Fertility and Sterility@

of symptoms and enhancement of fertility in women

with uterine fibroids. Procedures such as uterine artery
embolization (4, 5), myolysis (6), and laparoscopic
myomectomy (7) have been used in the treatment of
uterine fibroids. he most common conservati ve sur!i cal
treat ment used i n "amaica is abdominal myomectomy.
he ma#or problem wi th myomectomy i s e$cessi ve
bleedin! from increased uterine blood supply. his can be life%
threatenin!, resultin! in blood transfusions, febrile
morbidity, and potentially in loss of reproductive potential
from hysterectomy. &nowled!e of the effectiveness of the in%
terventions used to reduce blood loss durin! myomectomy is
essential to enable evidence%based clinical decisions (').
( number of trials have been carried out to assess the effec%
tiveness and safety of interventions to reduce blood loss durin!
myomectomy ()). *uch trials include intramyometrial vaso%
pressin (+,), intravenous o$ytocin (++), tourni-uets (+., +/),
chemical dissection with sodium%.% mercaptoethanesulfon ate
(mesna) (+4), intramyometrial bupivacaine plus epinephrine
(+5), and the enucleation of myoma by morcellation while it
is attached to the uterus and clampin! of the bilateral uterine
and0or ovarian arteries (+6, +7).
1n this study, we investi!ated the effectiveness of a sin!le
dose of preoperative rectal misoprostol alon! with perivascular
vasopressin compared with perivascular vasopressin alone for
the reduction of blood loss at the time of myomectomy. ( previous
study was performed in a ur2ish population of .5 women
in .,,. which investi!ated the efficacy of a preoperative sin!le
va!inal dose of 4,, (! of misoprostol in reducin! blood loss at
the time of myomectomy. hey found a si!nificant reduction in
blood loss with the use of misoprostol alone (+').
3asopressin already has been shown to decrease the
bl ood l oss at t he t i me of myomect omy (+,, +.). 1t i s
currently bein! used at the 4niversity 5ospital of the 6est
1ndies (4561) and (ndrews 7emorial 5ospital ((75) in
patients under!oin! myomectomies. 6e thou!ht that the
additive effect of misoprostol should si!nificantly improve
the outcome of myomectomies.
7isoprostol, an analo!ue of prosta!landin 8l, was re!is%
tered in many countries durin! the +)',s under the proprietary
name 9ytotec (Pharmacia) for the treatment of peptic ulcers,
particularly those caused by nonsteroidal anti%inflammatory
dru!s. 7isoprostol is now bein! used by obstetricians and !y%
necolo!ists worldwide for the evacuation of the uterus for
missed abortions, intrauterine deaths, induction of labor (+)),
and more recently the prevention of postpartum hemorrha!e
(.,). 1ts popularity especially in developin! countries such as
"amaica maybe accounted for by the fact that it is able to pro%
duce powerful uterine contractions (.+) and lead to a reduction in
myometrial hemorrha!e, while at the same time bein! ine$pensive
and easy to store. 6e chose to investi!ate the use of misoprostol in
a lar!er subset of patients than previously studied in ur2ey (+')
in con#unction with vasopressin in a "amaican population with a
hi!h incidence of myomectomies (+,, ..).
MATERIALS AND METHODS
8nrollment for the study commenced in :ebruary .,,5 and was
completed by (pril .,,5. ( sample size of .5 in each !roup
would allow us to detect a + standard deviation difference
in mean blood loss between the two !roups with ),
0
/ b
power and an alpha of 5;. 6e enrolled 5, informed
premenopausal women in the study althou!h only 45 of these
cases could be analyzed as a result of missin! data for five cases.
hese women were chosen by invitin! patients to participate who
were scheduled to under!o myomectomy for symptomatic uterine
fibroids from the !ynecolo!y clinic at 4561 and from the private
practice of the participatin! doctors. hey were included in a ran%
domized, prospective, double%blind study, and were re-uired
to !ive informed consent before participation.
he e$clusion criteria included patients who had a previ %
ous myomectomy or previous pelvic sur!ery, those who were
severely anemic or had si!nificant medical conditions such as
cardiac or pulmonary disease, those who refused to !ive con%
sent for the procedures, and those with 2nown aller!ies to any
of the studied dru!s.
1nstitutional review board approval for the protocol of
this study was obtained by the 4niversity of the 6est 1ndies
ethics committee in .,,5, number 89P +.,.,,/0.,,4. here
are no conflicts of interest pertainin! to any of the authors.
( preoperative evaluation was performed to ensure that
no medical conditions precluded the use of vasopressin
(such as heart disease) or the use of misoprostol (such as pre!%
nancy). ( history was also obtained from all the patients to
establish their symptoms as well as their fertility status. *oci%
odemo!raphic and clinical factors also were recorded such as
a!e parity, body mass inde$, blood pressure, pulse rate, temperature,
and size of the uterus. <ther preoperative variables included
hemo!lobin, hematocrit, white blood cell count, and platelet
count.
he patients were randomized to receive or not to receive
4,, =! of preoperative rectal misoprostol /, minutes before sur%
!ery. >ru! administration was determined usin! a table of
random numbers, and at the end of the study the code was
bro2en to see which patient had received the assi!ned treatment. (ll
the patients enrolled and scheduled for myomectomy had a rectal
e$amination, but only half received the misoprostol. he rectal
e$amination was performed with copious amounts of
lubricant so that the patients did not 2now who was receivin!
the dru!. >ru! administration was performed by the interns on
the ward, and the sur!eons performin! the operation were blinded as
to who had received the dru!. he interns did not participate in the
postoperative mana!ement of the patients.
<ne ampule of vasopressin containin! ., units in + ml
was diluted in +) ml of normal saline. his was in#ected peri%
vascularly around vessels in the broad li!ament before the
myomectomy in all patients.
he sur!eons were as2ed to limit the number of incisions
to only one anteriorly and or posteriorly, if possible. 1f neces %
sary, hysterectomy was performed for complications such as
blood loss ? / liters. 4terine defects were closed in three
layers usin! poly!lactin sutures with round body needles
/ O R I G I N A L A R T I C L E : G Y N E C O L O G Y A N D ME N O PAU S E
TABLE 1
TkWsocwcWnoga characteristicses of the

sa!"e#
i
$i
WWSN%1229~
foca fi&!
'()$*+
( , I - I - # Ur g e s t . a i n e r / !0 1Si2e o$fiart.t,+ai3 te
a- @% (-$- % .1 . . I - I
- in("re
%W- 4r5# 06e#
*
gnanc7---W&0-
T+ta--87-ei-ghtof,M17o!as#/90-a-:-
N:!;er of :terine incisions-
A3hesionS;
No1 -
Y e s
En3o!etriosis; ;
No
Yes
Da!age3- t:;esb
No-
<aso"ressin on7 /n 2!
*=* (()+0,3+1)%
29-) =% 5-20`=_
9.5 />? >>0
'.4 A /.' ,
22 /." >+0?:1
)@) /2@# 2#9**0
2 /$# >0
$
@
@
$9-
$+
)
Miso"rosto =~8aso"resAinl
35,01f;5.1..-
Z.,
.7
. /2
-
B''0
'-2 )-*
-$+** 220
-->*'--@ /'@? >#@)+0-
2-(/$#>0
'
-

is :
'
22 >
2)
# 2 $ ! P v a l u e .
C*
NS
NSi
NS
NS -
*@@
NS
NS NS
NIS.,
NS
NS
NS
NS
Note:.Valves are meant stanar ev!at!"n #1)), $nless n"te otherwise. '
Val$es a!e me!an (m!n ma%).
b Values are &"$nts. . - . .
Fredenck. Misoprostol reduces blood loss at myomectomy. Ferri! Sterti [ 013.
the procedure, but those used were also included for esti %
matin! additional blood loss. <$idized re!enerated cellulose
film was used to cover the uterine incisions as prophyla$is
a!ainst adhesions. 1ntraoperative and postoperative antibi %
otics were routinely used. 1ntraoperatively, the patientsD pulse,
blood pressure, electrocardio!raphic chan!es, need for blood
transfusion, and need for hysterectomy were monitored. he
decision to transfuse was made by the anesthesiolo!ists,
and this was usually based on a blood loss of . liters or
more or if there was cardiovascular instability if the blood
loss was less.
Postoperatively, the blood loss, the size of the lar!est
fibroid, wei!ht of the fibroids removed, and the number of fi %
broids were chec2ed. <n the ward, the postoperative blood
counts were performed, and the hi!hest postoperative pulse
and temperature and the need for transfusion were recorded.
:ebrile morbidity was defined as core body temperature over
/'E9 within 4' hours after sur!ery.
Statistica Ana7sis
3alues were e$pressed as counts, mean A standard deviation
(*>1. the !eometric mean with )5; confidence interval (91),
or the median with ran!e as appropriate. he distribution of
blood loss was ri!ht s2ewed, and this was normalized by
Capier lo!arithmic transformation. >escriptive statistics
were performed in the sample to e$amine the baseline
differences in continuous variables and associations between
cate!orical variables by treatment groups. An
independent t%test was used to compare the mean of continuous
variables, and the 7ann%6hitney test was used to compare
the distributions of skewed continuous variables
between treatment groups. >ifferences between
cate!orical variables and treatment groups were
tested with the chi%s-uare statistic.
he primary outcome of this study was to determine the
difference in blood loss in a sample of women treated with
vasopressin only vs. vasopressin and misoprostol. he sec %
ondary outcome was to determine whether there was a differ %
ence in perioperative morbidity in the vasopressin%only !roup
compared with the vasopressin and misoprostol !roup. 6e
performed multivariate linear re!ression analysis to -uantify
the treatment !roup differences on the primary outcome vari %
ables, ad#ustin! for clinical and operative variables.
RESULTS
6e found no statistically si!nificant difference in baseline so%
ciodemo!raphic or baseline clinical characteristics between
the two groups (P?.,5) (ables +, ., and /). 1mportantly, the
characteristics of the myomas, such as the total number of
myomas and t he si ze of t he l ar!est myoma, were not
different between the !roups (ables + and 4). he number
of uterine incisions was not different between the groups
(P=.7) (Table 1).
Flood loss, however, was statistically si!nificantly lower in
the !roup of women who received misoprostol and vasopressin
compared with the !roup of women receivin! vasopressin only.
9onsistentwith this findin!, the chan!e in hemo!lobin concen%
tration was greater in the vasopressin %only treated
!roup compared with the !roup treated with vasopressin plus
misoprostol (PG.,.). 1n the misoprostol plus vasopressin
!roup, no patient re-uired blood transfusions. 1n the
vasopressinonly !roup, five patients re-uired blood transfusions
in the postoperative period. his difference in proportion
between the two groups was statistically
signifcant (P<.02).
(lthou!h the chan!e in preoperative and postoperative
pulse after .4 hours was not stat isti call y
signifcantly different, the mean postoperative pulse
was statisticall y signifcantly diferent between
the two groups (P<.05). The diference in febrile
morbidity between the two groups was not
statistically signifcant. There was no
I rkAr I
<OL- $** NO- ) B OCTOCER
Fertility and Sterility
TABLE 2
%lood loss and &osto&erati'e &atient c(aracteristics)
*aso&ressin only+,n =
2!Blood loss (m0'
n Transfusio n
N!"
#
$#%!&l!in
'&/()
*+#!,#+-.i/#*
!0.!,#+-.i/#1
2-n&#
W2i.# l!!( 3#ll
3!4n. 5'l#6
*+#!,#+-.i/#*
!0.!,#+-.i/#1
2-n&#
*l-.#l#.0
5'1096A-
*+#!,#+-.i/#*
!0.!,#+-.i/#1
2-n&#7*4l0#+-.
#
*+#!,#+-.i/# 83 9 13
Af.#+ 2: 2 100 9 1
12-n&# -f.#+ 2: 2
&
-1; 9 2
Af.#+ :8 2 101 ( 1
12-n&# -f.#+ :8 2
&
-18 9 19
Note: Val$es are mean ( stanar ev!at!"n (SI)). NS n"t stat!st!&all* s!gn!+!&ant.
Val$es are ge"metr!& mean ,!t- 95% &"n+!en&e !nterval (0).
; Val$es are &"$nts.
&
.-an&e var!ables &al&$late as t-e !++eren&e bet,een be+"re an a+ter t-e s$rger*/ (0re"1 - 0"st"1).
Fred-rck. Mt5oprostolreduces brood loss at myomectomy. Ferri! Stent 2013.
9 1.
9
3.0 9 2-
1
9 1-
<=-
3.;-2.9 9
:.
9
;0.5212.3,
2!s"1r"-t"l + vas"1ress!n (n 25)
>23 '35: .! 1,09:6 33: '2>1 .!
:28
25
0
val$eval$e
3.03
11.; 9
0.810.1
9 1.51.6
9 1.
NS
NS
3.02
6.6
3A9.5 9
3.2-3.: 9
3.
2>8 9
61.223; 9
55.12;.1
82.; 9 9.
91 9 11-
8 9 1
92
?11.%10-
1$
N
S
N
N
S
N
S
N
NS
@.05 'NS6
NS .
05:
NS
DISCUSSION ine artery to induce vasoconstriction,
producin! a second
<ur study supports the efficacy of the additive effect of miso%
mechanism throu!h which this dru! can act. Hectal misopros%
prostol to vasopressin in reducin! blood loss at the time
oftol was administered appro$imately 1 hour before
sur!ery, myomectomy. 6e found that when misoprostol was
com%the duration of action is appro$imately 4 hours (.4),
e$ertin! bined with vasopressin, the blood loss at the time of
sur!ery, uterine contractions for the e$tent of the sur!ical procedure
the need for transfusion, and the chan!e in hemo!lobin were
a n d d u r i n ! t h o s e c r u c i a l
TABLE 3
-.lood &ress/re0 tem1erat$re, an +ebr!le m"rb!!t*.
*aso&ressin "nl * ( n 20
,erp ra %"c1- DL4
,,45r . eo
I
&
A1ter
"2 h
6+ter). hT
...
.78l""
.
1ress$+!.E-(rrm.9#)
Fighest s*st"l!&
g est-!a6:!;
. e s ' s * s t " l ! & 7
-7
.
1>A#0.
(i-0.!li3
2Val$es
r
1re
&"$nts
> -$ :L 0.#
$)>E(((G
n09#311
hbodfoB, at m*"m< '01
Variable
thetimeofmyomectomywhencomparedwithplacebo(+,)
0.NS *-)NS
NsS
0
-
NS
1/ ORI GI NAL ARTI 1LE< G"NE1OLOG" ANB
CENO*ADSE
to myomectomy for reducing blood loss and the subsequent
risk of symptomatic anemia or transfusion.
o3e 'aria4le lo5 o1)4lood loss))
Lo)W06 5r)00)7))I8)&&er
.
tficient value : 9$: ;l 9$:);l
-
d i a r r i e
2 . 0 5
Thefibroid,
L 6 4 < o
f t i u m
)<9
f + vas!"1ressi~ Misoprost
olQ.59
=<
)
. . . 0 .
2 2
N"te7 /6=#>e&r?2 <<,.##. @"g ra1!eri
er rp
Frederick: Misoprostol reduces blood
od at myomectomy.Fertul Steril 013.
and when compared with a tourniquet placed around the
lower uterus to occlude the uterine vessels (12).
Although misoprostol in gynecology has not yet gained
widespread use and acceptance, it has advantages over other
interventions to reduce blood loss at myomectomy. These ad-
vantages include lower cost (average US$21box), thermto and
light stability, and a shelf-life of several years even in tropical
conditions. It is easy to use, is independent of any blood pres%
sure side%effects, and is not related to any bronchoconstrictive
action to the lun!s (as it is bronchodilatory). he more com%
mon side effects of a 4,, (! dose of misoprostol include chills
(+7./;), nausea and vomitin! (+,..;), headache and verti!o
(7. +;), abdominal pain (7).6;), and diarrhea (4.+;) (.4).
6hen compared with interventions such as preoperative
use of !onadotropin%releasin! hormone (InH5) analo!ues
and perivascular use of vasopressin, misoprostol side effects
are far less disturbing, and most of the side effects are seen
within 90 minutes of administration (25). In our study,
these side effects were more li2ely to occur while the patient
was under anaesthesia and hence were not clinically si!nificant.
4se of InH5 analo!ues has been restricted in our settin!,
!enerally only to decrease the myoma volume preoperatively
and hence reduce intraoperative blood loss (.6). 5owever, it is
believed by some that this theoretical advanta!e may be lost
throu!h a decrease in the distinction between the capsule and
myomet ri um, ma2i n! enucl eat i on di ffi cul t and hence
increasin! blood loss. he ma#or advanta!e of InH5 ana%
lo!ues is in their ability to reduce menorrha!ia and optimize
the patientDs hemo!lobin status before sur!ery.
3asopressin has been safely used at a dose of ., units in
+) mJ of normal saline at the time of myomectomy (+,, .5).
5owever, it is important that the sur!eon avoids intravascular
in#ection of vasopressin as this has been associated with
severe hypotension secondary to coronary artery spasm (.7).
There was no diference in febrile morbidity between the
two groups. Shivering and hyperpyrexia are reported as side
efects associated with orally administered misoprostol at
dosa!es of 600 Ag and Boo pg. These side efects have been
reported at a much lower incidence with the rectal and
vaginal routes (28).
The use of misoprostol plus vasopressin vs. vasopressin
alone in this randomized, double-blind, controlled trial
comparing blood loss during abdominal myomectomy
showed a statistically signifcant beneft to using misoprostol.
There was no statistically signifcant febrile morbidity associ-
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