PPH_2nd_edn_Chap-44

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Carbetocin for the Prevention of PostpartumHemorrhageD. Cordovani, J. C. A. Carvalho, M. Boucher and D. Farine

INTRODUCTION

Considering the physical and emotional costs ofpostpartum hemorrhage (PPH) worldwide, it is not

surprising that institutions as diverse as the WorldHealth Organization, the International Confederationof Midwives (ICM) and the International Federationof Gynecology and Obstetrics (FIGO) all recommendactive management of the third stage of labor(AMTSL) even for patients with low risk for PPH1,2

(see Chapters 14 and 15). Their consensus is under-standable given that numerically more women with-out risk factors for PPH suffer from it than do womenwith obvious risk factors2.

The administration of a uterotonic medication soonafter the delivery of the fetus is an essential part of theAMTSL2 that is capable of decreasing the incidence ofPPH by 40%3,4. However, these medications posesome challenges, in that individually and collectivelythey have side-effects, contraindications and problemswith storage and administration. As such, the searchfor the ideal uterotonic continues, and today themain uterotonic agents are oxytocin, ergonovine,carboprost, carbetocin and misoprostol. This chapterfocuses on carbetocin.

Oxytocin is the most widely available and useduterotonic agent3,5 (see Chapter 43). It binds to themyometrial oxytocin receptors and stimulates contrac-tion of the uterine muscle by increasing the intra-

cellular concentration of calcium6,7. However, its useis not without some limitations. Oxytocin has a shorthalf-life of 317 minutes, and a continuous intra-venous (IV) infusion is necessary to achieve sustaineduterotonic activity3,5,7. Moreover, large doses orboluses of oxytocin are associated with adverseeffects in the form of hypotension, nausea, vomiting,dysrhythmias, ST-T changes, pulmonary edema andsevere water intoxication with convulsions3,8,9.

In contrast, carbetocin (1-deamino-1-carba-2-tyrosine(O-methyl)-oxytocin) is a synthetic oxytocinanalogue that binds to the same oxytocin receptors

in the myometrium with an affinity similar to thatof oxytocin6,7. Its main advantage over oxytocinis a four-fold longer uterotonic activity, a factwhich precludes the necessity of a continuousinfusion10,11.

PHARMACOLOGY

As noted above, carbetocin is a synthetic oxytocinanalogue that binds to the same myometrium recep-

tors as oxytocin with similar affinity7,12

. Despite a sim-ilar affinity, its potency in animal models is aboutone-tenth that of oxytocin on a mole per mole basis13.At the same time, its plasma half-life is approximately40 minutes after IV injection, which is 410 timeslonger than that of oxytocin10. Similarly to oxytocin,it causes an increase in the intracellular concentrationof calcium that promotes uterine contractility, throughthe generation of inositol phosphates14.

Oxytocin and vasopressin are neurohypophysialhormones with a short half-life in plasma. By remov-ing the primary amino group from the vasopressinmolecule, a prolongation of the half-life was achieved,something which did not happen when the same alter-ation was made in the oxytocin molecule. A furtheralteration of the molecule was necessary in order toachieve this same goal. The disulfide bond had beenproven not to be important in the mechanism ofaction of oxytocin6. By removing the amino group(1-deamino), and replacing the sulfur atom at position1 with a carba group (CH2), a prolonged myo-metrial action was observed6,7. Carbetocin is the carbaanalogue being used clinically in order to preventand/or treat PPH. The deamination protects carbe-tocin from aminopeptidase cleavage, and the replace-

ment of the disulfide bond by CH2S protects theanalogue from disulfidase cleavage15 (Figure 1). This isthe suggested explanation for the protracted half-life ofcarbetocin in plasma. Another suggested explanationfor the prolonged activity of carbetocin is its higherlipophilicity that can alter its tissue distribution7,13.Atke et al . suggested that this increased lipophilicitywas responsible for an increased half-life in thereceptor compartment7.

The structural differences between the moleculesof oxytocin and carbetocin could also explain thedecreased potency of the latter when compared with

the former. The current recommended dose ofcarbetocin for the prevention of PPH is 100 g, whichis roughly equivalent to 10 g (5 IU) of oxytocin13.However, it is important to highlight that these figuresare derived from animal data. Human myometrium

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departments drug of choice for prevention of PPHwas converted from oxytocin to carbetocin). In con-trast to the previous studies, there was no significantdecrease in the need for additional uterotonics. On theother hand, there was a significant decrease in postop-erative IV iron administration in the carbetocin group(6.5% vs. 14.5%, p= 0.03) and fewer compression

sutures were necessary (although not significant) in thecarbetocin group (0.6% vs. 4.5%,p= 0.06).

A recent dose-finding study performed byCordovani et al . attempted to calculate the ED95 ofcarbetocin for elective cesarean delivery in low-riskpatients for PPH25. The authors were unable to calcu-late the ED95 of carbetocin, as the failure rate wasevenly distributed across all dose groups (80, 90, 100,110 and 120g). Overall, 12.5% of patients failed topresent a firm uterus after 2 min of drug administra-tion, and 11.25% of women required additionaluterotonic therapy within 4 h. It is important to point

out that, three of the women requiring additionaluterotonics in fact had a firm uterus after 2 min ofcarbetocin administration.

In general, the studies on cesarean deliveries haveshown a decrease in the necessity of additionaluterotonic intervention, although none demonstrateda decrease in either the incidence of PPH or the meanblood volume loss, as the study design practically elim-inated such end points. At the same time, fewerpatients in the carbetocin arms of the studies lost largeramounts of blood21,22. The optimal dose of carbetocinis yet to be determined, but recent data suggest thatdoses as low as 80 g are as effective as the currentrecommended dose of 100g25.

CARBETOCIN IN VAGINAL DELIVERY

Six studies on carbetocin therapy used in vaginaldeliveries are presented in Table 2 in chronologicalorder.

Van Dongen et al . performed an ascending dose-tolerance study with IM carbetocin administered afterlow risk vaginal deliveries10. Their findings revealed amaximum tolerated dose of 200g due to the pres-ence of limiting side-effects, namely retained placenta,

blood loss of 1000 ml or more and blood transfusion.Optimal results were within the 75125 g dose rangein keeping with the 100 g dose determined in theoriginal dose-finding study19.

Boucheret al ., in a double-blind randomized con-trolled trial involving 160 patients with at least one riskfactor for PPH, compared carbetocin 100 g IM withoxytocin 10 IU IV infusion over a 2 h period26. Theirfindings showed no difference in the requirement ofadditional uterotonics or in the presence of PPH.However, significantly fewer women in the carbe-tocin arm required uterine massage compared with in

the oxytocin arm.Leung et al . compared carbetocin 100g IM(n= 165) with Syntometrine, a combination of oxy-tocin and ergometrine, IM (n= 164) given after lowrisk vaginal deliveries17. No significant difference was

observed in hemoglobin drop or use of additionaluterotonics, but women treated with Syntometrinehad a significantly higher incidence of nausea, vomit-ing and hypertension.

Ngan et al ., in a retrospective study involving 118low risk patients, found that carbetocin was associatedwith less blood loss compared with a combination of

oxytocin and ergometrine27.Nirmala et al . studied 120 women at high risk for

PPH who delivered vaginally in another randomizedcontrolled trial which compared carbetocin 100 gIM with Syntometrine IM16. In contrast to the find-ings observed in a low risk population17, these authorsfound a significant decrease in the mean blood loss aswell as a significant smaller decrease in hemoglobindrop in the carbetocin group. However, there was nodifference in the necessity of additional uterotonicagents or blood transfusion. Interestingly, also incontrast to the findings of Leung et al .17, there was

no difference in the incidence of side-effects.Su et al . performed yet another comparison of

carbetocin with Syntometrine28 evaluating 370women with low risk for PPH. Similar to previousfindings17, no differences were found in the require-ments for additional uterotonic agents, in blood lossor in the incidence of PPH. On the other hand,side-effects were noticeably more prevalent in theSyntometrine group.

In general, studies of vaginal deliveries found nodifference in the requirement for additional uterotonicmedication when compared with oxytocin or with acombination of oxytocin and ergometrine. However,when compared with oxytocin alone, carbetocin-treated patients with at least one risk factor for PPHrequired less uterine massage. The findings regardingdecrease in blood loss are conflicting. The most con-sistent finding was a decrease in the incidence of nau-sea and vomiting when compared with a combinationof oxytocin and ergometrine.

SIDE-EFFECTS AND CONTRAINDICATIONS

Oxytocin and carbetocin are without differencesregarding either the types of side-effects or their

frequency9,20,22,23. The incidence of side-effects inthree reports is presented in Table 39,20,22. Althoughnot shown in the table, Borruto et al . described28.8% of arrhythmias after oxytocin injection, butnone for carbetocin22. Similarly, Boucheret al. found a3.6% incidence of premature ventricular contractionafter oxytocin administration, but none aftercarbetocin20. The safety of carbetocin in patientswith severe cardiovascular disease has not yet beendetermined.

As carbetocin should not be administered prior tofetal delivery, under no circumstances should it be

used for induction of labor or labor augmentation. Itshould be administered as an IM injection or slow IVbolus over 1 min after fetal or placental delivery1,11.The following is an extract from the product leafletprovided by its manufacturer:

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POSTPARTUM HEMORRHAGE


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Carbetocin for the Prevention of Postpartum Hemorrhage

Author

Year

Typeofstudy

Population

Intervention

Outcomes

VanDongen

etal.1

0

1998

Ascendingdose

tolerance

Low-risk,vaginal

delivery(n=45)

CarbetocinIM(15,30,50,75,100,125,150,

175,200g)immediatelyafterbirthofinfant

Maximumbloodlossattheupperandlowerdoselevels.Lowestinthe70125grange

Maximumtolerateddosecalculatedtobe200g(4/18retainedplacenta,3/18bloo

dtransfusion,4/18

additionaloxytocics)

Boucheretal.26

2004

Double-blind

RCT

Atleast1riskfacto

r

forPPH(n=16

0)Carbetocin100gIM+IVplacebo(n=8

3)

vs.placeboIM+oxytocin10IU2hIV

infusion(n=77)afterdeliveryofplacenta

Nodifferenceinrequirementforadd

itionaluterotonicmedication,norinlaboratoryPPHindicators

Uterinemassagerequiredin43.4%vs.62.3%(p

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