Keywords
hysteroscopy - misoprostol - complications - side effects
Palavras-chave
histeroscopia - misoprostol - complicações - efeitos colaterais
Introduction
The hysteroscopic procedure emerged ∼ 200 years ago, providing the direct visualization
of diffuse or focal uterine abnormalities, the anatomical configuration of the cervical
canal and the uterine cavity, path permeability, access for biopsies, and direct removal
of lesions.[1]
[2]
[3] It is considered a minimally invasive procedure, and its use is quite common both
in the diagnosis and in the treatment of several conditions, such as abnormal uterine
bleeding, the evaluation of infertile patients, surgeries including myomectomy and
polypectomy, the diagnosis of endometrial and endocervix hyperplasia and carcinoma,
among others, often being performed in clinics or as outpatient follow-up procedures.[1]
[2]
[3]
[4]
[5] This method has an important advantage over other diagnostic techniques: the anatomopathological
confirmation of lesions visually identified through guided biopsy.[4]
In order to carry out the procedure, it is often necessary to dilate the cervix, especially
in surgical hysteroscopies in which the equipment for performing the procedure is
larger than the endocervical canal.[6] The most frequent causes of unsatisfactory exams are cervical stenosis, pain or
patient intolerance, bleeding that hinders hysteroscopic view, and technical difficulties.[7] In an attempt to reduce these technical problems and the number of unsatisfactory
exams, several methods of cervical dilation have been developed over the years, such
as the use of hydrophilic laminators, bladder catheter balloons, and Hegar dilators.
These techniques, however, cause great discomfort to patients and increase the risk
of complications during the dilation process.[3]
[4]
[5]
[8] The complication rate varies between 0.3 and 5% according to the definition used,
the most common being pain, vagal reaction, uterine perforation, false passage formation,
and cervical lacerations. Serious complications, such as organ perforation and pelvic
infection, are seldom reported.[7]
[9]
Therefore, there was a need to develop new methods of cervical dilation, which should
include cervix preparation for a limited time, acceptable for the patient, with ease
of administration, quick action, and providing adequate cervical ripening to facilitate
the procedure. Misoprostol is one of the most studied agents in this context.[10] It is a synthetic analog of prostaglandin E1 that has been used for cervical preparation
prior to performing hysteroscopy because it promotes effective cervical ripening,
as well as being an inexpensive, easy to store and administer, and widely available
method.[4]
[5] The most common adverse effects of misoprostol occur mainly before the procedure
and include cramping, abdominal and/or pelvic pain, nausea, changes in intestinal
transit, vaginal bleeding of varying intensity, and fever and/or chills. However,
these effects are generally described as tolerable and rarely motivate the cancellation
or alteration of the procedure.[11]
[12]
According to the scientific literature, misoprostol is effective in cervical ripening
in the preoperative period of hysteroscopy, reducing the time needed for cervical
dilation and increasing the mean cervical diameter. Nevertheless, the optimal dose,
the route of administration, and the ideal time of administration prior to hysteroscopy,
in addition to whether the drug reduces the rates of pre- and postmenopausal complications,
remain unclear, a fact that justifies the importance of carrying out the present study
in daily gynecological practice, whose objectives were to assess the ease of the operative
hysteroscopic technique with the use of misoprostol, evaluated by the complete performance
of the steps of the procedure, to assess the presence of side effects with the use
of the drug, and to analyze the occurrence of hysteroscopic complications with its
use.[5]
[8]
Methods
The present analytical, observational, case-control study was conducted by reviewing
the medical records of patients followed up at the Gynecological Videoendoscopy Sector
of the HCFMRP – USP in the period from 2014 to 2019. Using a list provided by the
Medical Support Service (SAME, in the Portuguese acronym), a total of 508 patients
with prescriptions for the drug misoprostol for intrahospital use at the HCFMRP– USP
were identified in the analyzed period. By cross-referencing the data of patients
followed-up at the Gynecological Videoendoscopy Sector of the same hospital and who
had used misoprostol prior to hysteroscopy, 207 patients were identified. The medical
records of these 207 patients were reviewed, evaluating: age, parity, type of delivery,
time since menopause, associated diseases (systemic arterial hypertension [SAH], type
2 diabetes mellitus [DM2], obesity, and other comorbidities), use of continuous medication,
symptoms, postmenopausal bleeding, presence of endometrial thickening, side effects
of the drug, procedure complications, and complete performance of the procedure. Among
the total patients, 74 lacked data in their medical records or had their hysteroscopy
procedures suspended for various reasons unrelated to the use of misoprostol or to
the procedure itself and were therefore excluded. The 133 patients included in the
study were compared with another 133 age-matched patients also followed-up at the
Gynecological Videoendoscopy Section of the HCFMRP – USP who underwent hysteroscopy
procedures but who did not use misoprostol previously (control group), regarding the
ease of the technique, considered easy when all steps of the hysteroscopy procedure
were carried out completely, the presence of side effects, and the occurrence of complications.
Patients who used misoprostol before the hysteroscopy did so by vaginally introducing
2 tablets of 200 micrograms (µg) each the night before the procedure, totaling a single
dose of 400 µg.
After filling out the study database, which evaluated age, parity, type of delivery,
time since menopause, associated diseases (SAH, DM2, obesity, and other comorbidities),
the use of continuous medication, symptoms, postmenopausal bleeding, presence of endometrial
thickening, drug side effects, procedure complications, and its complete performance,
a statistical analysis was carried out using SPSS Statistics for Windows, Version
17.0 (SPSS Inc., Chicago, IL, USA). The distribution of the variables was assessed
using the Kolmogorov-Smirnov test. Normally-distributed data were analyzed with the
t-test, while abnormally distributed data were evaluated using the Kruskal-Wallis test.
Mean values were presented with statistical significance (SS), which was accepted
for p < 0.05. Numerical data were presented as mean ± standard deviation (SD) or median
and range, depending on their distribution. The chi-squared test was used for variables
expressed as percentages, considering a significance level of p < 0.05.
Since this was a retrospective study involving medical record analysis, the Research
Ethics Committee of the HCRP – USP was asked to waive the application of informed
consent through a Letter of Exemption from the collection of the consent form, given
most of the patients were no longer being followed-up at the hospital. The present
study, as well as the waiver of written informed consent, were approved by the Research
Ethics Committee (REC) of the HCRP – USP on February 17, 2020, under CAAE Protocol
No. 28983920.0.0000.5440. All ethical precepts were followed as recommended by the
Helsinki Convention.
Results
Regarding the clinical characteristics of the studied patients, no significant difference
was observed between those who used misoprostol or not prior to the hysteroscopy procedure
in relation to age (p = 0.9005), the number of pregnancies (p = 0.4586), the number of vaginal deliveries (p = 0.5531), the time since menopause (p = 0.9193), history of previous cesarean delivery (p = 0.8723), or regarding the number of prior abortions (p = 0.8528) ([Tables 1] and [2]). When analyzing the comorbidities presented by the patients at the time of hysteroscopy,
we observed a significant difference in relation to SAH (p = 0.0041), but not regarding DM2 (p = 0.0622), obesity (p = 0.5082), or other comorbidities (p = 0.3510). The fact that the patients used continuous medications for these comorbidities
also did not differ significantly between the 2 groups (p = 0.3023) ([Table 2]).
Table 1
Clinical characteristics of the studied population
|
With misoprostol
|
Without misoprostol
|
p-value
|
|
Mean ± SD
|
Mean ± SD
|
|
|
Age (years old)
|
60.08 ± 8.5
|
59.95 ± 8.15
|
0.9005
|
|
Pregnancy
|
3.44 ± 1.96
|
3.24 ± 2.47
|
0.4586
|
|
Vaginal delivery
|
2.13 ± 2.17
|
1.96 ± 2.37
|
0.5531
|
|
Time since menopause
|
10.98 ± 7.48
|
11.08 ± 8.22
|
0.9193
|
Abbreviation: SD, standard deviation.
Table 2
Clinical characteristics of the studied population
|
With misoprostol
|
Without misoprostol
|
p-value
|
|
n (133)
|
%
|
n (133)
|
%
|
|
|
Cesarean delivery
|
|
|
|
|
0.8723
|
|
0
|
61
|
45.86
|
69
|
51.88
|
|
|
1
|
33
|
24.81
|
27
|
20.30
|
|
|
2
|
23
|
17.29
|
23
|
17.29
|
|
|
3
|
15
|
11.28
|
13
|
9.77
|
|
|
4
|
1
|
0.75
|
1
|
0.75
|
|
|
Miscarriage
|
|
|
|
|
0.8528
|
|
0
|
99
|
74.44
|
99
|
74.44
|
|
|
1
|
24
|
18.05
|
23
|
17.29
|
|
|
2
|
8
|
6.02
|
6
|
4.51
|
|
|
3
|
1
|
0.75
|
2
|
1.50
|
|
|
4
|
1
|
0.75
|
2
|
1.50
|
|
|
5
|
0
|
0.00
|
1
|
0.75
|
|
|
SAH
|
|
|
|
|
0.0041
|
|
Yes
|
111
|
83.46
|
91
|
68.42
|
|
|
No
|
22
|
16.54
|
42
|
31.58
|
|
|
DM2
|
|
|
|
|
0.0622
|
|
Yes
|
63
|
47.37
|
48
|
36.09
|
|
|
No
|
70
|
52.63
|
85
|
63.91
|
|
|
Obesity
|
|
|
|
|
0.5082
|
|
Yes
|
44
|
33.08
|
39
|
29.32
|
|
|
No
|
89
|
66.92
|
94
|
70.68
|
|
|
Other comorbidities
|
|
|
|
|
0.3510
|
|
Yes
|
89
|
66.92
|
96
|
72.18
|
|
|
No
|
44
|
33.08
|
37
|
27.82
|
|
|
Continuous use of medications
|
|
|
|
|
0.3023
|
|
Yes
|
127
|
95.49
|
123
|
92.48
|
|
|
No
|
6
|
4.51
|
10
|
7.52
|
|
|
Menopause
|
|
|
|
|
1.0000
|
|
Yes
|
123
|
92.48
|
123
|
92.48
|
|
|
No
|
10
|
7.52
|
10
|
7.52
|
|
|
Symptoms
|
|
|
|
|
<0.001
|
|
Yes
|
124
|
93.23
|
96
|
72.18
|
|
|
No
|
9
|
6.77
|
37
|
27.82
|
|
|
Postmenopausal bleeding
|
|
|
|
|
<0.001
|
|
Yes
|
124
|
93.23
|
92
|
69.17
|
|
|
No
|
9
|
6.77
|
41
|
30.83
|
|
|
Endometrial thickening
|
|
|
|
|
0.6419
|
|
Yes
|
124
|
93.23
|
122
|
91.73
|
|
|
No
|
9
|
6.77
|
11
|
8.27
|
|
Abbreviations: DM2, diabetes mellitus type 2; n, number of samples; SAH, systemic arterial hypertension.
Both groups had the same number of patients before and after menopause, with no difference
in hormonal status in relation to the use of misoprostol (p = 1.000). The presence of symptoms reported by the patients for the indication of
the hysteroscopic procedure showed a difference between the 2 groups (p < 0.001); 93.23% of the patients in the group that used misoprostol had at least
1 symptom versus 72.18% of the patients in the control group. Among the most reported
symptoms was postmenopausal uterine bleeding, which also showed a significant difference
between the 2 groups (p < 0.001); 93.23% of the patients in the group that used misoprostol had this symptom
versus 69.17% of the patients in the control group. Meanwhile, asymptomatic endometrial
thickening showed no statistically significant difference between the 2 groups (p = 0.6419). Regarding the adverse effects observed in the patients who used the drug
prior to hysteroscopy, only 2 patients (1.5%) reported symptoms: both presented tremors,
and 1 presented with symptoms of anxiety. Although no significant difference was observed
in relation to the occurrence of complications during the procedure (p = 0.0662), a higher total number of complications was observed in the group that
used misoprostol (n = 7; 5.26%) compared with the group that did not (n = 1; 0.75%), which is clinically relevant. In the control group, the only reported
complication was false passage formation. Meanwhile, in the group that used misoprostol,
the most frequent complication was the absence of uterine cavity distension, which
was observed in three of the patients. The other observed complications included cervical
laceration (n = 1), uterine perforation (n = 2), and increased fluid absorption (n = 1), the latter 2 of which compelled the termination of the procedure. In the group
of patients who used misoprostol, false passage formation was not reported ([Table 3]).
Table 3
Complications reported after the hysteroscopy procedure
|
With misoprostol
|
Without misoprostol
|
p-value
|
|
n (133)
|
%
|
n (133)
|
%
|
|
|
Complications
|
|
|
|
|
0.0662
|
|
Yes
|
7
|
5.26
|
1
|
0.75
|
|
|
No
|
126
|
94.74
|
132
|
99.25
|
|
|
Uterine Cervical Laceration
|
|
|
|
|
0.9999
|
|
Yes
|
1
|
0.75
|
0
|
0
|
|
|
No
|
132
|
99.25
|
133
|
100
|
|
|
Absence of uterine cavity distension
|
|
|
|
|
0.2619
|
|
Yes
|
3
|
2.26
|
0
|
0
|
|
|
No
|
130
|
97.74
|
133
|
100
|
|
|
Uterine perforation
|
|
|
|
|
0.5079
|
|
Yes
|
2
|
1.50
|
0
|
0
|
|
|
No
|
131
|
98.50
|
133
|
100
|
|
|
Increased fluid absorption
|
|
|
|
|
0.9999
|
|
Yes
|
1
|
0.75
|
0
|
0
|
|
|
No
|
132
|
99.25
|
133
|
100
|
|
|
False passage
|
|
|
|
|
0.9999
|
|
Yes
|
0
|
0
|
1
|
0.75
|
|
|
No
|
133
|
100
|
132
|
99.25
|
|
Abbreviation: n, number of samples.
Finally, upon evaluating the technical ease (performing all steps of the procedure),
we noted that although there was no difference between groups (p = 0.0586), the control group had more than twice as many incompletely performed procedures
(n = 17) when compared with the group that used misoprostol previously (n = 8), which is clinically relevant.
Discussion
The present study compared 133 women who used misoprostol prior to hysteroscopy with
133 who did not use the medication. This drug is a prostaglandin E1 analog oxytocin
that causes changes in the physicochemical structure of cervical collagen. After its
administration, misoprostol undergoes de-esterification in the liver into misoprostolic
acid. This active metabolite exerts direct action on prostaglandin receptors, leading
to the softening and ripening of the cervix, favoring its dilation, in addition to
promoting an increase in intracellular calcium, which is responsible for the contraction
of uterine muscles.[13] All of these mechanisms enable progressive cervical effacement and dilation.[4]
[5]
The systematic review of misoprostol suggests variations in the plasma concentration
of this drug depending on the route of administration. Orally, the drug is rapidly
and completely absorbed in the gastrointestinal tract; however, it is also quickly
and extensively metabolized into its acidic form in the first hepatic pass (de-esterification).
A single 400-µg dose of oral misoprostol reaches its peak concentration in 30 minutes
and declines in ∼ 120 minutes, remaining at a low level. After vaginal administration,
on the other hand, there is a gradual increase in the plasma concentration of misoprostol,
reaching a maximum level after 70 to 80 minutes, followed by a slow decline, with
the drug level still detectable after 6 hours. It has also been reported that the
mean concentration peak via the sublingual route is higher than that achieved via
the oral and vaginal routes, which is due to the rapid absorption by the sublingual
mucosa, avoiding first-pass metabolism in the liver. When administered rectally, the
absorption curve of the drug is similar to that seen when using the vaginal route.[14]
Corroborating another study carried out with 77 women between January 2005 and March
2006, we did not observe a significant difference in age and the number or type of
previous births between the study group and the control group.[15] Although no significant difference was found in the present study regarding pre-
and postmenopausal patients, some studies suggest that the use of misoprostol is more
effective in dilating the cervix of premenopausal patients, mainly due to the hormonal
difference between these women.[4] Regarding the comorbidities presented by the patients at the time of the procedure,
only SAH showed significance.
In our study, postmenopausal uterine bleeding was the most prevalent symptom, observed
in 93.23% of the patients in the study group and in 69.17% of those in the control
group. A case review coordinated by Gimpelson et al.[16] revealed a high incidence of abnormal bleeding, which was observed in 76% of the
cases as the chief complaint of patients to undergo hysteroscopy. In addition, a descriptive,
cross-sectional study with 26 women showed that the primary complaint of 65.3% of
the patients was uterine bleeding.[17]
The occurrence of adverse effects to the use of misoprostol was reported by only 2
patients (1.5%), who presented tremors and anxiety. A meta-analysis evaluating 14
studies showed that significantly more adverse effects were reported when misoprostol
was administered compared with procedures without previous use of the drug (odds ratio
[OR] = 3.56; 95% confidence interval [CI]: 1.60–7.93).[18] Two other studies described the incidence of adverse effects among women randomized
to 200 or 400 μg of misoprostol, but their data were conflicting: the first did not
demonstrate a dose-related increase in adverse effects (nausea and abdominal pain)
in women randomized to 200 or 400 μg (p = 1.0 and p = 0.055, respectively); however, the second study showed a significant increase in
the number of adverse events related only to 400 μg (p = 0.015), such as fever, abdominal pain, diarrhea, nausea, vomiting, and vaginal
bleeding.[18] Regarding the administration time, these studies showed that there was no significant
difference in the incidence of abdominal cramps (p = 0.64), nausea (p = 0.79), diarrhea (p > 0.99), genital tract bleeding (p = 0.62), and fever (p > 0.99) among women who received misoprostol 12 hours or 3 hours before hysteroscopy.[18] One study with 160 women comparing oral, sublingual, and vaginal administration
of the drug concluded that the 3 groups were comparable, and all the adverse effects
were similar in all groups and were tolerable. This result is in line with a recent
meta-analysis that analyzed 7 randomized, controlled studies involving 568 individuals,
evaluating the use of misoprostol in surgical hysteroscopy. Compared with the placebo
group, there was an increase in side effects (cramps, vaginal bleeding, nausea, and
diarrhea) in the misoprostol group (relative risk [95%CI]: 4.28 [1.43–12.85]).[19]
[20]
The incidence of complications in our study was low compared with the mean described
in the literature.[9] A total of 7 complications occurred in patients who had previously used misoprostol
(5.26%) and in 1 patient who did not use the medication (0.75%). The primary complication
reported among patients who used misoprostol was the absence of uterine cavity distension,
which occurred in 3 patients. This was also found by Batukan et al.[15] in a randomized, double-blind, placebo-controlled study carried out with the objective
of evaluating the efficacy of 400 µg of misoprostol 10 to 12 hours before surgical
hysteroscopy in premenopausal women, via the vaginal route. One of the reported disadvantages
of vaginal administration was excessive cervical dilation, resulting in difficulty
distending the uterine cavity due to fluid leakage through the cervical canal.[8] Another study, prospectively conducted between January 2005 and March 2006 at the
Department of Obstetrics and Gynecology of the Faculty of Medicine of Erciyes University,
with 77 women, showed that vaginal administration of misoprostol (400 μg) prior to
operative hysteroscopy in premenopausal women was superior to the same dose of orally
administered misoprostol. The complication rates during cervical dilation, as well
as drug side effects, were comparable between the two regimens. Fluid leakage caused
by excessive cervical dilation and effacement appeared to be the most important potential
disadvantage of vaginal misoprostol. Since the intrauterine pressure did not reach
the ideal desired level in these cases, the uterine distension was suboptimal and,
therefore, the procedure was more difficult.[15]
In the present study, the other complications observed in patients who used misoprostol
were cervical laceration (n = 1; 0.75%), uterine perforation (n = 2; 1.5%), and increased absorption of distension media (n = 1; 0.75%). The patient who did not use misoprostol presented false passage formation
as a complication. In a study carried out at Bringham and Women's Hospital, located
in Boston, MA, USA, Propst et al.[21] verified a total number of 925 surgical hysteroscopies between 1995 and 1996, with
the occurrence of complications in 2.7% of the patients. Among these complications
was cervical laceration, which was present in all cases. In another study carried
out by Jansen et al.,[22] in which 13,600 hysteroscopies in 82 hospitals in the United States were evaluated
in 1997, as well as in the study by Agostini et al.,[23] performed in Marseille, France, in which 2,116 surgical hysteroscopies between 1990
and 1999 were analyzed, the most frequent complication among the surgical procedures
was uterine perforation, with 0.76% and 1.61% of cases, respectively.[22]
[23] The study by Propst et al.[21] also reported complications related to uterine distension media in 1.4% of the surgical
hysteroscopy cases. In a randomized, controlled, double-blind study conducted by Oppengard
et al.,[24] in which each participant received 1,000 µg of misoprostol or placebo, which was
self-inserted vaginally at least 12 hours before operative hysteroscopy, there were
a total of 9 (11%) complications reported.
Regarding technical ease, which was evaluated by the complete performance of all steps
of the procedure, we observed that although there was no statistically significant
difference, the number of patients who did not use misoprostol and did not undergo
the complete procedure was more than double in relation to the patients who used the
medication (8 patients who used the drug versus 17 patients who did not), which is
of substantial clinical relevance. Fernandez et al.[25] reported in a larger series that the administration of 400 µg of oral misoprostol
12 or 24 hours before surgery or 200 µg of vaginal misoprostol 9 to 10 hours before
surgery, respectively, demonstrated greater ease of cervical dilation. However, to
date, no placebo-controlled trials have shown a significant decrease in the rate of
serious complications such as cervical laceration or perforation.[25]
The prospective study conducted between January 2005 and March 2006 at the Department
of Obstetrics and Gynecology of the Faculty of Medicine of Erciyes University showed
that vaginally administered misoprostol (400 µg) prior to operative hysteroscopy in
premenopausal women was superior to the same dose of orally administered misoprostol
in terms of shorter cervical dilation and surgery duration, as well as the need for
cervical dilation for No. 9 Hegar.[15] Other previous studies comparing patients who used misoprostol or placebo previously
to prepare the cervix, as evidenced by Uckuyu et al.[26] in Ankara, Turkey, also show a relevant rate of failure in dilation with Hegar dilators,
especially in patients who had had previous cesarean sections. In the aforementioned
study, the reported failure rate of cervical dilation using Hegar dilators was 25%.[26]
Our study had some limitations, such as the absence of a patient-reported pain assessment,
given most of the analyzed patients underwent the procedure in the operating room
under anesthesia; lack of evaluation of different doses and routes of administration
of misoprostol, since all of the patients used the drug at a dose of 400 µg via the
vaginal route; the absence of evaluation of the time of misoprostol administration,
seeing that, in all patients, the drug was introduced the night before the procedure.
Costa et al.[27] conducted a randomized study with 120 postmenopausal women who received 200 µg of
vaginal misoprostol or placebo 8 hours before outpatient hysteroscopy. There was a
significant reduction in the pain scale during the procedure, a fact that would facilitate
the performance of outpatient surgical procedures. In 2018, Fouda et al.[28] evaluated the effect of timing of vaginal misoprostol administration (3 hours versus
12 hours) before diagnostic hysteroscopy in nulliparous women, who are at increased
risk for cervical canal stenosis. The group of women given the drug just 3 hours before
hysteroscopy reported more pain during the procedure than those given the medication
12 hours earlier. However, the pain intensity 30 minutes after the procedure, its
mean duration, and the occurrence of side effects to misoprostol were similar between
the 2 groups. The passing of the hysteroscope through the cervical canal was also
assessed by the examiners and was found to be easier in the 12-hour group.
Conclusion
The use of misoprostol prior to hysteroscopy in our service showed that the drug can
facilitate the performance of the procedure; however, this drug is not free from side-effects
and higher complication rates. Also, misoprostol is a well-tolerated drug. We agree
with most authors that there is a need for further studies to better identify the
ideal dose, route of administration, and time to indicate misoprostol before the procedure.
