Carbetocin in the Prevention of Postpartum Haemorrhage:

An Asian Perspective
Shilla Mariah Yussof, MB BCh BAO (Hons) (Dublin); Horng Yen Wee, MB BCh
BAO (Dublin), BA (Dublin), FAMS (Singapore), MRCO (!")
INTRODUCTION
#os$par$u% hae%orrhage (##H) is one of $he lea&ing 'auses of %a$ernal %orbi&i$(
an& %or$ali$() While $he ra$e of ##H *aries +i&el( a%ong &ifferen$ 'oun$ries, i$
a''oun$s for appro,i%a$el( -./ of %a$ernal &ea$hs in Asia)
0
1he pre*alen'e of ##H
in Sou$h2eas$ern Asia +as es$i%a$e& $o be 3,44/, $he highes$ +i$hin Asia, +hi'h has
an a*erage ##H ra$e of 5,66/)
5
1he %ain 'ause of ##H is u$erine a$on() A'$i*e %anage%en$ of $he $hir& s$age of
labour, +hi'h 'onsis$s of earl( 'or& 'la%ping, 'on$rolle& 'or& $ra'$ion, an& $he
proph(la'$i' a&%inis$ra$ion of a u$e$oni' agen$, has been +i&el( use& +orl&+i&e $o
re&u'e ##H)
Of $hese %easures, ure$o$oni' agen$ is $he onl( one suppor$e& b( e,$ensi*e e*i&en'e)
-
1he Worl& Heal$h Organi7a$ion 'urren$l( re'o%%en&s a'$i*e %anage%en$ of $he
$hir& s$age of labour +i$h o,($o'in $o pre*en$ ##H)
3
Ho+e*er, $he half2life of $his
&rug is ra$her shor$ (320. %inu$es), an& i$ has $o be a&%inis$ra$e& 'on$inuousl( *ia
in$ra*enous infusion $o a'hie*e sus$aine& u$ero$oni' a'$i*i$()
628
9$s &ose an& &ura$ion
*ar( +i&el( a'ross ins$i$u$ions)
4200
Ano$her +i&el( use& u$ero$oni' agen$ is s(n$o%e$rine, a &eri*a$i*e of o,$o'in an&
ergo%e$rine) 9$ is superior $o o,($o'in in ris: re&u'$ion of %il& ##H (6..20... %;))
05
Ho+e*er, s(n$o%e$rine is li%i$e& b( i$s gas$roin$es$inal an& 'ar&io*as'ular si&e
effe'$s, +hi'h in'lu&e %a$ernal *o%i$ing, h(per$ension, an& pain re<uiring analgesia
o+ing $o i$s ergo$ al:aloi& 'o%ponen$)
0-
1he use of ergo$ al:aloi&s is also
'on$rain&i'a$e& in +o%en +i$h pre2e,is$ing h(per$ension, pree'la%psia, an& 'ar&ia'
'on&i$ions, an& in $hose +i$h a his$or( of %igraine or Ra(nau& pheno%enon)
=rgo%e$rine is also *er( uns$able an& has $o be :ep$ refrigera$e& an& shiel&e& fro%
ligh$, +hi'h li%i$s i$s use in rural areas)
CARBTOCIN ! PHAR"ACO#O$IC PROPRTI%
1able 0) Su%%ar( of o,($o'in &rugs 'urren$l( a*ailable 5>254)
Carbetocin
&'uratocin(
O)*tocin
&s*ntocinon(
o)*tocin+
ergometrine
& s*ntometrine(
A'$i*e
ingrre&ien$
'arbe$o'in o,($o'in 6 9! or 0. 9!
in 0 %l a%poule
o,($o'in 6 9! ? .)6
%g 0..ug
ergo%e$rine
%alea$e in in 0
%l a%poul
Dosage 9@ bolusA 0.. ug 9@ infusion ; 6 9!
9M A 620. 9!
9M; %a,i%u% $hree
a%poules +i$hin
53 h ( in$er*a:
of 5 h)
Onse$ of
&ura$ion
Wi$hin 5 %in 9@ A B 0 %in
9MA 523 %in
25,6 %in
Dura$ion of
a'$ion
20 h 9@ A less $han 9M
9MA -.2>. %in
2 - h
A&*erse
rea'$ion
Causea an&
*o%i$ing,
ab&o%inal pain,
h(po$ension
Hea&a'he, h(po$ension,
$a'h('ar&iaDbra&('a
r&ia
Causea an&
*o%i$ing,
h(per$ension,
'ar&ia'
arrh($h%ias
Carbe$o'in is an o,($o'in agonis$) Wi$h phar%a'ologi' proper$ies si%iliar $o na$ural
o,($o'in, $he &rug bin&s $o $he s%oo$h %us'le re'ep$irs of $he u$erus, 'ausing
rh($h(%i' 'on$ra'$ion an& in'reasing $he fre<uen'( of 'on$ra'$ions as +ell as u$erine
$one)
03,06
A&%inis$ere& ei$her in$ra*enousl( or in$ra%us'ular( as a single &ose of 0..
ug, 'arbe$osin has a half life of abou$ 3. %inu$es; 320. $i%es longer $han of
o,($o'in)
0>
Con$ra'$ion of $he u$erus 'an be a'hie*e& +i$hin 5 %inu$es follo+ing
inEe'$ion, persis$ing for an e*erage of 05. %inu$es follo+ing in$ra%us'ular inEe'$ion
an& an a*erage of >. %inu$es +i$h in$ra*enous inEe'$ion)
08
1he %ain a&*<$age of
'arbe$o'in o*er o,($o'in is i$s longer &ura$ion of a'$ion, allo+ing a single
in$ra%us'ular inEe'$ion ins$ea& of an in$ra*enous infusion) As su'h, 'arbe$o'in is a
pro%ising al$erna$i*e u$ero$oni' agen$ for $he pre*en$ion of ##H)
CARBTOCIN IN ,A$INA# D#I,RI%
A nu%ber of s$u&ies ha*e e*alua$e& $he effi'a'( of 'arbe'o$in in *aginal &eli*eries)
Asian &a$a for% a s$u&( b( ;eung e$ al in Hong "ong 'o%pare& 'arbe$o'in an&
s(n$o%e$rine in $he %anage%en$ of $he $hir& s$age of labour in -.. +o%en
un&ergoing *aginal &eli*er()
04
1he au$hors foun& $ha$ in$ra%us'ular 'arbe$o'in +as as
effe'$i*e as in$ra%us'ular s(n$o%e$rine in pre*en$ing pri%ar( ##H bu$ +as less li:el(
$o in&u'e h(per$ension af$er &eli*er()
04
1here +as no &ifferen'e in $he &rop of he%oglobin 'on'en$ra$ion +i$hin $he firs$ 34
hours be$+een $he $+o groups)
04
1he in'i&en'e of a&&i$ional o,($o'in inEe'$ions,
##H, an& re$aine& pla'en$a +ere also fa%iliar)
04
Ho+e*er, $he use of 'arbe$o'in +as
asso'ia$e& +i$h a signifi'an$l( lo+er in'i&en'e of nausea, *o%i$ing, an& h(per$ension
af$er &eli*er()
04
Ano$her s$u&( b( Cgan e$ al in Ma'au 'o%pare& 0.. %i:rogra% 'arbe$o'in an& a
'o%bina$ion of 6 9! of o,($o'in an& .)5 %g of ergo%e$rine in $he 'on$rol of
pos$par$u% bloo& loss in 004 +o%en follo+ing *aginal &eli*er()
0F
1he( foun& $ha$
'arbe$o'in +as asso'ia$e& +i$h signifi'an$l( less bloo& loss (%ean, 0>- %; less) an&
hae%a$o'ri$ &rop, an& a s$a$is$i'all( signifi'an$ re&u'$ion in $he ris: of ##H)
0F
Cir%ala e$ al in Mala(sia 'o%pare& $he use of 'arbe$o'in an& s(n$o%e$rine folo+ing
*aginal &eli*er( in 05. +o%en +i$h ris: fa'$ors for ##H)
5.
Co signifi'an$ &ifferen'ies in $er%s of re<uire%en$ for a&&i$ional o,($o'i' agen$s,
$i%e in$er*al $o +ell'on$ra'$e& u$erus, bloo& $ransfusion re<uire%en$s, a&*erse
e*en$s, or 'o%pli'a$ions +ere no$e&)
5.
Carbe$o'in, ho+e*er, +as asso'ia$e& +i$h a signifi'an$l( lo+er %ean es$i%a$e& bloo&
loss)
5.
1he hae%oglobin sho+e& a signifi'an$l( re&u'es &rop in $he 'arbe$o'in group
'o%pare& +i$h $ha$ in $he s(n$o%e$rine group)
5.
Su e$ al in Singapore 'on&u'$e& a &oubleblin&, ran&o%i7e&, 'on$rolle& $rial of -8.
+o%en 'o%paring $he use of 'arbe$o'in an& s(n$o%e$rine for $he $hir& s$age of labour
follo+ing *aginal &eli*er()
50
Carbe$o'in +as sho+n $o be as effe'$i*e as s(n$o%e$rine
in $he pre*en$ion of ##H bu$ ha& fe+er a&*erse e*en$s)
50
Wo%en gi*en s(n$o%e$rine
+ere four $i%es %ore li:el( $o e,perien'e nausea an& *o%i$ing 'o%pare& +i$h $hose
+ho ha& 'arbe$o'in)
1re%or, s+ea$ing, re$'hing, an& u$erine pain +ere also li:el( in $he s(n$o%e$rine
group 'o%pare& +i$h $he 'arbe$o'in group)
50
CARBTOCIN IN CA%ARAN %CTION%
1here are no 'urren$l( no Asian s$u&ies e*alua$ing $he effi'a'( an& safe$( of
'arbe$o'in in 'aesarean se'$ions)
Ce*er$heless, a''or&ing $o a re'en$ Co'hrane re*ie+, $he ris: of ##H in 'aesarean
&eli*eries +as si%ilar in +o%en $rea$e& +i$h 'arbe$o'in an& o,($o'in (rela$i*e ris:
GRRH, .,F0; F6/ C9, .,-F25,06; $+o $rials, 3-5 +o%en))
55
9n a&&i$ion, 'o%pare& +i$h
$he o,($o'in group, $he nee& for subse<uen$ a&&i$ional u$ero$oni's +as lo+er in $he
'arbe$o'in group (RR, .,>5; F6/ C9, .,332.,44; four $rials, 008- +o%en))
55
1here
+as no s$a$is$i'all( signifi'an$ &ifferen'e in $he nee& for bloo& $ransfusion be$+een
$he 'arbe$o'in an& s(n$o%e$rine group)
55
Si%ilar $o *aginal &eli*eries, $here +as also
a re&u'e& nee& for u$erine %assage +hen 'o%paring 'arbe$o'in an& o,($o'in (RR,
.,63; F6/ C9, .,-82.,8F; $+o $rials, 8-F +o%en))
55
CARBTOCIN %A-T. AND TO#RABI#IT.
1he re'en$ Co'hrane re*ie+ b( Su et al also 'o%pare& $he a&*erse effe'$s of &ifferen$
u$ero$oni' agen$s)
55
1he ris: of e,perien'ing hea&a'he, 'hills, ab&o%inal pain,
&i77iness, $re%or, nausea, *o%i$ing, ba': pain, pruri$us, feeling of +ar%$h, %e$alli'
$as$e, flushing, s+ea$ing, shor$ness of brea$h, an& pre%a$ure *en$ri'ular 'on$ra'$ions
+ere si%ilar be$+een $he 'arbe$o'in an& o,($o'in groups for bo$h *aginal an&
'aesarean &eli*eries) Al$hough +o%en +ho un&er+en$ *aginal &eli*eries e,perien'e&
fe+er hea&a'hes, nausea, an& *o%i$ing +hen $rea$e& +i$h 'arbe$o'in 'o%pare& +i$h
o,($o'in, $he &ifferen'e +as no$ s$a$is$i'all( signifi'an$) When 'o%pare& +i$h
s(n$o%e$rine in *aginal &eli*er(, $he ris: of nausea (RR, .,53; F6/ C9, .,062.,3.)
an& *o%i$ing (RR, .,50; F6/ C9, .,002.,-F) +as signifi'an$l( lo+er in $he +o%en
$rea$e& +i$h 'arbe$o'in)
55
Wo%en +ho re'ei*e& 'arbe$o'in +ere also less li:el( $o ha*e h(per$ension a$ -.
%inu$es (RR, .).8; F6/ C9, .).02.)3F; $+o $rials, 68. +o%en) an& a$ >. %inu$es
(RR, .).8; F6/ C9, .).02.)63; $+o $rials, 63. +o%en) af$er *aginal &eli*er()
55
See
$able 0 for a su%%ar( of o,($o'i' &rugs 'urren$l( a*ailable)
CO%T /--CTI,N%% O- CARBTOCIN
Man( fa'$ors, su'h as 'ul$ural &ifferen'es, go*ern%en$ poli'(, a*ailabili$( of $raine&
%e&i'al s$aff, s$orage spa'e, an& 'os$2effe'$i*eness, %a( 'on$ribu$e $o &ifferen'es in
$he %anage%en$ of ##H an& ul$i%a$el(, $he 'hoi'e of u$ero$oni' agen$s) Al$hough$
$here is 'urren$l( li%i$e& &a$a on $he 'os$effe'$i*eness of in&i*i&ual u$ero$oni' agen$s,
one s$u&( fro% Me,i'o 'o%pare& $he 'os$2effe'$i*eness of proph(la'$i' 'arbe$o'in
+i$h o,($o'in follo+ing 'aesarean &eli*er()
5-
1he au$hors 'o%pare& $he in'i&en'e of
u$erine a$on( in pa$ien$s re'ei*ing 'arbe$o'in *s o,($o,in (4/ *s 0F/; # B.)...0)
an&, +i$h a&&i$ional finan'ial &a$a fro% Me,i'an 9ns$i$u$e of So'ial Se'uri$(, +ere
able $o 'al'ula$e $he %ean 'os$2effe'$i*eness ra$io using in're%en$al 'os$2
effe'$i*eness ra$io anal(sis)
5-
1ha$ %ean 'os$ per pa$ien$ $rea$e& +as lo+er for $he
'arbe$o'in group ( !SI-,656 *s !SI3,.63; #B.)...0), sugges$ing $ha( 'arbe$o'in
+as 'os$2effe'$i*e)
5-
CURRNT U% O- CARBTOCIN
Carbe$o'in has been appro*e& for use in $he pre*en$ion of u$erine a$on( af$er &eli*er(
b( 'aesarean se'$ion +i$h spinal or epi&ural anaes$hesia in 5- 'oun$ries, i'lu&ing
China, Hong:ong, Mala(sia, an& Siangapore) 1he Ro(al College of Obs$e$ri'ians an&
(nae'ologis$s s$a$es $ha$ 'arbe$o'in is as effe'$i*e as o,($o'in infusion for $he
pre*en$ion of ##H in 'aesarean an& se'$ion an& s(n$o%e$rine in *aginal &eli*er()
53
Ho+e*er, $he &rug is 'urren$l( no$ re'o%%en&e& for rou$ine use o+ing $o $he li%i$e&
&a$a $o suppor$ i$s 'os$2effe'$i*eness) 1he So'ie$( of Obs$e$ri'ians ang
(nae'ologis$s of Cana&a re'o%%en&s $he use of 'arbe$o'in for $he pre*en$ion of
##H ins$ea& of 'on$inous o,($o'in infusion in ele'$i*e 'aesarean se'$ion an& for
+o%en &eli*ering *aginall( +i$h one ris: fa'$or for ##H)
56
CONC#U%ION
#os$par$u% hae%orrhage is one of $he %os$ 'o%%on 'auses of %a$ernal %orbi&i$(
an& %or$ali$( +orl+i&e) #roph(la'$i' a&%inis$ra$ion of a u$ero$oni' agen$ pla(s an
i%por$an$ role in $he pre*en$ion of ##H) While $here are alrea&( nu%erous affe'$i*e
agen$s a*ailableon $he %ar:e$, ea'h agen$ has i$s o+n an& a&*an$ages an& &ra+ba':s)
While bo$h o,($o'in an& ergo%e$rine are efee'$i*e in pre*en$ing ##H, o,($o'in is
li%i$e& b( i$s shor$ &ura$ion of a'$ion, +hereas s(n$o%e$rine is asso'ia$e& +i$h
%ul$iple si&e effe'$s) Carbe$o'in is a long2a'$ing o,($o'in analogue $ha$ 'o%bines $he
safe$( an& $olerabili$( of o,($o'in +i$h sus$aine& u$ero$oni' a'$i*i$() So far, &a$a fro%
se*eral s$u&ies, in'lu&ing %e$a2anal(ses, ha*e sho+n $ha$ 'arbe$o'in is effe'$i*e an&
safe in bo$h 'aesarean an& *aginal &eli*er(, +i$h a be$$er si&e effe'$ profile) 1hese
pro%ising fin&ings sugges$ $ha$ 'arbe$o'in %a( be sui$able as $he &rug of 'hoi'e for
pri%ar( pre*en$ion of ##H)
Fur$her s$u&ies on $he 'os$ effe'$i*enes of 'arbe$o'in, 'o%pare& +i$h o$her u$ero$oni'
agen$s, an& $he use of 'arbe$o'in as a $herapeu$i' agen$ for ##H are useful areas $o be
e,plore&)