in the HB level among all groups of the study, but
they recorded the values if assessed during the routine
care leading to biased results (22).
The decrease in hemoglobin level in the carbetocin
group was insignificant when comparing between preo-
perative and postoperative values (11.8 ± 1.2 and
11.2 ± 1.2, respectively) with an estimated blood loss of
about 424.75 ± 182.59 ml. This agreed with a previous
study by Elgazayerli, 2019 (10.90 ± 0.93 and 10.68 ± 0.88,
respectively, with an estimated blood loss of
436.2 ± 36.2 ml) (23). In the study conducted by Dell-
Kuster et al., the change in hemoglobin levels was minor
(12.4 and 11.2), with an estimated blood loss of about
530 ml (24). The reported difference between both studies
would be rendered to their inclusion of patients under-
going unplanned CS for different obstetric causes, espe-
cially for the amount of blood loss. Besides, the
hemoglobin level was not correlated with the amount of
blood loss in the carbetocin group, as reported previously
(r = −0.179 with a p-value of 0.096) (25). Besides, there is
an extreme heterogeneity between the previous studies
concerned with carbetocin. This was because of the dif-
ferent criteria for patient recruitment, together with dif-
ferent dosing regimens for oxytocin (26).
No additional uterotonic was required in the carbetocin
group while as high as 85% of women in the oxytocin group
needed additional uterotonic. In Uy et al., study, 34.3% of
the participants in the oxytocin group required additional
uterotonic (19).
Control group (Oxytocin) (n = 80) p-value
1224 ± 182 1379 ± 200 <0.001*
200.75 ± 78.59 300.5 ± 145.25 <0.001*
424.75 ± 182.59 679.5 ± 200.25 <0.001*
80 100% 72 90% 0.1 (NS)
0 0% 8 10%
80 100% 12 15% <0.001*
0 0% 68 85%

There was a statistically significant difference
between both groups regarding the amount of blood
at the suction unit, which was a valid indicator for the
assessment of blood loss. The mean amount of blood
was 424.75 ± 182.59 ml with a carbetocin group while it
was as high as 679.5 ± 200.25 ml with oxytocin group.
Although this study agreed with El Behery et al., they
reported more blood loss in the oxytocin group than
the current study (1027 ± 659, 679.5 ± 200.25, respec-
tively). This would be rendered to their recruitment of
patients undergoing emergency CS which is known to
be associated with more blood loss than elective CS
(15). This resulted in more patients in need of blood
transfusion than the current one [14 (15.55%), 8 (10%),
respectively]. Additionally, a previous study reported
a significant increase in the amount of blood loss in
the oxytocin group than the carbetocin group (702.8 vs.
585.7 ml, respectively) (26). All the recruited cases had
their CS under regional anesthesia (spinal). Regional
anesthesia was associated with a slighter decrease in
patient hematocrit and less estimated blood loss (27).
There was a significant decrease in both systolic
and diastolic blood pressure among both groups,
with no significant difference between both drugs. It
was previously reported that when given as an intra-
venous bolus, oxytocin causes an increase in heart
rate and a decrease in mean arterial blood pressure
(28). This was consistent with previous studies that
showed no clinically significant differences between
carbetocin and oxytocin regarding the hemodynamic
parameters (10,20)., and (29). Although spinal
anesthesia would result in hypotension, which is
defined as a reduction in baseline blood pressure of
more than 80%(30), this was not evident in the
studied population.
Another concern with the use of carbetocin is its price.
Carbetocin is more expensive than oxytocin limiting its
use in our country. According to the meta-analysis con-
ducted by Jin et al., only one trial mentioned the cost-
effectiveness of carbetocin use in CS deliveries (31). In this
trial, uterine atony occurred in 19% and 8% women in the
oxytocin and carbetocin groups, respectively (p < 0.0001).
Bleeding was less than 500 mL in the carbetocin group
versus 500–1000 mL in the oxytocin one (p < 0.0001). The
mean cost per patient treated was 3525 USD vs. 4054 USD
with the carbetocin and oxytocin, respectively (p <
0.0001). The mean cost-effectiveness ratio for oxytocin
was 4944, USD while 3874 USD for carbetocin. The incre-
mental cost-effectiveness ratio documented that carbeto-
cin was superior (32). Together with its effectiveness in the
prevention of postpartum hemorrhage, it would be of
paramount benefit when used in women at risk for
major obstetric hemorrhage.
HYPERTENSION IN PREGNANCY 323
Research implications
In our study, the focus was on patients undergoing
elective CS and diagnosed with hypertensive disorders
in pregnancy, which limits the availability of uterotonic
drugs for the prevention of PPH. This group of patients
was not mentioned in previous researches properly. It
would be recommended to study the effect of both
drugs in patients having a vaginal delivery, which is
already known to be associated with less blood loss
than CS. Further researches to evaluate the cost-
effectiveness of carbetocin use should be conducted.
Strengths and limitations of the study
Our study included a small number of patients in each
group, which would be increased in further studies. We
used accurate methods for estimation of blood loss
either by weight difference between towels and drapes
before and after the operation as well as change differ-
ence in patients’ hemoglobin and hematocrit.
Conclusions
Our preliminary conclusion showed that a single IV carbe-
tocin of 100 µg was more effective than a continuous IV
infusion of oxytocin in maintaining adequate uterine tone
and in preventing PPH in hypertensive women undergoing
elective CS with similar safety profile.
Author’s contribution
ZM. Ibrahim: Protocol/project development, Manuscript
editing.
WA. Sayed Ahmed: Protocol/project development, manu-
script writing/editing.
AM.Elbahie: Data analysis, manuscript editing
EM. Abd El-Hamid: Data collection and management, data
analysis.
OT. Taha: Data collection and management, data analysis.
Key message
Carbetocin was more effective than oxytocin in reducing
intraoperative and postoperative blood loss in cesarean sec-
tion delivery, and both of them are safe with minimal toler-
able side effects.
Disclosure statement
No potential conflict of interest was reported by the authors.
Funding
Self-funded research
324 Z. M. IBRAHIM ET AL.
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