Keywords
delayed miscarriage - vaginal misoprostol - outpatient management
Palavras-chave
aborto retido - misoprostol vaginal - tratamento em ambulatório
Introduction
Non-viable first trimester intrauterine pregnancy is the most common complication
of early pregnancy. It accounts for 20% of all pregnancies,[1] and may present as delayed miscarriage (fetal loss and empty sac), spontaneous or
incomplete miscarriage. The approach to early pregnancy failure can be either surgical
(dilation and suction curettage), medical (with misoprostol or mifepristone) or expectant.
Traditionally, the surgical treatment was the first option in cases of incomplete
and delayed miscarriage. Moreover, we have now evidence that supports more conservative
approaches to early pregnancy loss, namely medical treatment and expectant management.[2]
[3] In a meta-analysis in which medical treatment was compared with expectant management,
the former was 2.77-fold more likely to induce complete evacuation of conception products.[4]
Over the years, many studies observed the efficacy and acceptance of misoprostol as
a treatment option for incomplete and delayed miscarriage,[3]
[5]
[6] and as an option in outpatient management protocols, with success rates ranging
from 77.3% to 92.7%.[5]
[7]
[8]
[9]
The efficacy of the medical treatment with prostaglandins depends on both the dose
and route of administration. Hence, the vaginal administration of misoprostol seems
to be more effective than the oral administration, and has less side effects.[10]
The aim of this study was to evaluate the efficacy of an outpatient protocol for the
medical management of delayed miscarriage with vaginal misoprostol.
Methods
Patient Selection and Outpatient Protocol
We performed a retrospective analysis of the women medically treated with misoprostol
for delayed miscarriage (fetal loss and empty sac) in an outpatient protocol. Data
was collected prospectively using a paper form that was presented and filled out at
each evaluation.
The women enrolled in this study were diagnosed either occasionally on a routine ultrasound
scan, or when they were admitted to the emergency department because of early bleeding
in pregnancy. The ultrasound findings considered necessary for the diagnosis of delayed
miscarriage were one of the following: an irregular intrauterine gestational sac with ≥ 25 mm
of diameter and no embryo and/or no yolk sac; an intrauterine gestational sac or an
embryo with an abnormal growth upon ultrasound over a minimum of one week; or an intrauterine
gestational sac with an embryo with a crown-rump length ≥ 7 mm and no cardiac activity
observed.
The inclusion criteria were: ultrasound-based diagnosis of delayed miscarriage with
gestational age based on ultrasound fetal measurement < 10 weeks; no heavy bleeding;
no signs of infection; no more than 2 previous spontaneous miscarriages; no history
of misoprostol allergy; no history of inflammatory bowel disease; and the preference
of the patient regarding the medical management. For patients with delayed miscarriage
with ≥10 weeks of gestation or with 2 or more previous spontaneous miscarriage, inpatient
management was recommended.
The women meeting these criteria were treated according to the following outpatient
protocol: a single dose of 800 µg of misoprostol administered intravaginally at the
emergency department, after which the patients were discharged home; clinical and
ultrasonography evaluation 48 hours later and, if the intrauterine gestational sac
was still present, a second dose of 800 µg of misoprostol was administered intravaginally,
and the patients were discharged home – if no gestational sac was observed, no further
evaluation was performed; clinical and ultrasonographic evaluation 7 days after the
initiation of the protocol for those who received a second dose of misoprostol – if
the intrauterine gestational sac was still present, surgical management was proposed.
Oral analgesia was prescribed to every woman, and they received written general recommendations.
They were instructed to return if any of the following symptoms occurred: heavy vaginal
bleeding, intense vomiting, abdominal cramps, or temperature > 38.5°C. The patients
also received a paper form to be presented and filled out at each evaluation.
If any of the following clinical findings were present, the women were considered
not eligible to enroll on the protocol: exuberant vaginal bleeding and/or hemoglobin < 10
mg/dL; signs or symptoms of infection; inflammatory bowel disease; allergy to misoprostol;
recurrent miscarriages; and ultrasound suspicion of gestational trophoblastic disease
or ectopic pregnancy.
The criterion used to document success after the medical management was the absence
of the gestational sac upon transvaginal ultrasound.
Written informed consent was not required because this protocol was introduced in
our department as a routine standard practice. The present study was approved by our
ethics committee.
Evaluated Outcomes
The main outcome evaluated was the global success rate of this protocol, represented
by women achieving a complete miscarriage with the medical treatment. The success
of the protocol was defined by the absence of the gestational sac upon a transvaginal
ultrasound evaluation. We also analyzed the success rate achieved with each misoprostol
application.
Statistical Analysis
The statistical significance was determined for the categorical variables with the
Chi-squared (χ2) test, and for the continuous variables, we used standard parametric tests; p < 0.05 considered statistically significant. The Statistical analysis was performed
using the Statistical Package for The Social Sciences (IBM SPSS Statistics, IBM Corp.,
Armonk, NY, US) software, version 21.0.
Results
A total of 377 women diagnosed with delayed miscarriage met the inclusion criteria
and were elected to enroll on this outpatient protocol. The average age of the women
enrolled was 33.8 years. We obtained information about parity regarding 321 women:
167 (52%) were nulliparous, 135 women (42.1%) were in their first pregnancy, and 32
(10%) had already had at least 1 previous abortion, spontaneous or not. The remaining
154 (48%) had had at least one live birth. According to the ultrasonographic criteria,
23.5% were diagnosed with empty sac, with a mean diameter of 23 mm, and 76.5% were
diagnosed with fetal loss, with a mean crown-rump length (CRL) of 12 mm. The women
diagnosed with fetal loss were older (34.12 years versus 32.64 years, p = 0.048) than the ones diagnosed with empty sac ([Table 1]).
Table 1
Study population characteristics
|
Median age (years)
|
 = 33.8
|
|
Nulliparous (n = 321)
|
n = 167 (52%)
|
|
 1st pregnancy
|
n = 135 (42.1%)
|
|
> 1 abortion
|
n = 32 (10%)
|
|
Parity ≥ 1 (n = 321)
|
n = 154 (48%)
|
|
Empty sac (n = 375)
|
n = 88 (23.5%)
|
|
Gestational sac diameter (mm)
|
 = 23
|
|
Fetal loss (n = 375)
|
n = 287 (76.5%)
|
|
Crown-rump length (mm)
|
= 12
|
Complete miscarriage with the medical treatment was observed in 340 (90.2%) women.
Surgical treatment was performed in the remaining 37 women (9.8%), representing the
global failure rate of the medical treatment ([Table 2]).
Table 2
Results observed for the treatment of delayed miscarriage with vaginal misoprostol
in an outpatient setting
|
n
|
%
|
|
Medical treatment (success)
|
340
|
90.2
|
|
After 1st dose of misoprostol
|
208
|
55.2
|
|
After 2nd dose of misoprostol
|
132
|
35
|
|
Surgery (treatment failure)
|
37
|
9.8
|
The miscarriage was complete after the first administration of misoprostol in 208
(55.2%) women, with a success rate after the second administration of 78.1% (132/169)
([Table 2]).
The mean age of the women who achieved complete resolution with the medical treatment
was superior to the mean age of those who required surgical procedures (33.99 years
versus 31.74 years; p = 0.031) ([Table 3]). The success of the medical treatment was not different between nulliparous and
multiparous women (p = 0.732).
Table 3
Success and failure rates in treating delayed miscarriage with vaginal misoprostol
|
Success
|
Failure
|
p*
|
|
Maternal age
|
= 33.99
|
= 31.74
|
0.031
|
|
Nulliparity
|
|
Nulliparous
|
150 (89.8%)
|
17 (10.2%)
|
0.732
|
|
Parity ≥ 1
|
141 (91.6%)
|
13 (8.4%)
|
|
Ultrasound findings
|
|
Empty sac
|
74 (84.1%)
|
14 (15.9%)
|
0.049
|
|
Fetal loss
|
264 (92%)
|
23 (8%)
|
|
Gestational sac diameter (mm)
|
= 23
|
= 19
|
0.194
|
|
Crown-rump length (mm)
|
= 12
|
= 13
|
0.733
|
Note: *p < 0.05 were considered statistically significant.
According to the ultrasonographic findings in the first evaluation, the women diagnosed
with fetal loss achieved greater success rates with the medical treatment when compared
with those diagnosed with empty sac (p = 0.049) ([Table 3]). The mean diameter of the gestational sac and the mean CRL were not statistically
different between the cases with and without success of the medical treatment (23 mm
versus 19 mm, p = 0.194; 12 mm and 13 mm, p = 0.733 respectively). This difference was also observed when considering only the
first administration of misoprostol (p = 0.014), but that was not the case for the second administration of misoprostol.
In terms of complications that may arise from this approach, we could obtain information
from 329 cases (87.3%). There was one case of major vaginal bleeding after the first
dose of vaginal misoprostol, which was treated with an emergency surgical management
(uterine aspiration), with no need of blood transfusion to stabilize the patient.
A case of infection treated with surgery and oral antibiotics was diagnosed one week
after initiating the medical treatment during the second routine visit to the emergency
department. The evolution of both cases was favorable, with no more complications
observed, and a global complication rate of 0.61%.
Discussion
Main Findings and Interpretation
In 2005, a study concluded that 400 µg of misoprostol self-administered intravaginally
every 4 hours, up to a maximum dose of 1,200 µg, had a success rate of 91%, and it
was a safe treatment option.[11] In the same year, the efficacy, safety, and acceptability of this treatment were
assessed in a large, randomized trial that concluded that treatment with 800 μg of
vaginal misoprostol is a safe and acceptable approach, with a success rate of ∼ 84%.[6] Two years later, 75 women were treated for delayed miscarriage with 800 µg of vaginal
misoprostol plus 2 additional doses of 400 µg each to take orally the following day:
77.3% of them achieved complete medical evacuation with this treatment.[7] Recently, in April 2017, a comprehensive review and meta-analysis[12] concluded that the administration of misoprostol is an effective method to solve
missed abortion, and both 600 μg of sublingual misoprostol or 800 μg of vaginal misoprostol
may be good choices as a first dose. However, they state that the ideal dose, medication
interval, and the safety of waiting at home need further research.
In this study, we present the results of an outpatient protocol for the medical treatment
of delayed miscarriage, and we observed success rates comparable to those of the most
recent studies on this topic. A 2012 study compared the effectiveness and adverse
effects of 800 µg and 600 µg of vaginal misoprostol every 24 hours for 2 days in an
outpatient setting, with the authors concluding that 600 µg was as effective as 800
µg in inducing complete uterus evacuation after missed abortion (with success rates
of 87.8% and 90.6% respectively; p = 0.18).[5] Moreover, this proved to be a safe treatment, with few adverse effects. Our success
rate (90.2%), which includes both women receiving doses of 800 µg and 1,600 µg (if
two doses were needed), is similar to that observed in the literature with the same
dose of misoprostol.[5]
Another study reported the prospective outcomes of the medical management of delayed
miscarriage in an Australian cohort composed of 264 women. Doses of 400 µg or 800
µg of misoprostol were administered intravaginally, at presentation, and repeated
the following day if the products of conception were still there. With a success rate
of 78%, this was considered an effective, safe and acceptable treatment.[8] The discrepancy observed between theirs and our results may be explained by the
success criteria used, as in their study they used an endometrium thickness > 30 mm
as an indication for surgery.
More recently, in 2014, a randomized control trial with 154 women assessed the differences
between outpatient and inpatient treatments with vaginal misoprostol. Doses of 800
µg of misoprostol were administered vaginally every 8 hours to a maximum of 3 doses.
The overall success rate was of 92.7%, and a higher success was observed with the
outpatient treatment compared with the inpatient treatment, even though this was not
statistically significant. Moreover, the side effects and complications were similar
between the two groups.[9] The higher success rate may be a consequence of the higher dose of misoprostol (a
total of 2,400 µg) administered within a shorter interval.
Our results are consistent with reports from previous studies in terms of effectiveness.
The differences observed in the success rate may be, in part, explained by the criteria
used to classify the treatment as successful. In our study, we used absence of gestational
sac upon transvaginal ultrasound as the criterion to document success after the medical
management of delayed miscarriage. This is associated with the highest short- and
long-term success rates, and also with mild symptoms following the treatment with
vaginal misoprostol.[13] However, other studies used endometrial cavity < 15 mm thick as the criterion for
success.[5]
[7]
[9]
[11] The occurrence of major side effects was rare (0.61%), which is in agreement with
previous findings that considered vaginal misoprostol a safe treatment.[8]
[14] We did not collect information about the long-term safety of the treatment, but
according to a study a recent study, vaginal misoprostol does not impair future fertility.[15]
In this study we achieved a greater success rate with the medical treatment among
the women diagnosed with fetal loss when compared with those diagnosed with empty
sac. Other researchers have also observed this difference and suggested that it would
be reasonable to divide first trimester miscarriages into different groups according
to the ultrasonography findings, because they have different success rates.[16]
Strengths and Limitations
Strengths and Limitations
This study assessed the efficacy of vaginal misoprostol for first trimester delayed
miscarriage according to the protocol described before. We also searched for adverse
effects after the initiation of the medical protocol, with only one case of infection
and one of vaginal bleeding leading to surgical treatment. Our findings are concordant
with previous studies that concluded for the safety of this drug when administered
vaginally, with only minor adverse effects (diarrhea, nausea, fever and crampy abdominal
pain), none of them life-threatening. In the randomized control trial by Zhang et
al[6], nausea was observed in 53% of the sample, vomiting in 20%, diarrhea in 24%, and
abdominal pain in 99%, with hemorrhage and pelvic infection being rare (1% or less).
We did not have any case of gastrointestinal side effects, and this may be due to
the prophylactic prescription of antiemetic drugs and painkillers.
Conclusion
In summary, our study shows that vaginal misoprostol for the outpatient medical management
of delayed miscarriage is an effective and safe option in the majority of the cases,
reducing the number of women subjected to surgical procedures and the consequences
of such an approach. Moreover, it combines the advantages of being performed in an
outpatient setting (with lesser costs and more comfort for the patients), with the
reassurance that the misoprostol administration is performed by doctors, not depending
on the patients' skills, and enabling an evaluation between the administration of
the doses of misoprostol.
