Miscarriage in First Trimester
Conditions
Keywords
misoprostol, miscarriage
Brief summary
Local current protocol for cervical ripening in 1st trimester miscarriage recommends 400 µg of misoprostol intravaginally 3 hours before uterine evacuation. This regime has been recommended by some international guidelines . So far, there are no recent studies comparing cervical dilatation between 400 µg of misoprostol and a reduced dose (e.g., 200 µg) for 6 hours. If cervical ripening is similar between these two regimens(i.e., 200µg regimen is not inferior to 400µg regimen), costs reductions and lower side effects may be issued without losing quality of cervix dilatation.
Detailed description
Miscarriage is defined by the World Health Organization as the interruption of the pregnancy up to 20-23 weeks, or the products of pregnancy weighing less than 500 grams (1). Nearly 15% of known pregnancies end in miscarriage, especially in the first 12 weeks. Estimates indicate that 68000 women die worldwide each year, as a result of unsafe abortions. Abortions are the major cause of maternal death, particularly in Latin America and the Caribbean. In cases of retained and incomplete abortions, uterine emptying is recommended. In the first trimester of pregnancy, either pharmacological or surgical procedure is accepted according to international guidelines. Pharmacological treatment for uterine evacuation includes the administration of mifepristone and misoprostol or misoprostol alone. Nevertheless, surgical methods have been shown a greater acceptability and patient satisfaction due to a reduced incidence of adverse effects. Currently, Manual Vacuum Aspiration (MVA) is the technique recommended by the Brazilian Ministry of Health and the Brazilian Federation of Gynecology and Obstetrics. MVA should be performed after cervical ripening. This pre-surgical procedure makes the procedure safer and more effective. In Brazil, misoprostol is the most suitable drug to be used in these cases because of its efficacy, ease of use, low cost, stability at room temperature, and availability. Misoprostol is a synthetic prostaglandin E1 analog and can be administered by oral, sublingual, buccal, rectal, and vaginal routes.
Interventions
400µg of misoprostol (2 tablets)
200µg of misoprostol (1 tablet)
Sponsors
Hospital de Clinicas de Porto Alegre
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Caregiver, Investigator)
Masking description
Patients, operators and statistical analysis were performed blindly.
Eligibility
Sex/Gender
FEMALE
Age
18 Years to 50 Years
Healthy volunteers
No
Inclusion criteria
* All patients admitted at the Gynecological emergency Unit at Hospital de Clínicas de Porto Alegre scheduled for uterine evacuation with \<12 weeks of gestation.
Exclusion criteria
* patients who do not wish to participate in the project; * patients with ectopic pregnancy; * patients with comorbidities (heart failure congestive, chronic obstructive pulmonary disease); * patients with hypovolemic shock; * patients with cervical incompetence; * patients with infected miscarriage/abortion (presence of fever, pus from the cervix, leukocytosis \[\> 14000\]); * patients with twin pregnancy; * patients with Marfan syndrome; * patients allergic to misoprostol; * patients with coagulopathy; * patients with opening of cervical internal os (4 mm of dilatation at the time of consultation); * patients with previous surgery of the cervix (conization); * patients with concomitant use of IUDs.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants Who Required Cervix Dilation at Initiation of the Manual Vacuum Aspiration | baseline at initiation of the Manual Vacuum Aspiration | this outcome identifies patients that had to have a mechanical dilator for opening the cervix to perform appropriate Manual Vacuum Aspiration |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With a Presence of a Uterine Cervical Canal With ≥8 mm of Dilation | Baseline before Manual Vacuum Aspiration procedure | This outcome measures how many mm of dilation the cervical canal has before the procedure. Cervical permeability (≥8 mm of dilation, used as a cut-off) was measured using Karman cannulas, from higher to low diameter. |
Other
| Measure | Time frame | Description |
|---|---|---|
| Pain Score (VAS) | before Manual Vacuum Aspiration | Pain scores were assessed using a verbal analog scale (VAS), ranging from zero (no pain) to 10 (worst possible pain) |
Countries
Brazil
Participant flow
Recruitment details
Participants with diagnosis of miscarriage and scheduled for Manual Vacuum Aspiration at the Gynecologic Emergency Unit of Hospital de Clínicas de Porto Alegre, a tertiary teaching hospital, were recruited. The first participant was enrolled on December 21, 2016.
Pre-assignment details
A total of 269 were screened. From these, 211 were enrolled and randomized to treatment. After randomization, 2 cases, one case of infected abortion and one case with previous cervical conization were identified and they were treated as for intention to treat.
Participants by arm
| Arm | Count |
|---|---|
| Misoprostol 400 µg Misoprostol 400 µg 6 hours before Manual Vacuum Aspiration | 106 |
| Misoprostol 200 Misoprostol 200 µg 6 hours before Manual Vacuum Aspiration | 105 |
| Total | 211 |
Baseline characteristics
| Characteristic | Misoprostol 400 µg | Misoprostol 200 | Total |
|---|---|---|---|
| Age, Continuous | 30 years | 31 years | 30 years |
| Gestational age | 7 weeks STANDARD_DEVIATION 1.4 | 7.1 weeks STANDARD_DEVIATION 1.5 | 7.1 weeks STANDARD_DEVIATION 1.5 |
| Obstetric history Gesta | 2 cases | 2 cases | 2 cases |
| Obstetric history Miscarriages | 1 cases | 1 cases | 1 cases |
| Obstetric history Para | 1 cases | 1 cases | 1 cases |
| Race/Ethnicity, Customized Asian | 1 participants | 1 participants | 2 participants |
| Race/Ethnicity, Customized Black | 29 participants | 26 participants | 55 participants |
| Race/Ethnicity, Customized Brazilian indian | 0 participants | 1 participants | 1 participants |
| Race/Ethnicity, Customized White | 76 participants | 77 participants | 153 participants |
| Region of Enrollment Brazil | 106 participants | 105 participants | 211 participants |
| Sex: Female, Male Female | 106 Participants | 105 Participants | 211 Participants |
| Sex: Female, Male Male | 0 Participants | 0 Participants | 0 Participants |
| Time from misoprostol to procedure | 6.38 hours STANDARD_DEVIATION 1.47 | 6.37 hours STANDARD_DEVIATION 1.28 | 6.37 hours STANDARD_DEVIATION 1.39 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 106 | 0 / 105 |
| other Total, other adverse events | 1 / 106 | 3 / 105 |
| serious Total, serious adverse events | 0 / 106 | 0 / 105 |
Outcome results
Primary
Number of Participants Who Required Cervix Dilation at Initiation of the Manual Vacuum Aspiration
this outcome identifies patients that had to have a mechanical dilator for opening the cervix to perform appropriate Manual Vacuum Aspiration
Time frame: baseline at initiation of the Manual Vacuum Aspiration
Population: Intention to Treat Population (all participants assigned to misoprostol 400µg or 200µg)
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Misoprostol 400 µg | Number of Participants Who Required Cervix Dilation at Initiation of the Manual Vacuum Aspiration | It was necessary (inadequate cervix dilation) | 4 Participants |
| Misoprostol 400 µg | Number of Participants Who Required Cervix Dilation at Initiation of the Manual Vacuum Aspiration | It was not necessary (adequate cervix dilation) | 102 Participants |
| Misoprostol 200 µg | Number of Participants Who Required Cervix Dilation at Initiation of the Manual Vacuum Aspiration | It was necessary (inadequate cervix dilation) | 16 Participants |
| Misoprostol 200 µg | Number of Participants Who Required Cervix Dilation at Initiation of the Manual Vacuum Aspiration | It was not necessary (adequate cervix dilation) | 89 Participants |
Comparison: If there is a true difference in favour of the standard treatment of 10% (96% vs 86%), then 184 patients are required to be 95% sure that the upper limit of a one-sided 97.5% confidence interval (or equivalently a 95% two-sided confidence interval) will exclude a difference in favour of the standard group of more than 25%p-value: 0.025difference between proportions
p-value: 0.00495% CI: [0.037, 0.192]Chi-squared
Secondary
Number of Participants With a Presence of a Uterine Cervical Canal With ≥8 mm of Dilation
This outcome measures how many mm of dilation the cervical canal has before the procedure. Cervical permeability (≥8 mm of dilation, used as a cut-off) was measured using Karman cannulas, from higher to low diameter.
Time frame: Baseline before Manual Vacuum Aspiration procedure
Population: Intention to Treat (all patients assigned to 400mg or 200µg of misoprostol)
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Misoprostol 400 µg | Number of Participants With a Presence of a Uterine Cervical Canal With ≥8 mm of Dilation | Inadequate (<8 mm) | 30 Participants |
| Misoprostol 400 µg | Number of Participants With a Presence of a Uterine Cervical Canal With ≥8 mm of Dilation | Adequate (≥8 mm) | 76 Participants |
| Misoprostol 200 µg | Number of Participants With a Presence of a Uterine Cervical Canal With ≥8 mm of Dilation | Inadequate (<8 mm) | 50 Participants |
| Misoprostol 200 µg | Number of Participants With a Presence of a Uterine Cervical Canal With ≥8 mm of Dilation | Adequate (≥8 mm) | 55 Participants |
Other Pre-specified
Pain Score (VAS)
Pain scores were assessed using a verbal analog scale (VAS), ranging from zero (no pain) to 10 (worst possible pain)
Time frame: before Manual Vacuum Aspiration
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Misoprostol 400 µg | Pain Score (VAS) | 0 units on a scale - Verbal Analog Scale |
| Misoprostol 200 µg | Pain Score (VAS) | 0 units on a scale - Verbal Analog Scale |
p-value: 0.995% CI: [0, 0]Wilcoxon (Mann-Whitney)