Introduction: Incomplete early miscarriage is defined as early miscarriage with persistent intrauterine material on ultrasound. Intrauterine retention of trophoblastic debris is not an uncommon phenomenon. These retentions may initially be asymptomatic but are often responsible for persistent metrorrhagia and endometritis. This symptomatology often accentuates the psychological distress of patients mourning the pregnancy. Incomplete miscarriages are mainly managed by the gynecological emergency department. The recommendations of the Collège National des Gynécologues et Obstétriciens Français (CNGOF) suggest as a first line of treatment: either surgical management or expectant care. The choice between the two is left to the discretion of the doctor and the patient. there are no clear recommendations as to the choice between hysteroscopy and aspiration. Within the teams, the choice is often made according to the habits and protocols of the service, according to the equipment available and the skills of the gynaecologists.
Aim: The main objective is to compare the efficacy of management by endo-uterine aspiration versus management by hysteroscopy of trophoblastic retention after early miscarriage, at 6 weeks after surgery, by endovaginal ultrasound.
The secondary objectives are:
- the comparison of the rate of complications of the two techniques, during and after surgery
- the comparison of the rate of recourse to a second line surgical management between the two arms,
- the comparison of the rate of synechiae diagnosed by hysterosonography between the two techniques at 6 weeks after surgery,
- the comparison of the time to conception in the two arms during the 2 years after surgery
- the comparison of the fertility rate at 2 years after surgery in the two arms.
Methods: This is a prospective, multicenter, randomized, open-label, two-arms, parallel therapeutic clinical trial comparing hysteroscopy versus endouterine aspiration for the management of trophoblastic retention after spontaneous miscarriage.
Patients will be randomized (110 per arm) after verification of eligibility criteria and signature of consent, on the day of the operation:
- Arm A: 110 patients treated by operative hysteroscopy
- Arm B: 110 patients treated by endo-uterine aspiration Randomization will be stratified by center, age (<35 years, 35 years and over), size of trophoblastic retention (<30mm, 30mm and over) and scheduled by random size block. It will be centralized (Ennov-clinical software) and parameterized by the Unité́ de Recherche Clinique & Biostatistiques of the Montpellier University Hospital.
Statistics: The effectiveness of operative hysteroscopy is expected to be 100%, and that of aspiration 90%. To show this difference with an alpha risk of 5%, and with a power of 90%, 98 patients per arm will have to be analysed (exact binomial distribution calculation, epiR package of R implemented in biostatgv). To take into account a 10% loss of sight rate, 220 patients will be recruted.
Patients will be included in the study on the morning of the procedure, after verification of the selection criteria.
The expected number of lost to follow-up is estimated at 10%; in fact, the main criterion is evaluated relatively early (6 weeks), in patients having a desire for pregnancy and therefore relatively compliant, the rate of lost to follow-up will be a fairly low.
A flow-chart will be constructed to describe the evolution of the populations during the study. It will detail the causes of non-inclusion and the causes of loss to follow-up.
All study data will be described according to the randomization arm, in the randomized population: mean, standard deviation, median and quartiles, extrema and number of missing data for quantitative variables, numbers and percentages of each modality for qualitative data.
The clinical comparability of the randomized population and the ITT population for the primary endpoint will be assessed.
Primary analysis:
The uterine vacuity rate will be compared between the two arms in the ITT population for the primary endpoint by a Chi-square test or by a Fisher exact test if the conditions for Chi-square validity are not met. The significance level was set at 5%, two-sided.
Secondary endpoint analysis:
The rates of complications, use of second-line surgical management, synechiae, and fertility at 2 years after surgery will be compared between the two arms in their respective ITT populations, by a Chi-square test or by a Fisher's exact test if the conditions for the validity of Chi-square are not met.
The time to conception will be compared between the two arms of the randomized population by a log-rank test.
Within this family of endpoints, the alpha risk will be controlled by a Hochberg procedure.
Visit 1: Pre-operative consultation between 1 and 21 days before the operation
- Clinical examination performed as part of routine care: measurement of blood pressure and pulse, temperature, speculum examination to ensure the absence of significant bleeding indicating emergency surgical management.
- Diagnosis of trophoblastic retention by endovaginal ultrasound
At the end of the consultation:
- Verification of eligibility criteria
- Oral information on the study and information leaflet given to the patient
- Collection of informed and written consent after a reflection period
- Collection of the following data:
- Demographic data
- History, smoking habits and concomitant treatments
- Pregnancy data leading to the current miscarriage
- Results of pelvic ultrasound
Intervention (D0):
- Verification of eligibility criteria and randomization on the morning of the procedure
- Surgical management of trophoblastic retention by operative hysteroscopy (Arm A) or endo-uterine aspiration (Arm B)
- Collection of adverse events during the operation and before the patient is discharged
Visit 2: Consultation at 6 weeks after surgery +/- 7 days
This consultation will be performed by an investigator trained in pelvic ultrasound and hysterosonography, blinded to the allocated procedure:
- Plasma HCG measurement before hysterosonography to ensure that there is no current pregnancy
- Endovaginal ultrasound to check uterine vacuity
- Hysterosonography for the diagnosis of uterine synechia
- Collection of complications and adverse events after surgery
Visit 3: Telephone consultation at 6 months +/- 15 days after surgery
Carried out by the clinical research associate (CRA):
- Evaluation of fertility by questionnaire
- Evaluation of the time to conception if pregnancy in progress A letter will be sent to the patient if she cannot be reached by phone (questionnaire + return envelope)
Visit 4: Telephone consultation at 12 months +/- 1 month after surgery
Carried out by the CRA:
- Evaluation of fertility by questionnaire.
- Evaluation of the time to conception if pregnancy in progress. A letter will be sent to the patient if she cannot be reached by phone (questionnaire + return envelope)
Visit 5: Telephone consultation at 24 months (+/- 2 months) after surgery
Carried out by the CRA:
- Evaluation of fertility by questionnaire
- Evaluation of the time to conception if pregnancy in progress A letter will be sent to the patient if she cannot be reached by phone (questionnaire + return envelope). The patients will be followed until a pregnancy is obtained with a term greater than or equal to 24 weeks of amenorrhea or over a maximum period of 26 months after the surgery.
