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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
www.obstetanesthesia.com

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 Oxytocin, a naturally occurring hormone, has been


available as a synthetic agent since 19527 and is the most
Postpartum haemorrhage (PPH) is a major cause of commonly used uterotonic in obstetric practice. It is
maternal morbidity and mortality worldwide. It is a routinely administered after both vaginal and caesarean
leading cause of death in the developing world, account- delivery to initiate and maintain adequate uterine tone
ing for 27% of maternal deaths.1 In well-resourced coun- and thereby minimise blood loss.
tries it is the most signicant cause of maternal There has been recent controversy about the optimal
morbidity. The incidence is increasing, with data from dose of oxytocin to achieve adequate uterine tone at cae-
the USA showing a doubling in the rate of severe PPH sarean delivery.8,9 Common practice is to administer an
from 19982008,2 and similarly in England the recorded intravenous bolus dose followed by an infusion over sev-
incidence of PPH increased from 7% of all maternities in eral hours. Oxytocin, however, is associated with dose-
20042005 to 13% in 20112012.3 related side effects including hypotension, tachycardia,
Uterine atony is the most common cause of PPH, nausea, vomiting, myocardial ischaemia and severe
accounting for approximately 70% of cases. After deliv- water intoxication. If the initial bolus is given slowly
ery of the baby and placenta, immediate haemostasis as an intravenous infusion rather than rapidly, many
requires myometrial contraction to cause occlusion of of these side effects are minimised. A variety of studies
uterine blood vessels and prevent blood ow from the have sought to re-evaluate and dene the appropriate
vascular space to the uterine cavity. Active pharmaco- dosing strategy for oxytocin.1012 Although it has been
logical management of the third stage of labour is an identied that a dose as low as 0.5 to 3 U is sufcient
evidence-based intervention, which has been shown to to induce adequate uterine tone following elective cae-
reduce the occurrence of PPH by 60% compared with sarean delivery, the same studies did not effectively eval-
expectant or physiological management.4 International uate clinically important outcomes such as PPH. There
recommendations are that uterotonics be used for third is also a lack of clarity on the role of oxytocin infusions,
stage management of all births.5,6 Recommended either following an intravenous bolus or as sole PPH
uterotonics include intravenous or intramuscular oxy- prophylaxis. With a lack of consensus, and conicting
tocin as rst-line, with the alternatives of ergometrine evidence about the safe and effective dose of oxytocin,
or misoprostol suggested if oxytocin is unavailable, or there is a need to evaluate alternative therapies.
as second-line 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
Accepted October 2016
Correspondence to: D.N. Lucas, Department of Anaesthetics, North- been approved for the prevention of uterine atony in
wick Park Hospital, Harrow, Middlesex, UK. over 70 countries and in the UK is indicated for the
E-mail address: nuala.lucas@nhs.net

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62 Carbetocin

prevention of uterine atony following delivery of the and was followed by rhythmic contractions for an addi-
infant in caesarean delivery where spinal or epidural tional 119 69 minutes. The time required for absorp-
anaesthesia has been used. However, it has not been tion from the intramuscular route may account for
approved in the UK for use following vaginal birth. In this difference but in addition carbetocin is a more lipo-
this review we examine the current evidence for the philic agent.
use of carbetocin as an alternative to oxytocin, as a The effects of carbetocin on uterine muscle have been
rst-line agent in the pharmacological management of evaluated in vitro. The contractile effects of a variety of
the third stage of labour. uterotonic agents, including oxytocin and carbetocin,
used in the management of PPH have been investigated
Pharmacology in myometrial strips from pregnant women.17 Morrison
et al. measured and compared the potency and maximal
Carbetocin was initially developed in the 1970s as a vet- response values using maximal amplitude and mean
erinary product; it is a long-acting synthetic octapeptide contractile force as indices of contraction. Single,
analogue of oxytocin (which is a nonapeptide) with ago- EC50 concentrations of the drugs were administered
nist properties at the oxytocin receptor. Structural dif- after which both force and contraction peak parameters
ferences to oxytocin include replacement of the amino- were compared. A wide difference in potencies using
group of cysteine by a hydrogen atom, modication of both measures of contractility was noted, with oxytocin
the disulphide bond by a thio-ether bond and a substitu- and carbetocin being the most potent.
tion of the hydroxyl group of tyrosine by a methyloxyl A prospective study examining the effects of intra-
group. These molecular changes give carbetocin more muscular carbetocin versus oxytocin in women 24
stability and avoid early decomposition by disulphidase, 48 hours postpartum found a signicantly prolonged
aminopeptidase and oxidoreductase enzymes (Fig. 1).13 duration of activity for carbetocin.18 An intrauterine
The pharmacodynamic properties of carbetocin are pressure transducer was used to measure frequency,
comparable to those of endogenous oxytocin. Carbe- amplitude and duration of contractions following the
tocin selectively binds to oxytocin receptors in the administration of either oxytocin 10 U or carbetocin
smooth muscle of the uterus resulting in rhythmic uter- 30 lg. Carbetocin resulted in contractions of sustained
ine contractions, increased frequency of existing con- higher amplitude and frequency, with the initial pattern
tractions, and increased uterine tone.14 of hypertonic activity peaking at 60 minutes with a mean
Early pharmacokinetic studies in non-pregnant frequency of 4.09 contractions/10 min in the rst
women suggested that the half-life of carbetocin when 60 minutes. In contrast oxytocin induced an initial pat-
given intravenously was 42 9 minutes, up to 10 times tern of hypertonic activity peaking at 20 minutes with
longer than that of oxytocin.15,16 Intravenous injection a mean frequency of 4.55 contractions/10 min in the rst
of carbetocin 830 lg produced a tetanic uterine con- 60 minutes.18 In another in vitro study, Cole et al. exam-
traction within two minutes that lasted about six min- ined the contractile response effect of oxytocin and car-
utes, and was followed by rhythmic contractions for a betocin on human myometrium after pre-exposure to
further 60 18 minutes; intramuscular injection of car- oxytocin.19 They found a decreased contractile response
betocin 1070 lg also produced tetanic contraction in to both carbetocin and oxytocin, most likely as a result
less than two minutes but lasted for about 11 minutes, 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.
Fig. 1 Chemical structures of oxytocin and carbetocin Two studies in pregnant women at term, undergoing

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L.S. Meshykhi et al. 63

caesarean delivery and with low risk of PPH, found that (RR) 0.55; 95% CI 0.31 to 0.95; three trials, 820
a dose as low as 20 lg was effective.21,22 These studies women). The review also found that carbetocin resulted
used doses ranging from 20120 lg and found a high in a statistically signicant reduction in the need for
incidence of hypotension (55% and 42.5%). Another, additional therapeutic uterotonics compared to oxytocin
double-blind, dose-nding study of women undergoing for those who underwent caesarean delivery (RR 0.62;
elective caesarean delivery under spinal anaesthesia 95% CI 0.44 to 0.88; four trials, 1173 women). Com-
investigated the intravenous dose of carbetocin required pared to oxytocin, carbetocin was associated with a
to produce effective uterine contraction in 90% of reduced need for uterine massage following caesarean
women (ED90). The dose of carbetocin for each patient delivery (RR 0.54; 95% CI 0.37 to 0.79; two trials, 739
was determined according to a biased-coin up-and-down women).
sequential allocation scheme designed to cluster doses The role of carbetocin in PPH prophylaxis with cae-
close to the ED90. The initial dose was 10 lg, with incre- sarean delivery has been assessed in a number of other
ments/decrements of 5 lg. Uterine tone was assessed at studies published subsequent to the Cochrane Review.
one-minute intervals for ve minutes after carbetocin The studies looked at both elective and emergency cases
administration. The authors found that the ED90 of car- with variable results, which are summarised in Table 1.
betocin was 14.8 lg (95% CI 13.7 to 15.8 lg), which is A major limiting factor in interpretation of these studies
less than one-fth the currently recommended dose of is the variation in dose and mode of administration of
100 lg.23 The authors commented that it is unclear the drug used for comparison.
how the dose of 100 lg was initially recommended.
Another study conducted to assess the ED90 of carbe- Vaginal delivery
tocin required to provide adequate uterine tone at cae- Of the 11 studies included in the Cochrane Review, ve
sarean delivery for labour arrest found contrasting examined the role of carbetocin in vaginal delivery
results.24 For women whose labours had been augmented (Table 2). Four trials compared intramuscular carbe-
by oxytocin and who then required caesarean delivery for tocin and intramuscular Syntometrine for women
labour arrest in the rst or second stage, the ED90 for undergoing vaginal delivery and one study compared it
carbetocin was 121 lg; (95% CI 111 to 130 lg). This dose to oxytocin. Three of these trials included only women
is at least eight times higher than the ED90 identied pre- with no risk factors for PPH, while one trial specically
viously for women undergoing elective caesarean delivery recruited women with risk factors for PPH. In the four
at term. The authors attributed this nding to the desen- studies comparing the use of carbetocin and Syn-
sitization phenomenon but cautioned against increasing tometrine, pooled data showed that there was no statis-
the dose of carbetocin in this situation due to the higher tically signicant difference in PPH rates between the
rate of side effects observed. two drugs (RR 1.00; 95% CI 0.48 to 2.07). Three studies
reported on the outcome of severe PPH and also found
Carbetocin and the prevention of postpartum no difference between carbetocin and Syntometrine (RR
haemorrhage 0.50; 95% CI 0.09 to 2.72). In the only study comparing
carbetocin with oxytocin the occurrence of PPH was
Caesarean delivery also similar in both groups (RR 0.95; 95% CI 0.43 to
The role of carbetocin in the prevention of PPH was the 2.09).
subject of a Cochrane Review published in 2012.25 The Requirement for additional uterotonics was also
review included 11 studies (2635 women), which com- examined. In contrast to caesarean delivery, the use of
pared carbetocin with other uterotonic agents, oxytocin carbetocin in vaginal delivery did not result in a statisti-
and Syntometrine (ergometrine 500 lg + oxytocin 5 U), cally signicant reduction in the need for therapeutic
following either vaginal or caesarean delivery. In one uterotonics when compared to either Syntometrine
study intravenous carbetocin was compared with a pla- (RR 0.83; 95% CI 0.60 to 1.15) or oxytocin (RR 0.93;
cebo agent. In all the included studies carbetocin was 95% CI 0.44 to 1.94).
administered as a 100 lg bolus. Where oxytocin was Subsequent to the publication, two studies have eval-
the comparison agent, the dose varied considerably uated the role of carbetocin in PPH prophylaxis in vagi-
between studies. nal delivery with more positive results. In a double-blind
The primary outcomes used in the review were severe trial 200 women were randomised to receive either an
PPH (measured or clinically estimated blood loss intramuscular injection of oxytocin 5 U with ergome-
61000 mL) irrespective of the mode of delivery, and trine 200 lg or carbetocin 100 lg after delivery.43 The
maternal death or severe morbidity (e.g. major surgery, primary outcome measure was haemoglobin level
organ failure, intensive care unit admission). Pooled 24 hours after delivery compared to haemoglobin level
data from the review showed that for women who on admission to the labour ward. The secondary out-
underwent caesarean delivery, carbetocin resulted in a come measure was the requirement for additional utero-
lower risk of PPH compared to oxytocin (Risk Ratio tonic medication, with criteria for additional uterotonic

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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 Carbetocin

usage being estimated blood loss >500 mL with or with- following vaginal birth. Need for further uterotonic
out hypotension or tachycardia and poor uterine tone. agents was assessed at two minutes following drug deliv-
The mean fall in haemoglobin level in the carbetocin ery. Further blood loss was measured from the weight of
group (0.39 g/dL) was signicantly lower than the oxy- swabs. Signicant ndings were that measured blood loss
tocin/ergometrine group (1.04 g/dL, P<0.001). There was lower in those given carbetocin versus oxytocin (811
was a signicant difference between the two groups in 389 mL vs. 1010 526 mL; P=0.034) and as with
the requirement for additional uterotonic agents (carbe- other studies, the use of second-line uterotonics was
tocin 1%, oxytocin/ergometrine 11%; P=0.002). Fewer reduced. However, no signicant effect on the incidence
adverse effects were reported with carbetocin but the of major PPH >1000 mL was demonstrated.49
difference was not signicant.
Another prospective double-blind randomized study Adverse effects
was conducted on 200 pregnant women who received
either intramuscular carbetocin 100 lg or oxytocin 5 U That carbetocin has a close structural relationship to
after delivery of the baby and placenta.41 The occur- oxytocin is reected in a similar side effect prole:
rence of PPH (dened as bleeding >500 mL), need for hypotension, nausea, ushing and abdominal pain can
other uterotonics and difference between haemoglobin all occur. The Cochrane Review also considered side
levels were all signicantly lower in the carbetocin effects associated with the use of carbetocin for PPH
group. However, there was no difference between the prevention. In studies comparing carbetocin with oxy-
two groups with occurrence of major PPH (blood loss tocin, pooled data did not reveal any statistically signif-
>1000 mL) and need for blood transfusion. icant differences in terms of adverse effects. Specically,
In addition to these randomised trials the role of car- there was a similar risk of headache, abdominal pain,
betocin has been subject to analysis in observational nausea, vomiting and premature ventricular contrac-
studies with variable results. In a study in ve Dutch tions in women given carbetocin or oxytocin. The side
hospitals, outcomes of patients treated with carbetocin effect prole of carbetocin also compared favourably
were compared with those of women who had received with Syntometrine. Women who received carbetocin
oxytocin (dose varying from 510 U as a bolus or infu- were much less likely to experience nausea (RR 0.24;
sion). The investigators found that the use of carbetocin 95% CI 0.15 to 0.40) and vomiting (RR 0.21; 95% CI
diminished the need for additional uterotonics by as 0.11 to 0.39) compared to women who had received Syn-
much as 50%.45 Another single centre before and after tometrine. In addition, women who received carbetocin
analysis compared the use of carbetocin to oxytocin were much less likely to suffer post-delivery hyperten-
and found that carbetocin did not appear to be more sion (RR 0.07; 95% CI 0.01 to 0.49).
effective than oxytocin in reducing PPH.46 A study comparing the maternal heart rate and blood
pressure effects of carbetocin and oxytocin during elec-
Systematic reviews tive caesarean delivery under spinal anaesthesia found
Carbetocin has been subject to further systematic statistically indistinguishable haemodynamic effects for
review. Gizzo et al. concluded that while oxytocin was both drugs.50 Cardiovascular parameters were measured
the rst choice drug for PPH prophylaxis, they acknowl- non-invasively for 500 seconds after slow intravenous
edged the role that carbetocin can have in elective cae- bolus of either carbetocin 100 lg or oxytocin 5 U. Heart
sarean deliveries for PPH prevention when compared rate increases were 14.20 2.45 beats/min for carbetocin
to continuous oxytocin infusion.47 Jin et al. examined and 17.98 2.53 beats/min for oxytocin. Interestingly,
12 studies, including several evaluated in the Cochrane following maximal effect, the heart rate and blood pres-
Review.48 They found that carbetocin was associated sure of women treated with carbetocin recovered slowly
with a signicantly reduced need for subsequent inter- to baseline values asymptomatically whereas women
vention with additional uterotonics and uterine massage treated with oxytocin displayed a slight rebound brady-
in women who undergo caesarean delivery. However, cardia after three minutes. Similar results were conrmed
they found no difference in PPH rates, estimated blood by Rosseland et al. who found that the haemodynamic
loss or haemoglobin changes. side effects of oxytocin and carbetocin were broadly
comparable.51
Role in treatment of postpartum haemorrhage There has been one case report to date of an inci-
Perhaps surprisingly, given the evidence that carbetocin dence of acute coronary syndrome in a low-risk cardio-
produces longer-term effective uterine muscle contrac- vascular woman undergoing emergency caesarean
tion than its rival oxytocin, there is currently very limited delivery, who developed chest pain associated with tran-
data about the role of carbetocin in the management of sient electrocardiogram changes after the intravenous
established PPH. A blinded study on 100 women administration of carbetocin 100 lg. Postoperative
assessed the efcacy of carbetocin versus oxytocin in investigation did not demonstrate a troponin rise or
the treatment of recognised atonic PPH >500 mL echocardiogram abnormality.52 An observational study

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L.S. Meshykhi et al. 67

has also demonstrated an effect of prolonging the QT a nancial analysis.60 Data on clinical outcomes includ-
interval,53 which has also been described following ing frequency of PPH, transfusion requirements, change
administration of oxytocin; however, there was no con- in haemoglobin, use of additional uterotonics were col-
trol group in this study, and no arrhythmias were seen. lected from patients records at hospital discharge and
Highlighted contraindications in the manufacturers these data were then matched according to age, parity,
labelling include use of carbetocin during labour or for body mass index and gestation at delivery with women
induction of labour and in cases of preeclampsia and who had a caesarean delivery in the immediate period
eclampsia, cardiovascular disorders and epilepsy. Since before the introduction of carbetocin. The authors found
its release, however, there has been a randomised con- no signicant benet across the range of clinical out-
trolled trial concluding that the use of carbetocin in 60 comes assessed. A composite nancial analysis of aspects
patients with severe preeclampsia had no major adverse of care including staff costs, recovery times and pharma-
haemodynamic effect.54 ceutical disposables showed that associated costs
increased by 18.52 per patient. Only 16.93 was directly
Other effects attributable to the cost of the drug itself, leaving a small
additional cost, 1.59, incurred simply with the introduc-
Aside from the main pharmacological effects, there has tion of carbetocin. However, the study had a number of
been some interest in the potential neuroendocrine and limitations with regard to both the clinical and nancial
analgesic effects of carbetocin, which are similar to oxy- analysis and the results should be treated with caution.61
tocin. In animal studies, carbetocin has been described Another UK group had more positive results when eval-
as having similar effects to uoxetine on improving uating outcomes from elective and emergency caesarean
social interaction and reducing learned helplessness in deliveries after the introduction of carbetocin. They
tree shrews.55 While it has been shown that oxytocin found that women who received carbetocin spent less
may exhibit similar effects on mood, molecular studies time in recovery than a historical cohort and that there
demonstrate that carbetocin does not mimic the receptor was a reduced need for additional third stage uteroton-
afnities for endogenous oxytocin in the brain, and exhi- ics. In this study the different drug costs per patient when
bits selective afnity for certain oxytocin and vaso- all third stage requirements were included was minimal:
pressin receptor subtypes.56 One study evaluating the 7.87 for carbetocin versus 6.37 for oxytocin. The
effect of carbetocin on pain after caesarean delivery authors further calculated that reduced theatre recovery
demonstrated a signicant reduction of pain intensity time could potentially generate savings in stafng costs
after a single injection of carbetocin 100 lg compared of up to 189 000 per year.62,63
with oxytocin 10 U followed by an oxytocin infusion.57
A secondary analysis of data from a randomised con- Conclusion
trolled trial set up to study differences in haemodynamic
effects between carbetocin, oxytocin and placebo, exam- The role of carbetocin in PPH prophylaxis has been
ined opioid consumption. The analgesic agents adminis- widely but not comprehensively studied. The most
tered in the rst 72 hours post-delivery were converted encouraging evidence currently would appear to be
to morphine milligram equivalents but the differences when carbetocin is used at elective caesarean delivery.
between the groups were not statistically signicant.58 In a descriptive analysis of guidelines on PPH from
the American College of Obstetricians and Gynecolo-
Economic impact of carbetocin gists practice bulletin, the Royal Australian and New
Zealand College of Obstetricians and Gynaecologists,
Another key consideration when evaluating a new agent the Royal College of Obstetricians and Gynaecologists,
is the economic impact associated with its use. This has and the Society of Obstetricians and Gynaecologists of
been subject to relatively little scrutiny so far. In one Canada (SOGC), only one (SOGC) currently recom-
study, included in the Cochrane Review, an economic mends the use of carbetocin in PPH prophylaxis.64
evaluation of carbetocin versus oxytocin for the preven- The currently available evidence justies further large-
tion of uterine atony was undertaken. This study was scale studies to more clearly dene the role of carbetocin
only published in abstract format and the mode of deliv- and also in light of evidence about the effective dose to
ery was not described. The authors found that clinically identify the appropriate dose and route of administra-
carbetocin compared favourably with oxytocin for the tion.23 A potential barrier to the interpretation of com-
prevention of uterine atony. In addition the mean cost parative studies is the lack of consensus on the
per patient treated with carbetocin was $3525 versus appropriate dose and mode of administration of other
$4054 for oxytocin (P<0.0001).59 uterotonic agents, particularly oxytocin.65,66
Another study examined the impact of the introduc- Carbetocin, as with oxytocin, is temperature-sensitive
tion of carbetocin for PPH prophylaxis at caesarean and requires sustained cold-temperature distribution
delivery on a range of clinical outcomes and performed and storage and this has been a factor limiting its use

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68 Carbetocin

in the under-resourced world where cold storage may 18. Amsalem H, Aldrich CJ, Oskamp M, Windrim R, Farine D.
not be readily available. A new room-temperature- Postpartum uterine response to oxytocin and carbetocin. J Reprod
Med 2014;59:16773.
stable formulation of carbetocin has been developed 19. Cole NM, Carvalho JC, Erik-Soussi M, Ramachandran N, Balki
and is that aims to evaluate the non-inferiority of intra- M. In vitro comparative effect of carbetocin and oxytocin in
muscular carbetocin 100 lg versus oxytocin 10 U for the pregnant human myometrium with and without oxytocin pre-
prevention of PPH after vaginal delivery.67 Thirty thou- treatment. Anesthesiology 2016;124:37886.
sand women across 10 countries will be recruited. This 20. Silcox J, Schulz P, Horbay GL, Wassenaar W. Transfer of
carbetocin into human breast milk. Obstet Gynecol 1993;82:4569.
major study will undoubtedly shed further light on the 21. Cordovani D, Balki M, Farine D, Seaward G, Carvalho JC.
role of carbetocin. Carbetocin at elective Cesarean delivery: a randomized controlled
trial to determine the effective dose. Can J Anaesth 2012;59:7517.
22. Anandakrishnan S, Balki M, Farine D, Seaward G, Carvalho JC.
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