International Journal of Obstetric Anesthesia (2016) 28, 6169
0959-289X/$ - see front matter 2016 Published by Elsevier Ltd.
http://dx.doi.org/10.1016/j.ijoa.2016.10.003
REVIEW ARTICLE
The role of carbetocin in the prevention and management of
postpartum haemorrhage
L.S. Meshykhi,a M.R. Nel,a D.N. Lucasb
a
Department of Anaesthetics, The Hillingdon Hospital, Uxbridge, Middlesex, UK
b
Department of Anaesthetics, Northwick Park Hospital, Harrow, Middlesex, UK
ABSTRACT
Carbetocin is a new synthetic analogue of oxytocin. It has a longer half life than oxytocin. This review examines the current
evidence for the use of carbetocin as an alternative to oxytocin, as a rst-line agent in the pharmacological management of the
third stage of labour.
2016 Published by Elsevier Ltd.
Introduction
Postpartum haemorrhage (PPH) is a major cause of
maternal morbidity and mortality worldwide. It is a
leading cause of death in the developing world, account-
ing for 27% of maternal deaths.1 In well-resourced coun-
tries it is the most signicant cause of maternal
morbidity. The incidence is increasing, with data from
the USA showing a doubling in the rate of severe PPH
from 19982008,2 and similarly in England the recorded
incidence of PPH increased from 7% of all maternities in
20042005 to 13% in 20112012.3
Uterine atony is the most common cause of PPH,
accounting for approximately 70% of cases. After deliv-
ery of the baby and placenta, immediate haemostasis
requires myometrial contraction to cause occlusion of
uterine blood vessels and prevent blood ow from the
vascular space to the uterine cavity. Active pharmaco-
logical management of the third stage of labour is an
evidence-based intervention, which has been shown to
reduce the occurrence of PPH by 60% compared with
expectant or physiological management.4 International
recommendations are that uterotonics be used for third
stage management of all births.5,6 Recommended
uterotonics include intravenous or intramuscular oxy-
tocin as rst-line, with the alternatives of ergometrine
or misoprostol suggested if oxytocin is unavailable, or
as second-line therapies.
Accepted October 2016
Correspondence to: D.N. Lucas, Department of Anaesthetics, North-
wick Park Hospital, Harrow, Middlesex, UK.
E-mail address: nuala.lucas@nhs.net
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www.obstetanesthesia.com
Oxytocin, a naturally occurring hormone, has been
available as a synthetic agent since 19527 and is the most
commonly used uterotonic in obstetric practice. It is
routinely administered after both vaginal and caesarean
delivery to initiate and maintain adequate uterine tone
and thereby minimise blood loss.
There has been recent controversy about the optimal
dose of oxytocin to achieve adequate uterine tone at cae-
sarean delivery.8,9 Common practice is to administer an
intravenous bolus dose followed by an infusion over sev-
eral hours. Oxytocin, however, is associated with dose-
related side effects including hypotension, tachycardia,
nausea, vomiting, myocardial ischaemia and severe
water intoxication. If the initial bolus is given slowly
as an intravenous infusion rather than rapidly, many
of these side effects are minimised. A variety of studies
have sought to re-evaluate and dene the appropriate
dosing strategy for oxytocin.1012 Although it has been
identied that a dose as low as 0.5 to 3 U is sufcient
to induce adequate uterine tone following elective cae-
sarean delivery, the same studies did not effectively eval-
uate clinically important outcomes such as PPH. There
is also a lack of clarity on the role of oxytocin infusions,
either following an intravenous bolus or as sole PPH
prophylaxis. With a lack of consensus, and conicting
evidence about the safe and effective dose of oxytocin,
there is a need to evaluate alternative therapies.
Carbetocin is a newer agent that can potentially pro-
vide the benet of longer acting maintenance of oxytocic
action without the need for post-delivery infusion. It has
been approved for the prevention of uterine atony in
over 70 countries and in the UK is indicated for the
62
prevention of uterine atony following delivery of the
infant in caesarean delivery where spinal or epidural
anaesthesia has been used. However, it has not been
approved in the UK for use following vaginal birth. In
this review we examine the current evidence for the
use of carbetocin as an alternative to oxytocin, as a
rst-line agent in the pharmacological management of
the third stage of labour.
Pharmacology
Carbetocin was initially developed in the 1970s as a vet-
erinary product; it is a long-acting synthetic octapeptide
analogue of oxytocin (which is a nonapeptide) with ago-
nist properties at the oxytocin receptor. Structural dif-
ferences to oxytocin include replacement of the amino-
group of cysteine by a hydrogen atom, modication of
the disulphide bond by a thio-ether bond and a substitu-
tion of the hydroxyl group of tyrosine by a methyloxyl
group. These molecular changes give carbetocin more
stability and avoid early decomposition by disulphidase,
aminopeptidase and oxidoreductase enzymes (Fig. 1).13
The pharmacodynamic properties of carbetocin are
comparable to those of endogenous oxytocin. Carbe-
tocin selectively binds to oxytocin receptors in the
smooth muscle of the uterus resulting in rhythmic uter-
ine contractions, increased frequency of existing con-
tractions, and increased uterine tone.14
Early pharmacokinetic studies in non-pregnant
women suggested that the half-life of carbetocin when
given intravenously was 42 9 minutes, up to 10 times
longer than that of oxytocin.15,16 Intravenous injection
of carbetocin 830 lg produced a tetanic uterine con-
traction within two minutes that lasted about six min-
utes, and was followed by rhythmic contractions for a
further 60 18 minutes; intramuscular injection of car-
betocin 1070 lg also produced tetanic contraction in
less than two minutes but lasted for about 11 minutes,
Fig. 1 Chemical structures of oxytocin and carbetocin
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Carbetocin
and was followed by rhythmic contractions for an addi-
tional 119 69 minutes. The time required for absorp-
tion from the intramuscular route may account for
this difference but in addition carbetocin is a more lipo-
philic agent.
The effects of carbetocin on uterine muscle have been
evaluated in vitro. The contractile effects of a variety of
uterotonic agents, including oxytocin and carbetocin,
used in the management of PPH have been investigated
in myometrial strips from pregnant women.17 Morrison
et al. measured and compared the potency and maximal
response values using maximal amplitude and mean
contractile force as indices of contraction. Single,
EC50 concentrations of the drugs were administered
after which both force and contraction peak parameters
were compared. A wide difference in potencies using
both measures of contractility was noted, with oxytocin
and carbetocin being the most potent.
A prospective study examining the effects of intra-
muscular carbetocin versus oxytocin in women 24
48 hours postpartum found a signicantly prolonged
duration of activity for carbetocin.18 An intrauterine
pressure transducer was used to measure frequency,
amplitude and duration of contractions following the
administration of either oxytocin 10 U or carbetocin
30 lg. Carbetocin resulted in contractions of sustained
higher amplitude and frequency, with the initial pattern
of hypertonic activity peaking at 60 minutes with a mean
frequency of 4.09 contractions/10 min in the rst
60 minutes. In contrast oxytocin induced an initial pat-
tern of hypertonic activity peaking at 20 minutes with
a mean frequency of 4.55 contractions/10 min in the rst
60 minutes.18 In another in vitro study, Cole et al. exam-
ined the contractile response effect of oxytocin and car-
betocin on human myometrium after pre-exposure to
oxytocin.19 They found a decreased contractile response
to both carbetocin and oxytocin, most likely as a result
of the desensitization phenomenon.
The pharmacokinetic properties of carbetocin allow
for its use as a single bolus dose; there is a biphasic elim-
ination pattern after intravenous injection in the pre-
scribed dose range, with a terminal elimination half-life
of approximately 40 minutes due to modication of the
molecular structure of the drug which confers lipophilic
properties and stability against aminopeptidase, oxidore-
ductase and disulphidase enzymatic cleavage, prolonging
its pharmacological effects. By comparison, the terminal
half-life of oxytocin is around ve minutes. Renal clear-
ance of the unchanged form is low, with <1% of the
injected dose excreted unchanged by the kidney. Small
amounts of carbetocin have been shown to pass into
breast milk following single bolus dosing, but it is
assumed to be degraded in the infant gut.20
Clinical dose-nding studies have largely been con-
ned to women undergoing elective caesarean delivery.
Two studies in pregnant women at term, undergoing
L.S. Meshykhi et al.
caesarean delivery and with low risk of PPH, found that
a dose as low as 20 lg was effective.21,22 These studies
used doses ranging from 20120 lg and found a high
incidence of hypotension (55% and 42.5%). Another,
double-blind, dose-nding study of women undergoing
elective caesarean delivery under spinal anaesthesia
investigated the intravenous dose of carbetocin required
to produce effective uterine contraction in 90% of
women (ED90). The dose of carbetocin for each patient
was determined according to a biased-coin up-and-down
sequential allocation scheme designed to cluster doses
close to the ED90. The initial dose was 10 lg, with incre-
ments/decrements of 5 lg. Uterine tone was assessed at
one-minute intervals for ve minutes after carbetocin
administration. The authors found that the ED90 of car-
betocin was 14.8 lg (95% CI 13.7 to 15.8 lg), which is
less than one-fth the currently recommended dose of
100 lg.23 The authors commented that it is unclear
how the dose of 100 lg was initially recommended.
Another study conducted to assess the ED90 of carbe-
tocin required to provide adequate uterine tone at cae-
sarean delivery for labour arrest found contrasting
results.24 For women whose labours had been augmented
by oxytocin and who then required caesarean delivery for
labour arrest in the rst or second stage, the ED90 for
carbetocin was 121 lg; (95% CI 111 to 130 lg). This dose
is at least eight times higher than the ED90 identied pre-
viously for women undergoing elective caesarean delivery
at term. The authors attributed this nding to the desen-
sitization phenomenon but cautioned against increasing
the dose of carbetocin in this situation due to the higher
rate of side effects observed.
Carbetocin and the prevention of postpartum
haemorrhage
Caesarean delivery
The role of carbetocin in the prevention of PPH was the
subject of a Cochrane Review published in 2012.25 The
review included 11 studies (2635 women), which com-
pared carbetocin with other uterotonic agents, oxytocin
and Syntometrine (ergometrine 500 lg + oxytocin 5 U),
following either vaginal or caesarean delivery. In one
study intravenous carbetocin was compared with a pla-
cebo agent. In all the included studies carbetocin was
administered as a 100 lg bolus. Where oxytocin was
the comparison agent, the dose varied considerably
between studies.
The primary outcomes used in the review were severe
PPH (measured or clinically estimated blood loss
61000 mL) irrespective of the mode of delivery, and
maternal death or severe morbidity (e.g. major surgery,
organ failure, intensive care unit admission). Pooled
data from the review showed that for women who
underwent caesarean delivery, carbetocin resulted in a
lower risk of PPH compared to oxytocin (Risk Ratio
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63
(RR) 0.55; 95% CI 0.31 to 0.95; three trials, 820
women). The review also found that carbetocin resulted
in a statistically signicant reduction in the need for
additional therapeutic uterotonics compared to oxytocin
for those who underwent caesarean delivery (RR 0.62;
95% CI 0.44 to 0.88; four trials, 1173 women). Com-
pared to oxytocin, carbetocin was associated with a
reduced need for uterine massage following caesarean
delivery (RR 0.54; 95% CI 0.37 to 0.79; two trials, 739
women).
The role of carbetocin in PPH prophylaxis with cae-
sarean delivery has been assessed in a number of other
studies published subsequent to the Cochrane Review.
The studies looked at both elective and emergency cases
with variable results, which are summarised in Table 1.
A major limiting factor in interpretation of these studies
is the variation in dose and mode of administration of
the drug used for comparison.
Vaginal delivery
Of the 11 studies included in the Cochrane Review, ve
examined the role of carbetocin in vaginal delivery
(Table 2). Four trials compared intramuscular carbe-
tocin and intramuscular Syntometrine for women
undergoing vaginal delivery and one study compared it
to oxytocin. Three of these trials included only women
with no risk factors for PPH, while one trial specically
recruited women with risk factors for PPH. In the four
studies comparing the use of carbetocin and Syn-
tometrine, pooled data showed that there was no statis-
tically signicant difference in PPH rates between the
two drugs (RR 1.00; 95% CI 0.48 to 2.07). Three studies
reported on the outcome of severe PPH and also found
no difference between carbetocin and Syntometrine (RR
0.50; 95% CI 0.09 to 2.72). In the only study comparing
carbetocin with oxytocin the occurrence of PPH was
also similar in both groups (RR 0.95; 95% CI 0.43 to
2.09).
Requirement for additional uterotonics was also
examined. In contrast to caesarean delivery, the use of
carbetocin in vaginal delivery did not result in a statisti-
cally signicant reduction in the need for therapeutic
uterotonics when compared to either Syntometrine
(RR 0.83; 95% CI 0.60 to 1.15) or oxytocin (RR 0.93;
95% CI 0.44 to 1.94).
Subsequent to the publication, two studies have eval-
uated the role of carbetocin in PPH prophylaxis in vagi-
nal delivery with more positive results. In a double-blind
trial 200 women were randomised to receive either an
intramuscular injection of oxytocin 5 U with ergome-
trine 200 lg or carbetocin 100 lg after delivery.43 The
primary outcome measure was haemoglobin level
24 hours after delivery compared to haemoglobin level
on admission to the labour ward. The secondary out-
come measure was the requirement for additional utero-
tonic medication, with criteria for additional uterotonic
 Table 1 Characteristics of studies evaluating carbetocin in postpartum haemorrhage prophylaxis following caesarean delivery

64
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Participants Mode of delivery Dose of Comparison agent Outcome

carbetocin
*
Attilikos 201026 377 El & Emg CD Carbetocin 100 lg iv Oxytocin 5 U iv Carbetocin signicantly reduced need for additional
neuraxial bolus uterotonics (45.5% vs. 33.5%, RR 0.74, 95% CI 0.57 to 0.95).
anaesthesia No signicant dierences in PPH, blood transfusion and fall
in haemoglobin
*
Barton 199627 119 El CD Carbetocin 100 lg iv Saline iv Carbetocin signicantly reduced the need for additional
For personal use only. No other uses without permission. Copyright 2017. Elsevier Inc. All rights reserved.

uterotonics and increased uterine tone for 20 min post

administration
*
Borruto 200928 104 CD Carbetocin 100 lg iv Oxytocin 10 U iv infusion Mean blood loss after carbetocin 30 mL less than after
urgency not stated over 2 h oxytocin (P=0.5). Percentage with blood loss 6500 mL
higher with carbetocin (81% vs. 55%; P=0.05). Carbetocin
enhanced early postpartum uterine involution
*
Boucher 199829 60 El CD Carbetocin 100 lg iv, Oxytocin 2.5 U iv bolus Carbetocin as eective as oxytocin infusion in controlling
followed by saline + 10 U rapid infusion intraoperative blood loss after placental delivery. Percentage
infusion + 16 h infusion with blood loss 6200 mL higher with carbetocin (79% vs.
53%; P=0.041). Carbetocin enhanced early postpartum
uterine involution
*
Dansereau 199930 694 El CD Carbetocin 100 lg iv, Oxytocin 5 U iv bolus, + 20 Odds of treatment failure requiring oxytocic intervention
followed by saline U iv infusion was 2.03 (95% CI 1.1 to 2.8) times higher with oxytocin
infusion group compared to carbetocin (10.1% vs. 4.7%; P<0.05)
Elbohoty 201631 263 El CD Carbetocin 100 lg iv Oxytocin 10 U iv bolus + 20 In prevention of uterine atony, carbetocin was comparable
U infusion over 4 h with oxytocin (RR 0.41, 95%CI 0.14 to 1.25) and superior to
+ misoprostil 400 lg sl misoprostol (RR 0.21, 95%CI 0.07 to 0.58)
El Behery 201632 180 Emg CD Carbetocin 100 lg iv Oxytocin 20 U infusion Carbetocin signicantly reduced need for additional
obese parturients over 8 h uterotonics (71.5% vs. 0%; P<0.01). No dierence in PPH
between groups
Elgafor 201333 380 CD Carbetocin 100 lg iv Misoprostol 400 lg sl + No dierence between groups in fall in haemoglobin,
urgency not stated oxytocin 20 U estimated blood loss or blood transfusion
Larciprete 201334 102 El CD Carbetocin 100 lg iv Oxytocin 20 U infusion Carbetocin signicantly reduced need for additional
over 6 h uterotonics (23.5% vs. 0%, P=0.01). No dierence between
groups in fall in haemoglobin or PPH rate
Maged 201635 300 El & Emg CD Carbetocin 100 lg iv Oxytocin 5 U + Carbetocin signicantly reduced need for additional
ergometrine 200 lg) uterotonics and incidence of primary PPH. No signicant
dierence between groups in fall in haemoglobin and
haematocrit and mean blood loss
Razali 201636 547 Emg CD Carbetocin 100 lg iv Oxytocin 10 U iv Carbetocin signicantly reduced need for additional
uterotonics (38.8% vs. 57.2%; P<0.001). No dierence in
perioperative blood loss, severe PPH and blood transfusion
Whigman 201637 114 Emg CD Carbetocin 100 lg iv Oxytocin 5 U iv No signicant dierence in need for additional uterotonics,

Carbetocin
fall in haemoglobin, estimated blood loss and rates of PPH
or blood transfusion
*
Studies included in Cochrane Review.
El CD: elective caesarean delivery; Emg CD: emergency caesarean delivery; iv: intravenous; im: intramuscular; sl: sublingual; Syntometrine: oxytocin 5 U and ergometrine 500 lg.
 L.S. Meshykhi et al.
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Table 2 Characteristics of studies evaluating carbetocin in postpartum haemorrhage prophylaxis following vaginal delivery
Participants Dose of carbetocin Comparison agent Outcome
*
Askar 2011 38
240 Carbetocin 100 lg im Syntometrine im Carbetocin signicantly reduced estimated mean blood loss
(81.5 mL) and mean drop of haemoglobin 24 h after
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delivery (0.8 vs 1.1 g/dL)

*
Boucher 200439 160 Carbetocin 100 lg im Oxytocin 10 U Carbetocin signicantly reduced requirement for uterine
infusion over 2 h massage (43.4% vs. 62.3%; P<0.02). Uterotonic
intervention clinically indicated in 44.6% receiving
carbetocin compared to 63.6% given oxytocin infusion
(P<0.02). No dierences in laboratory PPH indicators
between groups
*
Leung 200640 300 Carbetocin 100 lg im Syntometrine im No signicant dierence in fall in haemoglobin in rst 48 h,
incidence of additional uterotonics, PPH and retained
placenta
Maged 201641 200 Carbetocin 100 lg im Oxytocin 5 U im Carbetocin signicantly reduced amount of bleeding,
incidence of PPH (>500 mL), need for additional
uterotonics and haemoglobin fall. No signicant dierence
between groups in major PPH (>1000 mL) and need for
blood transfusion
*
Nirmala 200942 120 Carbetocin 100 lg im Syntometrine im Carbetocin signicantly reduced mean estimated blood loss
(244 114 mL vs. 343 143 mL, 95% CI 52 to 146 mL);
signicantly reduced fall in haemoglobin (0.3 0.2 g/dL vs.
0.4 0.2 g/dL, 95% CI 0.1 to 0.2 g/dL). No signicant
dierences in requirement for additional uterotonics, time
to well-contracted uterus, blood transfusion, adverse eects
or complications
Samimi 201343 200 Carbetocin 100 lg im Oxytocin 5 U + Carbetocin signicantly reduced fall in haemoglobin
ergometrine (0.39 g/dL vs. 1.04 g/dL; P<0.001)
200 lg im
*
Su 200944 370 Carbetocin 100 lg im Syntometrine im No signicant dierence in PPH and addition uterotonics
(carbetocin 13.5% vs Syntometrine 16.8%; P=0.38).
Carbetocin associated with fewer adverse eects
*
Studies included in Cochrane Review.
im: intramuscular; Syntometrine: oxytocin 5 U and ergometrine 500 lg.

65
66
usage being estimated blood loss >500 mL with or with-
out hypotension or tachycardia and poor uterine tone.
The mean fall in haemoglobin level in the carbetocin
group (0.39 g/dL) was signicantly lower than the oxy-
tocin/ergometrine group (1.04 g/dL, P<0.001). There
was a signicant difference between the two groups in
the requirement for additional uterotonic agents (carbe-
tocin 1%, oxytocin/ergometrine 11%; P=0.002). Fewer
adverse effects were reported with carbetocin but the
difference was not signicant.
Another prospective double-blind randomized study
was conducted on 200 pregnant women who received
either intramuscular carbetocin 100 lg or oxytocin 5 U
after delivery of the baby and placenta.41 The occur-
rence of PPH (dened as bleeding >500 mL), need for
other uterotonics and difference between haemoglobin
levels were all signicantly lower in the carbetocin
group. However, there was no difference between the
two groups with occurrence of major PPH (blood loss
>1000 mL) and need for blood transfusion.
In addition to these randomised trials the role of car-
betocin has been subject to analysis in observational
studies with variable results. In a study in ve Dutch
hospitals, outcomes of patients treated with carbetocin
were compared with those of women who had received
oxytocin (dose varying from 510 U as a bolus or infu-
sion). The investigators found that the use of carbetocin
diminished the need for additional uterotonics by as
much as 50%.45 Another single centre before and after
analysis compared the use of carbetocin to oxytocin
and found that carbetocin did not appear to be more
effective than oxytocin in reducing PPH.46
Systematic reviews
Carbetocin has been subject to further systematic
review. Gizzo et al. concluded that while oxytocin was
the rst choice drug for PPH prophylaxis, they acknowl-
edged the role that carbetocin can have in elective cae-
sarean deliveries for PPH prevention when compared
to continuous oxytocin infusion.47 Jin et al. examined
12 studies, including several evaluated in the Cochrane
Review.48 They found that carbetocin was associated
with a signicantly reduced need for subsequent inter-
vention with additional uterotonics and uterine massage
in women who undergo caesarean delivery. However,
they found no difference in PPH rates, estimated blood
loss or haemoglobin changes.
Role in treatment of postpartum haemorrhage
Perhaps surprisingly, given the evidence that carbetocin
produces longer-term effective uterine muscle contrac-
tion than its rival oxytocin, there is currently very limited
data about the role of carbetocin in the management of
established PPH. A blinded study on 100 women
assessed the efcacy of carbetocin versus oxytocin in
the treatment of recognised atonic PPH >500 mL
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Carbetocin
following vaginal birth. Need for further uterotonic
agents was assessed at two minutes following drug deliv-
ery. Further blood loss was measured from the weight of
swabs. Signicant ndings were that measured blood loss
was lower in those given carbetocin versus oxytocin (811
389 mL vs. 1010 526 mL; P=0.034) and as with
other studies, the use of second-line uterotonics was
reduced. However, no signicant effect on the incidence
of major PPH >1000 mL was demonstrated.49
Adverse effects
That carbetocin has a close structural relationship to
oxytocin is reected in a similar side effect prole:
hypotension, nausea, ushing and abdominal pain can
all occur. The Cochrane Review also considered side
effects associated with the use of carbetocin for PPH
prevention. In studies comparing carbetocin with oxy-
tocin, pooled data did not reveal any statistically signif-
icant differences in terms of adverse effects. Specically,
there was a similar risk of headache, abdominal pain,
nausea, vomiting and premature ventricular contrac-
tions in women given carbetocin or oxytocin. The side
effect prole of carbetocin also compared favourably
with Syntometrine. Women who received carbetocin
were much less likely to experience nausea (RR 0.24;
95% CI 0.15 to 0.40) and vomiting (RR 0.21; 95% CI
0.11 to 0.39) compared to women who had received Syn-
tometrine. In addition, women who received carbetocin
were much less likely to suffer post-delivery hyperten-
sion (RR 0.07; 95% CI 0.01 to 0.49).
A study comparing the maternal heart rate and blood
pressure effects of carbetocin and oxytocin during elec-
tive caesarean delivery under spinal anaesthesia found
statistically indistinguishable haemodynamic effects for
both drugs.50 Cardiovascular parameters were measured
non-invasively for 500 seconds after slow intravenous
bolus of either carbetocin 100 lg or oxytocin 5 U. Heart
rate increases were 14.20 2.45 beats/min for carbetocin
and 17.98 2.53 beats/min for oxytocin. Interestingly,
following maximal effect, the heart rate and blood pres-
sure of women treated with carbetocin recovered slowly
to baseline values asymptomatically whereas women
treated with oxytocin displayed a slight rebound brady-
cardia after three minutes. Similar results were conrmed
by Rosseland et al. who found that the haemodynamic
side effects of oxytocin and carbetocin were broadly
comparable.51
There has been one case report to date of an inci-
dence of acute coronary syndrome in a low-risk cardio-
vascular woman undergoing emergency caesarean
delivery, who developed chest pain associated with tran-
sient electrocardiogram changes after the intravenous
administration of carbetocin 100 lg. Postoperative
investigation did not demonstrate a troponin rise or
echocardiogram abnormality.52 An observational study
L.S. Meshykhi et al.
has also demonstrated an effect of prolonging the QT
interval,53 which has also been described following
administration of oxytocin; however, there was no con-
trol group in this study, and no arrhythmias were seen.
Highlighted contraindications in the manufacturers
labelling include use of carbetocin during labour or for
induction of labour and in cases of preeclampsia and
eclampsia, cardiovascular disorders and epilepsy. Since
its release, however, there has been a randomised con-
trolled trial concluding that the use of carbetocin in 60
patients with severe preeclampsia had no major adverse
haemodynamic effect.54
Other effects
Aside from the main pharmacological effects, there has
been some interest in the potential neuroendocrine and
analgesic effects of carbetocin, which are similar to oxy-
tocin. In animal studies, carbetocin has been described
as having similar effects to uoxetine on improving
social interaction and reducing learned helplessness in
tree shrews.55 While it has been shown that oxytocin
may exhibit similar effects on mood, molecular studies
demonstrate that carbetocin does not mimic the receptor
afnities for endogenous oxytocin in the brain, and exhi-
bits selective afnity for certain oxytocin and vaso-
pressin receptor subtypes.56 One study evaluating the
effect of carbetocin on pain after caesarean delivery
demonstrated a signicant reduction of pain intensity
after a single injection of carbetocin 100 lg compared
with oxytocin 10 U followed by an oxytocin infusion.57
A secondary analysis of data from a randomised con-
trolled trial set up to study differences in haemodynamic
effects between carbetocin, oxytocin and placebo, exam-
ined opioid consumption. The analgesic agents adminis-
tered in the rst 72 hours post-delivery were converted
to morphine milligram equivalents but the differences
between the groups were not statistically signicant.58
Economic impact of carbetocin
Another key consideration when evaluating a new agent
is the economic impact associated with its use. This has
been subject to relatively little scrutiny so far. In one
study, included in the Cochrane Review, an economic
evaluation of carbetocin versus oxytocin for the preven-
tion of uterine atony was undertaken. This study was
only published in abstract format and the mode of deliv-
ery was not described. The authors found that clinically
carbetocin compared favourably with oxytocin for the
prevention of uterine atony. In addition the mean cost
per patient treated with carbetocin was $3525 versus
$4054 for oxytocin (P<0.0001).59
Another study examined the impact of the introduc-
tion of carbetocin for PPH prophylaxis at caesarean
delivery on a range of clinical outcomes and performed
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For personal use only. No other uses without permission. Copyright 2017. Elsevier Inc. All rights reserved.
67
a nancial analysis.60 Data on clinical outcomes includ-
ing frequency of PPH, transfusion requirements, change
in haemoglobin, use of additional uterotonics were col-
lected from patients records at hospital discharge and
these data were then matched according to age, parity,
body mass index and gestation at delivery with women
who had a caesarean delivery in the immediate period
before the introduction of carbetocin. The authors found
no signicant benet across the range of clinical out-
comes assessed. A composite nancial analysis of aspects
of care including staff costs, recovery times and pharma-
ceutical disposables showed that associated costs
increased by 18.52 per patient. Only 16.93 was directly
attributable to the cost of the drug itself, leaving a small
additional cost, 1.59, incurred simply with the introduc-
tion of carbetocin. However, the study had a number of
limitations with regard to both the clinical and nancial
analysis and the results should be treated with caution.61
Another UK group had more positive results when eval-
uating outcomes from elective and emergency caesarean
deliveries after the introduction of carbetocin. They
found that women who received carbetocin spent less
time in recovery than a historical cohort and that there
was a reduced need for additional third stage uteroton-
ics. In this study the different drug costs per patient when
all third stage requirements were included was minimal:
7.87 for carbetocin versus 6.37 for oxytocin. The
authors further calculated that reduced theatre recovery
time could potentially generate savings in stafng costs
of up to 189 000 per year.62,63
Conclusion
The role of carbetocin in PPH prophylaxis has been
widely but not comprehensively studied. The most
encouraging evidence currently would appear to be
when carbetocin is used at elective caesarean delivery.
In a descriptive analysis of guidelines on PPH from
the American College of Obstetricians and Gynecolo-
gists practice bulletin, the Royal Australian and New
Zealand College of Obstetricians and Gynaecologists,
the Royal College of Obstetricians and Gynaecologists,
and the Society of Obstetricians and Gynaecologists of
Canada (SOGC), only one (SOGC) currently recom-
mends the use of carbetocin in PPH prophylaxis.64
The currently available evidence justies further large-
scale studies to more clearly dene the role of carbetocin
and also in light of evidence about the effective dose to
identify the appropriate dose and route of administra-
tion.23 A potential barrier to the interpretation of com-
parative studies is the lack of consensus on the
appropriate dose and mode of administration of other
uterotonic agents, particularly oxytocin.65,66
Carbetocin, as with oxytocin, is temperature-sensitive
and requires sustained cold-temperature distribution
and storage and this has been a factor limiting its use
68
in the under-resourced world where cold storage may
not be readily available. A new room-temperature-
stable formulation of carbetocin has been developed
and is that aims to evaluate the non-inferiority of intra-
muscular carbetocin 100 lg versus oxytocin 10 U for the
prevention of PPH after vaginal delivery.67 Thirty thou-
sand women across 10 countries will be recruited. This
major study will undoubtedly shed further light on the
role of carbetocin.
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