Download A double-blind randomized controlled trial of vaginal misoprostol

A double-blind randomized controlled trial of vaginal misoprostol before
outpatient hysteroscopy in postmenopausal women.
Daniela Angerame Yela, M.D., Ph.D, Fabiana Nakano, M.D.; Joao Paulo Leonardo
Pinto, MD; Talita Aparecida Riegas Mendes, MD; Lucia Helena Costa Paiva, M.D.,
Ph.D.
Department of Obstetrics and Gynecology, School of Medical Sciences, State
University of Campinas (UNICAMP), Campinas, São Paulo, Brazil.
Financial disclosure/conflicts of interest: None declared.
Correspondence:
Daniela Angerame Yela
Departamento de Tocoginecologia. Faculdade de Ciências Médicas
Universidade Estadual de Campinas - UNICAMP
Rua Alexander Fleming, 101, Cidade Universitária
CEP 13083-881 - Campinas, SP, Brazil
Telephone/fax: +55-19-3521-9306
E-mail: [email protected]
Precis: Previous use of misoprostol does not prepare the uterine cervix and fails to
decrease pain during the performance of diagnostic hysteroscopy without anesthesia in
postmenopausal women.
Abstract
Study Objective: To evaluate the efficacy of vaginal misoprostol for cervical ripening
in postmenopausal women before diagnostic hysteroscopy without anesthesia. Design:
double-blind randomized controlled clinical trial (Canadian Task Force Classification I)
Setting: Women’s Integrated Healthcare Center (CAISM) of the University of
Campinas (UNICAMP). Patients: One hundred and fifty-eight postmenopausal women
Intervention: postmenopausal women received 200µg of misoprostol or placebo by the
vaginal route before diagnostic hysteroscopy. Measurements and Main Results: The
following variables were studied: age, parity, time since menopause, associated
diseases, indication for the exam, duration of the procedure, frequency and severity of
pain during exam, need for additional cervical dilatation, adverse effects and
complications For statistical analysis, the chi-square tests of association were used.
Fisher’s exact test and the Mann-Whitney tests were used for the comparison between
groups, considering an alpha error lower than 5%. Women from both groups displayed
similar characteristics. The duration of hysteroscopy was similar in both groups: 2.5±2.7
minutes for the misoprostol group and 2.1±1.6 minutes for the placebo group (p=0.43).
Pain during grasping of the uterine cervix was rated as 3.29±3.09 for the misoprostol
group and 3.52±3.06 for the placebo group. During exam, pain was categorized as
5.27±3.52 for the misoprostol group and 5.53±3.36 for the placebo group. During
biopsy, pain was classified as 4.08±3.46 for the misoprostol group and 3.83±3.34 for the
placebo group. In both groups there was no significant difference in pain severity
(p=0.52, p= 0.69 and p= 0.68, respectively). Conclusion: Previous use of misoprostol
does not prepare the uterine cervix and fails to decrease pain during the performance of
diagnostic hysteroscopy without anesthesia in postmenopausal women.
Keywords: Hysteroscopy; postmenopausal women, misoprostol, cervical ripening.
Introduction
Hysteroscopy is commonly used in the diagnosis and treatment of intrauterine lesions
such as polyps, myomas, uterine septae and adhesions. It is also used for the evaluation
of abnormal uterine bleeding. Diagnostic hysteroscopy provides a panoramic view of
the uterine cavity, in addition to permitting biopsy of the endometrium (1,2). The
method can be performed without anesthesia. (3)
A limitation of the method is that pain may occur during the examination or
unsuccessful hysteroscopy due to stenosis of the cervical os (internal orifice) (4)
Various alternatives were used in an attempt to address the problem, including a
reduction in hysteroscope diameter and the use of local anesthesia in the uterine cervix
(5,6). Cervical ripening can be achieved by mechanical (laminaria tents) and
biochemical (prostaglandins) methods (7).
Misoprostol is a synthetic methyl-analogue of prostaglandin PGE1. Its major
advantages are thermostability, a lower risk of adverse effects and low cost, when
compared to natural prostaglandins. The main adverse effects of the drug are pelvic
cramping, diarrhea, vomiting, genital bleeding and hyperthermia (8).
The majority of studies on this subject are conducted in a well-controlled manner and
suggest favorable results with the previous use of misoprostol (9). However, evidence
on the use of misoprostol in diagnostic hysteroscopy is still scarce. Furthermore, there
are few studies involving patients who are in the postmenopausal period. Thus, the aim
of this study was to evaluate the results of the use of misoprostol or placebo for
postmenopausal women undergoing diagnostic hysteroscopy.
Material and Methods
A double-blind randomized clinical trial was conducted in postmenopausal women
undergoing diagnostic hysteroscopy without anesthesia and with previous application of
200 µg of misoprostol or placebo. Both tablets were administered by the vaginal route
for cervical ripening at the Women’s Integrated Healthcare Center (CAISM) of the
University of Campinas (UNICAMP) from September 2014 to February 2016.
One hundred and fifty-eight (158) patients were included in the study, and randomly
allocated into two groups (79 using 200µg of misoprostol and 79 using placebo).
Sample size was based on the prevalence of scores above five on the visual analog pain
scale during the procedure, in patients receiving misoprostol and placebo, observed in
previous studies of 44.6% and 66.7% (10). For calculation, an identical proportion of
patients was considered in both groups (1:1), Significance level was 5% and power of
the test was 80% for the chi-square test, resulting in n=158 cases, divided into two
groups (n=79 in each group).
Inclusion criteria were menopausal women who had an indication for endometrial
evaluation
such
as
polyps,
myomas,
endometrial
thickening
seen
during
ultrasonography, or genital bleeding. All patients signed consent term in order to
participate in the study. Exclusion criteria were genital infection, previous hysteroscopy,
women who had never had sexual intercourse, uterine malformations, women with
mental illness or women undergoing pelvic radiotherapy.
Randomization was performed with a random number computer-generated table in
Evitable, part of the Epi-Info 6.04d software program. Patients were allocated to both
study groups only after their consent terms were signed.
Envelopes sequentially numbered from 1-158 were prepared. Each number
corresponded to a 200 µg tablet of misoprostol or placebo (drug labelled A or B),
according to the random number table. The 200 µg misoprostol tablets were prepared
by Pfizer, a pharmaceutical company that also manufactured placebo tablets particularly
for the research, with shape, size, color and weight similar to the active drug.
The tablets were stored in paper envelopes and the contents were only known to the
pharmacist responsible. After study inclusion, the numbered envelope was opened to
each woman, and the main investigator inserted the tablets into the posterior vaginal
cul-de-sac of these women. Women were instructed to return to the hospital within 6
hours to undergo the examination. All procedures were performed by the main
investigator in a surgical setting, without anesthesia. In all hysteroscopies, a rigid
hysteroscope was used, based on a 2.9-mm rod-lens system with a 30-degree forward
oblique view (Karl Storz GmbH, Tuttlingen, Alemanha). The technique was applied as
described by Tantini (11). In all women a speculum was used, and a Pozzi tenaculum
forceps was used to grasp the uterine cervix. CO2 was the distension media and
endometrial biopsy was performed with a pipelle.
The duration of the procedure was measured with a Casio chronometer (Casio, Inc.,
Tokyo, Japan), starting with the introduction of the hysteroscope through the external
cervical os until its removal through the same route at the end of the procedure. The
presence and severity of pain during cervical grasping with a Pozzi tenaculum forceps,
during and after the exam was evaluated. Since pain is a subjective experience, it is
naturally hard to measure. Therefore, the use of standardized instruments is important to
overcome this problem, making it possible to compare different thearapeutic techniques.
In this study, a visual analog scale (VAS) was used, ranging from no pain to the worse
pain imaginable. The correlated numerical rating scale was printed on the back of the
scale (12).
Before the procedure, the VAS was presented to study participants, explaining the aims
and procedures for pain evaluation. The need for additional cervical dilatation and the
presence of secondary effects, including genital bleeding, nausea, vomiting, diarrhea,
and hyperthermia were recorded. Complications such as uterine perforation, false
passage, lacerations of the uterine cervix and infections were evaluated.
The present study was approved by the Research Ethics Committee of this
institution, under number 286144 and registered in REBEC (Registration of Brazilian
clinical trials).
For statistical analysis, the chi-square tests of association were used. Fisher’s exact test
and the Mann-Whitney test were used for the comparison between groups, considering
an alpha level (Type I error) below 5%. For the performance of these procedures, the
SAS computer program version 9.04 was used.
Results
Women from both groups diplayed similar characteristics relative to age, body mass
index, time since menopause, parity, number of cesarean sections, race, religion, marital
status, profession, school education and diseases associated with arterial hypertension
and diabetes (Table 1).
Indications for the performance of hysteroscopy were also similar in both groups.
Approximately 50% of the indications were due to postmenopausal bleeding and the
other half was due to endometrial thickening. The endometrial lining found on
ultrasound measured an average of 10mm for the group using misoprostol and 9 mm for
the group using placebo (p=0.65) (Table 2).
Of the 79 randomized women undergoing hysteroscopy and using misoprostol, the
exam could not be performed in 12 women due to severe stenosis associated with pain.
Of the 79 randomized women undergoing hysteroscopy and using placebo, the exam
failed to be performed in 14 women due to the same reason. Regarding pain in both
groups, the majority of women experienced pain during grasping of the uterine cervix,
during the exam and during biopsy. There was no need for cervical dilatation in the
majority of women from both groups. The group of women using misoprostol had
significantly more side effects (25.3%) than the group using placebo (2.5%). (Table 3).
The adverse effects reported were vaginal bleeding, pelvic cramping and diarrhea.
There were no complications with the use of placebo. In the misoprostol group, there
were 2 patients with lacerations and 2 with the creation of false passages (p=0.12).
The duration of hysteroscopy was similar in both groups: 2.5±2.7 minutes for the
misoprostol group and 2.1±1.6 minutes for the placebo group (p=0.43). Pain on
grasping of the uterine cervix was rated as 3.29±3.09 for the misoprostol group and
3.52±3.06 for the placebo group. During the exam, pain severity was classified as
5.27±3.52 for the misoprostol group and 5.53±3.36 for the placebo group and during
biopsy. Pain was rated as 4.08±3.46 for the misoprostol group and 3.83±3.34 for the
placebo group. In both groups, there was no significant difference in pain severity
(p=0.52, p= 0.69 and p= 0.68, respectively). (Table 4)
Discussion
Misoprostol is a medication that has been used in non-pregnant women for cervical
ripening prior to IUD insertion, endometrial biopsy, artificial intrauterine insemination
procedure and hysteroscopy (13)
Various studies show that misoprostol facilitates the performance of hysteroscopy in
women in the menacme by decreasing pain during the procedure (14, 15,16 )
There are few studies regarding this issue in menopausal women. In our study, we
found that no benefits arose from using misoprostol before diagnostic hysteroscopy
performed without anesthesia.
An Indian study with 50 postmenopausal women suggested that 200 mg of misoprostol
given by the vaginal route 12 hours before hysteroscopy, could be an effective
medication for the preparation of the uterine cervix (17). In a similar manner, a
Brazilian study with 120 women also suggested that 200mg of misoprostol administered
by the vaginal route could reduce pain severity during hysteroscopy in postmenopausal
women (10). Larger doses of misoprostol (1000mg) associated with estrogen therapy
are also thought to have an effect on cervical preparation (18).
A systematic review evaluating 17 randomized studies concluded that there was very
little evidence to recommend the routine use of misoprostol before hysteroscopy. (2). In
contrast, another review study indicated that the use of misoprostol was advantageous in
postmenopausal women before the performance of hysteroscopy only if the procedure
was performed with a 5-mm hysteroscope (6).
More recently, review sudies suggest that misoprostol should be used for uterine
cervical preparation only in women experiencing menacme, since the drug has no effect
on cervical preparation of postmenopausal women (1, 9). When used by another route,
misoprostol also seems to have no significant effect on cervical preparation. A study
with the use of 200mg of sublingual misoprostol showed that the drug does not have a
significant action on uterine cervical preparation in menopausal women(19). However,
another study using sublingual misoprostol showed its effect on the uterine cervix of
postmenopausal women during surgical hysteroscopy, i.e. misoprostol facilitated
dilatation of the uterine cervix (20).
In our study, women using misoprostol displayed significantly more adverse effects
(genital bleeding, cramping pain and diarrhea) than the placebo group. These results are
similar to those found in the literature. A review with 32 studies showed that
misoprostol has more effects than placebo (risk difference 0.07, 95% CI 0.01-0.12) (9).
However, some studies show that there is no difference between the adverse effects
reported with the use of misoprostol and placebo (p = 0.62, p=0.70) (10).
Conclusion
It may be concluded that misoprostol has no effect on cervical preparation in
postmenopausal women and thus its use is not recommended before diagnostic
hysteroscopy in this particular group of women.
References
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Table 1: Characteristics of menopausal women undergoing diagnostic hysteroscopy
with the previous use of misoprostol or placebo
Characteristics
Placebo ( n=79)
p-Value
62(8.2)
60(7.3)
0,2289
30.5(5.5)
31.2(5.4)
( mean,SD)
12(8.2)
11(8.3)
0.4470
Parity (mean,SD)
3(2.33)
3(2.11)
0.9180
1(1.13)
0(0.93)
0.3224
Race : white( n, %)
56(70.9)
48(60.8)
0.093
Religion: catolica(n,%)
45(57.0)
50(63.3)
0.5696
Marital status: married (n,%)
46(58.2)
50(63.3)
0.093
Profission: home (n,%)
36(45.6)
34(43.0)
0.8924
Schooling: elementary (n,%)
47(59.5)
43(54.5)
0.5367
Arterial hypertension (n,%)
50(63.3)
50(63.3)
1.000
Diabetes Mellitus (n,%)
18(22.8)
23(29.1)
0.3642
6(7.6)
0(0)
0.028
Age in years (mean, SD)
BMI (mean,SD)
Misoprostol ( n=79)
0.2025
Time since menopause-years
Cesarean sections (mean,SD)
Use hormonal therapy ( n,%)
SD = standard deviation; BMI = Body mass index
Fisherʹs exact test, Mann-Whitney test, X2 test
Table 2: Indications for the performance of diagnostic hysteroscopy with the previous
use of misoprostol or placebo
pIndications
Misoprostol ( n=79)
Placebo ( n=79)
Value
Abnormal bleeding (n,%)
36(45.6)
34(43.0)
0.4974
Endometrial thickening (n,%)
43(54.4)
45(57.0)
04974
10(5.1)
9(5.7)
0.6504
Endometrial thickening- mm
( mean,SD)
SD = standard deviation , Fisherʹs exact test, Mann-Whitney test
Table 3: Results of diagnostic hysteroscopy in menopausal women with the previous
use of misoprostol or placebo
Results
misoprostol
placebo
n
%
n
%
P value
RR
95%CI
Yes
12
15.2
14
17.7
0.6678
1.09 0.74-1.62
no
67
84.8
Yes
59
74.7
62
78.5
0.5730
1.12 0.75-1.65
No
20
25.3
17
21.5
Yes
67
84.8
72
91.1
0.2213
1.41 0.76-2.59
no
12
15.2
7
8.9
Yes
48
72.7
46
71.9
0.9135
0.98 0.66-1.44
No
18
27.3
18
28.1
Yes
8
10.1
7
8.9
0.7861
0.93 0.53-1.63
no
71
89.9
72
91.1
Yes
11
13.9
9
11.4
0.6323
1.13 0.68-1.88
no
68
86.1
70
88.6
Yes
20
25.3
2
2.5
˂0.0001
0.16 0.04-0.61
no
59
74.7
77
97.5
Examination not done
65
82.3
Pain of grasping of the
utrine cervix
Pain during examination
Pain of endometrial biopsy
Pain after examination
Dilatation of uterine
cervix
Adverse effects
RR = relative risk, CI = confidence interval Fisherʹs exact test, X2 test
Table 4: Duration of the exam and pain severity score (VAS) of menopausal women
with the previous use of misoprostol or placebo
Results
misoprostol
mean
placedo
SD
mean
SD
P value
Time of
examination(min)
2.5
2.7
2.1
1.6
04337
Pain of grasping of the
utrine cervix
3.29
3.09
3.52
3.06
-
-1.14-0.28
0.43
0.5297
0.27 -0.82-1.35
5.27
3.52
5.53
3.36
06953
Pain of endometrial
biopsy
95%CI
0.23 -0.74-120
Pain during
examination
RR
4.08
3.46
3.83
3.34
06887
0.25
Pain after examination
0.47
1.56
0.29
1.11
RR = relative risk ; CI, confidence interval, Mann-Whitney test
0.7201
-1.43-0.93
0.18
-0.6-0.25