Hysteroscopy and Misoprostol Project
Condition: Uterine Hemorrhage
MeSH terms: Uterine Hemorrhage; Hemorrhage
Study type: Interventional
Phase: Phase 3

Summary: 
      To investigate if self-inserted vaginal misoprostol prior to outpatient hysteroscopy will
      lead to satisfactory cervical ripening, compared to placebo.
    

Detailed description: 
      In gynaecological practice, diagnostic and therapeutic hysteroscopy is one of the most common
      methods for diagnosing intrauterine pathology. The complications encountered during
      hysteroscopy, such as cervical tears, creation of false passages, and uterine perforation,
      are mainly related to the difficulty of cervical dilatation in nulliparous and postmenopausal
      patients. GnRH agonist use, previous cone biopsy, and markedly retroverted uterus are
      additional risk factors for complications.

      Cervical ripening may be achieved either by mechanical means, such as with osmotic dilators,
      or biochemically with prostaglandins. Solid evidence supports the efficacy of misoprostol for
      cervical ripening before first-trimester suction curettage abortion. A consensus has emerged
      that the optimal treatment regimen to use is 400-μg misoprostol 3-4 hours pre-operatively,
      with vaginal administration being superior to the oral administration. However, two studies
      using 400-μg misoprostol via the oral and vaginal routes have previously shown that this does
      not result in satisfactory pre-operative dilatation in the majority of Norwegian women, and
      we have recommended that the minimum dosage be greater than 400-μg vaginal misoprostol fours
      hours pre-operatively.

      The first trials describing prostaglandin priming of the cervix to reduce the frequency of
      traumatic cervical and uterine lesions in non-pregnant women prior to hysteroscopy were
      published in 1985.

      Misoprostol for cervical priming in non-pregnant women is not well established. 16 published
      randomised controlled trials have shown different cervical response and outcomes. Most of the
      studies have separately, but not systematically compared the effect on different patient
      groups, such as nulliparous women and postmenopausal women. Seven of the studies included
      less than 50 patients, and almost all the trials were underpowered as regards to evaluating
      primary outcome measures. In the study with the largest number of patients included (Thomas
      et al), the authors have not explained why or how they converted the primary outcome measure
      from "the largest-number Hegar dilator that could be inserted without resistance" to a binary
      variable ("Hegar > 8/Hegar < 8) after they had analysed their results - an apparent protocol
      violation. It appears that none of the trials have been designed and conducted in accordance
      with the CONSORT statement. The dosages used in the studies have varied between 200 and
      1000-μg misoprostol given between 2 and 24 hours before hysteroscopy, via the oral,
      sublingual and vaginal routes. Trials that have used higher dosages of misoprostol, via the
      vaginal route, using the longest interval between administration of misoprostol and
      hysteroscopy have tended to show more favourable outcomes as regards to cervical priming.

      The hospital pharmacist will manufacture both active misoprostol ground up as a whitish
      powder in capsules (500-μg per capsule), as well as an inactive ingredient with an identical
      appearance (lactose) in capsules as placebo. The hospital pharmacist will prepare numbered,
      opaque, sealed envelopes. The envelopes will be numbered according to a randomisation list.
      The hospital pharmacy will then insert the prepared capsules into the envelopes. Each
      envelope will contain two capsules. Half of the envelopes will contain two capsules with
      500-μg misoprostol each, while the other half will contain two placebo capsules.

      All patients referred to outpatient hysteroscopy at Ullevål University hospital will be sent
      an invitation to be included in the study, together with dates for a prior out patient
      consultation and the hysteroscopy. The study invitation will include detailed information
      regarding the study, as well as an informed consent form. The out patient consultation will
      take place a few days prior to their scheduled hysteroscopy, where they will be given the
      option to participate in the study. The study authors will primarily be responsible for
      recruiting patients. During the study period, participant flow will be recorded.

      If the patients are recruited, the gynaecologist at the pre-operative consultation will
      record the pre-operative variables on the case report form, and the patients will be given an
      envelope containing the capsules before leaving the hospital. Hence those involved in
      administering the intervention and assessing the outcomes will be blinded to the dosage, as
      well as the patients. Each participant will be randomised by opening a numbered, sealed,
      opaque envelope at home, containing either misoprostol, or an inactive ingredient with an
      identical appearance, in capsules. The design method of randomization and blinding should
      obviate potential subjectivity bias. The patients will be instructed to insert the capsules
      at 9 p.m. the evening before the operation.

      Before the hysteroscopy, the gynaecologist will measure the pre-operative degree of cervical
      dilatation by passing Hegar dilators through the cervix in ascending order starting with a
      size two millimetres. The size of the largest dilator passed into the cervical os without
      subjective resistance felt by the operator will be recorded as the preoperative degree of
      dilatation. If there is resistance with Hegar dilator size two millimetres, the result will
      be recorded as < 2. Adverse events such as superficial cervical lacerations, false passage of
      the cervix during cervical dilatation, and perforation of the uterus will be recorded.

      The patient records will be reviewed after 60 days to see if the women have contacted the
      hospital for post-operative complications.

      A two sample sequential Wilcoxon test will be used to analyze the data. We performed a small
      pilot study in our department on 20 patients prior to hysteroscopy in January 2006 to
      investigate the pre-operative variability (SD) in cervical dilatation. The standard deviation
      was 1.3 mm in postmenopausal patients (n=5), and 1.4 mm in premenopausal patients (n=15). The
      mean cervical dilatation was 3.4 mm in postmenopausal patients and 5.4 mm in premenopausal
      patients. The design of the main trial is based on a significance level of 5% and a power of
      95% against a 1 mm difference in the cervical dilatation caused by misoprostol and placebo.
      As it seems unlikely that use of misoprostol could cause a constriction of the cervix, a
      one-sided test is chosen. The trial will continue until either the null hypothesis or the
      alternative hypothesis has been refuted.
    

Intervention name(s): misoprostol and cervical ripening
Intervention type(s): Drug
Intervention MeSH terms: Misoprostol
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Double
Primary purpose: Treatment
Keywords: Hysteroscopy; Misoprostol; Uterine hemorrhage; Uterine cervix; Dilatation