Keywords
Abortion - Miscarriage - Misoprostol - Curettage
Palavras-chave
Aborto - Aborto espontâneo - Misoprostol - Curetagem
Introduction
According to estimates from the World Health Organization (WHO), ∼ 55 million abortions
occurred between 2010 and 2014 worldwide, with 45% considered unsafe abortions. Africa,
Asia, and Latin America account for 97% of the unsafe abortions.[1] The WHO defines unsafe abortion as a procedure for the termination of pregnancy
performed by people without the necessary skills. Alternatively, it is defined as
a procedure performed in an environment not standardized to perform medical procedures,
or a combination of these two factors. Despite scientific advances that allow safe
abortions for patients, unsafe abortions continue to occur, causing increased healthcare
costs, complications, and maternal deaths.[2] In Brazil, abortion is a public health problem because of its magnitude and persistence.[3]
Additionally, several procedures have been performed in the face of abortion, such
as pharmacological, surgical, or expectant procedures.[4] Not all forms of treatment are widely available in public services, and not all
are accepted by patients. A previous meta-analysis comparing the possible management
of first-trimester miscarriages found that one other success was achieved for every
three patients treated surgically instead of medically. In contrast, expectant management
showed variable efficacy depending on the clinical presentation.[5]
The WHO defines abortion as the expulsion or extraction of a conceptus before reaching
22 weeks of gestational age or weighing < 500 grams.[6] Additionally, abortion can be classified and approached in different ways, including
gestational age (early or late), clinical presentation (threatened, inevitable, infected,
incomplete, complete, or missed), and origin (spontaneous or provoked).[7]
Incomplete abortion, the subject of the present study, has an eminent clinical diagnosis
and is characterized by transvaginal bleeding associated with an open uterine cervix
upon physical examination when the products of conception have not been wholly discharged.[5] This is the most frequent clinical presentation of this condition.[7]
[8]
[9]
Currently, misoprostol (prostaglandin E2 analog), along with mifepristone, is the
reference drug for medicated uterine emptying in cases of spontaneous or induced abortion,
both in the first gestational trimester and at more advanced gestational ages. However,
mifepristone is unavailable in Brazil.[4]
[5] Misoprostol works by inducing the uterus to contract and expel the remaining tissues,
with no immediate necessity for operating theatres, sterile equipment, or skilled
personnel. Thus, it is even more relevant in low-resource settings. Therefore, the
present systematic review and meta-analysis aimed to assess the efficacy, safety,
and acceptability of misoprostol in the treatment of incomplete miscarriage. Managing
these patients using a less invasive option may be essential.
Methods
The present systematic review was designed and reported according to the Preferred
Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA).[10] As this study is based on published studies, no ethical approval or patient consent
was required.
The study protocol was registered in the PROSPERO International Prospective Register
of Systematic Reviews (registration number: CRD42018116776).
The design of the present study followed the PICOS strategy for systematic reviews
as follows: Population (P): patients with incomplete miscarriage diagnosed up to 6/7
weeks of gestation; Intervention (I): treatment with misoprostol; Comparator (C):
a manual vacuum aspiration (MVA) or curettage; Outcomes (O): Efficacy: complete evacuation
of the uterus, with no need for additional intervention; Safety: adverse effect profile
(frequency and severity); Acceptability: patient's overall satisfaction and if she
would choose the same method again; Study design (S): randomized controlled trials
(RCTs).
The articles were searched in the PubMed/MEDLINE, SCOPUS, EMBASE, Web of Science,
Cochrane Library, and Clinical Trials databases using the following combinations of
Medical Subject Heading terms and Boolean operators: “(pregnancy OR pregnant
women OR abortion OR miscarriage) AND (misoprostol OR dilatation OR curettage OR vacuum OR aspiration) AND (Randomized controlled trial OR blind method OR trial OR RCT).” The final search was conducted on January 15, 2021, and updated on July 4, 2022.
No language restrictions were applied. The keyword details and complete search strategy
are provided in Supplemental file 1.
The inclusion criteria were randomized clinical trials with patients of gestational
age up to 13 weeks and 6 days, diagnosed with incomplete abortion and managed with
at least one of the three types of treatment studied. Nonrandomized studies and those
that analyzed nonspontaneous abortions or patients not in the first trimester were
excluded from the review.
Two researchers, TMS and ACZS, independently screened the studies according to their
titles and abstracts. Duplicate studies were excluded, and the full text was reviewed
to determine whether they met the selection criteria. A third researcher, ACAS, resolved
the disagreements between the reviewers regarding the inclusion of an article. Once
the studies were selected, the data of each were summarized in a single spreadsheet
to standardize all the results obtained; the latter process was conducted by two researchers,
MAGA and RO. Any missing data would have been retrieved by contacting the corresponding
author or their coauthors through phone or e-mail, but there was none.
The following data were included in the spreadsheet: author, year of study, country
in which the study was conducted, number of patients enrolled, age of patients, gestational
age, number of patients assigned to each treatment method, main adverse effects reported,
satisfaction with the technique, and follow-up time.
One of the researchers, AKG, used the Cochrane risk-of-bias analysis tool[11] to assess randomization, participant allocation, participant-practitioner blinding,
and outcome assessment. Incomplete data and possible conflicts of interests were also
considered. The risk of bias was assessed according to the predetermined criteria:
low, high, or uncertain.
Data were synthesized by another researcher, APFC, using the statistical package in
Review Manager V.5.1. For dichotomous outcomes, the OR and 95%CI were derived for
each study. The heterogeneity between the trial results was evaluated using a standard
test with p = 0.1 and the I2 statistic, which is a quantitative measure of inconsistency across studies, with
0% indicating no observed heterogeneity and values of 50% indicating substantial heterogeneity.
When heterogeneity was measured (I2 = 75%), a random-effects model was used to combine the trials and calculate the relative
risk (RR) and 95%CI using the DerSimonian and Laird algorithm in a meta-analysis package
for R. The other study characteristics and results have been summarized.
The quality of evidence of the studies was evaluated by one of the researchers, KSM,
according to the Grading of Recommendations Assessment, Development, and Evaluation
(GRADE).[12]
Results
Study Selection
Database searches identified 8,087 articles ([Fig. 1]). From this initial amount, 67 were excluded due to duplication, 7,985 were excluded
after title and abstract review, 1 study could not be retrieved, and 21 were excluded
because they did not meet the eligibility criteria. Case reports and series were excluded
from the present study. Ultimately, nine studies met the eligibility criteria and
were included in the final review ([Chart 1]).
Chart 1
Characteristics of the studies included in the systematic review
|
Author, year
|
Country
|
Study sesign
|
Sample
|
Average age of participants (years old)
|
Gestational age inclu ded
(weeks)
|
Intervention
|
Groups of comparison
(n° of patients)
|
Follow-up time (days)
|
Outcomes
|
|
Misoprostol
|
Manual vacuum aspiration (MVA)
|
|
Dabash R. et al, 2010
[24]
|
Egypt
|
RCT
|
695
|
28
|
0–12
|
400mcg sublingual x MVA
|
348
|
347
|
7
|
Favours MVA in safety.
|
|
R. Montesinos et al., 2011
[22]
|
Ecuador
|
RCT
|
203
|
18-33
|
0–12
|
600 mcg oral x MVA
|
106
|
97
|
7
|
Favours MVA in safety.
|
|
Taylor J. et al, 2011
[26]
|
Ghana
|
RCT
|
218
|
26
|
0–12
|
600 mcg oral x MVA
|
108
|
110
|
7–14
|
Favours misoprostol in acceptability.
|
|
Chigbu B. et al, 2012
[25]
|
Nigeria
|
RCT
|
320
|
29
|
0–12
|
600 mcg oral x MVA
|
160
|
160
|
7–14
|
Favours misoprostol in acceptability.
|
|
Shochet T. et al, 2012
[28]
|
Nigeria, Niger, Senegal, Burkina Faso, Mauritania
|
RCT
|
839
|
28
|
0–12
|
400 mcg sublingual x surgical evacuation
|
465
|
374 allocated to “surgical evacuation” (Curettage or MVA)
|
7–14
|
Favours “surgical evacuation” in efficacy and safety.
|
|
Das CM. et al., 2014
[20]
|
Pakistan
|
RCT
|
222
|
28
|
0–12
|
600 mcg x MVA
|
111
|
111
|
7
|
No difference between groups.
|
|
Ibyiemi KF. et al, 2019
[21]
|
Nigeria
|
RCT
|
198
|
28
|
0–13
|
600 mcg oral x MVA
|
100
|
98
|
7
|
Favours MVA in efficacy and safety (except for “pain”).
|
|
Ani VC. et. al, 2022
[27]
|
Nigeria
|
RCT
|
203
|
29
|
First trimester (9.1 ± 2.0)
|
400mcg sublingual x MVA
|
102
|
101
|
7
|
Favours MVA in efficacy, favours misoprostol in safety (specifically in pain).
|
|
Nwafor et al, 2021
[23]
|
Nigeria
|
RCT
|
94
|
18–45
|
0–13
|
600 mcg oral x MVA
|
48
|
46
|
7
|
Favours misoprostol in acceptability.
|
Abbreviation: MVA, manual vacuum aspiration.
Fig. 1 PubMed search strategy.
Throughout the search and selection of studies, seven articles,[13]
[14]
[15]
[16]
[17]
[18]
[19] which compared mifepristone and misoprostol, were analyzed. However, these were
discarded because they did not meet the inclusion criteria. The studies included patients
with a gestational age of 5 to 12 weeks but excluded incomplete abortion from their
analysis. These studies concluded that the treatment with mifepristone and misoprostol
was more effective than misoprostol alone for the management of missed miscarriages,
which was not the objective of our analysis. Nonetheless, given the relevance of this
drug in current studies and its future potential as another accessible treatment option,
the meta-analysis in question will be addressed in the “Discussion” section.
Study Characteristics
Of these studies, eight were RCTs comparing treatment with misoprostol and MVA. One
multicentric trial compared misoprostol with “surgical evacuation,” which could be
MVA or curettage, according to the usual practice of the service. However, there was
no information regarding the number of patients allocated to each procedure. A total
of 2,992 patients were enrolled, with a mean age of 28.1 years old and gestational
age up to 13 6/7 weeks. The follow-up time ranged from 24 hours to 28 days in the
study protocols. Eight studies involving 1,950 patients who underwent treatment with
either misoprostol or MVA were included for meta-analysis.[20]
[21]
[22]
[23]
[24]
[25]
[26]
[27]
Outcomes of Misoprostol
When comparing misoprostol with MVA, the rate of complete abortion was higher in the
MVA group (OR = 0.16; 95%CI = 0.07–0.36) ([Fig. 2]). Hemorrhage or heavy bleeding was more common in the misoprostol group (OR = 3.00;
95%CI = 1.96–4.59), but pain after treatment was more frequent in patients treated
with MVA (OR = 0.65; 95%CI = 0.52–0.80) ([Figs. 3] and [4]). Regarding the general acceptability of the treatment (in relation to overall satisfaction
and if the same method would be chosen again), misoprostol showed an OR of 0.67 with
a 95%CI of 0.38–1.19 ([Fig. 5]).
Fig. 2 Complete abortion.
Fig. 3 Hemorrhage.
Fig. 4 Pain.
Fig. 5 Acceptability.
Studies that could not be included in the meta-analysis were analyzed individually
and showed conflicting results. Shochet et al.[28] compared 465 patients who were given 400 μg of sublingual misoprostol with 374 patients
undergoing surgical evacuation (MVA or curettage) and observed higher efficacy (risk
ratio [RR] = 0.90; CI = 0.88–0.92) and lower rates of hemorrhage (0.6 versus 11.6%)
and pain (24.4 versus 54.8%) in the surgical group (p < 0.001). Nonetheless, a higher
number of patients in the misoprostol group said that they would choose the same treatment
again if needed (97.6 versus 87.8%; p < 0.001). No significant difference was noted in overall satisfaction with the method
(98.5 versus 98.1% in the misoprostol and surgical groups, respectively; p = 0.78).
Risk of Bias
In general, the studies presented a low risk of bias. The clinical trials were conducted
safely. However, Shochet et al. (2012), Ibiyemi et al. (2019), and Ani et al. (2022)
showed some risk of bias in the randomization process ([Fig. 6]).
Fig. 6 Risk of bias.
Quality of Evidence
The efficacy and satisfaction of outcomes presented high quality evidence. However,
the bleeding/hemorrhage and pain outcomes showed low-quality evidence, mainly due
to high heterogeneity between the studies and high CI of the results ([Chart 2]).
Chart 2
GRADE quality of evidence
|
Certainty assessment
|
N° of patients
|
Effect
|
Certainty
|
Importance
|
|
N° of studies
|
Study design
|
Risk of bias
|
Inconsistency
|
Indirectness
|
Imprecision
|
Other considerations
|
Misoprostol
|
Manual vacuum aspiration
|
Relative
(95% CI)
|
Absolute
(95% CI)
|
|
Inducing abortion
|
|
7
|
randomised trials
|
not serious
|
not serious
|
not serious
|
not serious
|
none
|
923
|
910
|
−
|
0
(0.07 higher to 0.4 higher)
|
⨁⨁⨁⨁
High
|
CRITICAL
|
|
Hemorrhage
|
|
5
|
randomised trials
|
not serious
|
serious[a]
|
not serious
|
serious[b]
|
none
|
713
|
699
|
−
|
0
(1.64 higher to 4.85 higher)
|
⨁⨁◯◯
Low
|
CRITICAL
|
|
Pain
|
|
6
|
randomised trials
|
not serious
|
very serious[c]
|
not serious
|
not serious
|
none
|
924
|
913
|
−
|
0
(0.1 higher to 1.1 higher)
|
⨁⨁◯◯
Low
|
CRITICAL
|
|
Acceptability
|
|
4
|
randomised trials
|
not serious
|
not serious
|
not serious
|
not serious
|
none
|
662
|
652
|
−
|
0
(0.38 higher to 1.21 higher)
|
⨁⨁⨁⨁
High
|
IMPORTANT
|
Abbreviation: CI: confidence interval.
a. Heterogeneity of 32%; b. 95%Cl: [1.96, 4.59]; c. Heterogeneity of 96%.
Discussion
Since miscarriage is still a complex health problem, often neglected by health policies,
discussion on management options and application of scientific evidence to provide
humanized, effective, and safe care that patients will accept is fundamental to alleviate
the physical and psychological burden of this event.
In this scenario, misoprostol is a suitable option, although the present meta-analysis
revealed that it has a slightly lower efficacy than MVA or curettage, with a higher
rate of heavy bleeding. However, the patients reported less pain when using misoprostol
and presented similar acceptability as surgical treatments. In addition, misoprostol
can be more accessible in low-resource settings, as not all areas have tertiary hospitals
with operating rooms where the patients can have proper treatment. Moreover, when
treated medically, the patient does not need to be hospitalized for the entire treatment
period, as outpatient care seems to be an alternative,[28] which may be better for patients with a good support network at home.
Furthermore, Von Hertzen et al. performed a randomized clinical trial with 2,066 patients
who received three doses of misoprostol 800 µg via different administration routes.
Their results showed that the commonly reported adverse effects were pain, diarrhea,
fever, or chills. In that study, only 0.04% of the patients had vaginal bleeding that
required a return to the hospital.[29] Recently, Sheldon et al. also published a randomized clinical trial using only 800
µg of misoprostol for induced abortion. In this study, treatment efficacy ranged from
84 to 87%, and adverse effects (diarrhea, nausea, vomiting, fever, or chills) were
self-limiting and well tolerated by patients. Only one woman had vaginal bleeding,
which required a return to the hospital for surgical completion.[30]
In the usual practice, some professionals are concerned about the occurrence of infection
when surgical treatment is not chosen. In 2006, the Miscarriage Treatment (MIST) Trial[31] randomized 1,200 patients diagnosed with a first-trimester miscarriage to be treated
surgically, medically, or expectantly. The results showed no difference in the incidence
of infection within 14 days of follow-up. A posterior analysis of fertility rates
in the three groups showed that medical treatment is safe from a reproductive future
point of view.[32] However, advising patients on the alarm signs, such as persistent fever, heavy bleeding,
change in mental state, dizziness, and fainting that may appear with an infection,
and consulting a health care provider is essential.[33]
Concerning the rates of complete evacuation of the uterus after treatment, a network
meta-analysis showed that all surgical and clinical methods for managing a miscarriage
might be more effective than expectant management and a placebo. Surgical techniques
were ranked highest for managing a miscarriage, followed by the clinical approach,
which ranked above expectant management and a placebo. Suction aspiration after cervical
preparation was the highest-ranking surgical procedure. Expectant management and placebo
had the highest chance of serious complications, including the need for unplanned
or emergency surgery. A subgroup analysis showed that surgical and clinical methods
might be more beneficial in patients with missed miscarriages than in those with incomplete
miscarriages.[34]
Concerning the limitations of the present study, we can cite: lack of standardization
for some of the outcomes considered. For instance, some studies reported “pain” as
the number of patients who presented with symptoms after treatment, whereas some reported,
using a mean visual analog scale (VAS). In addition, bleeding was sometimes reported
according to its intensity and sometimes referred to as any amount of bleeding. Regarding
misoprostol, each study had a specific protocol for dosing and route of administration,
which may be pointed out as another problem when comparing outcomes in different studies.
To minimize these effects, several strategies were used to test the evidence, such
as the assessment of quality and risk of bias.
Once the efficacy, safety, and acceptability of misoprostol in incomplete abortion
are well established, future researchers may be interested in finding the ideal route
of administration (oral, sublingual, or vaginal), perfect dosage, and intervals of
administration when necessary.
Conclusion
Misoprostol has been determined as a safe option with good patient acceptance. This
acceptance may be related to the fact that the patient did not need to be hospitalized
and reported less pain. Furthermore, misoprostol appears to be more accessible in
low-resource settings. However, the quality of the body of evidence for bleeding/hemorrhage
and pain outcomes was “low,” mainly because of the high heterogeneity between the
studies and an increased CI effect. Therefore, the results regarding the efficacy
of misoprostol in this meta-analysis cannot be generalized.
