Misoprostol in Office Hysteroscopy and Endometrial Biopsy

Office hysteroscopy (OH) and endometrial biopsy (EMB) is increasingly performed for
evaluation of various gynecologic conditions. It has replaced traditional dilatation and
curettage for evaluation of intrauterine pathology. It is more acceptable to most women as it
is quick, safe and cost effective with higher diagnostic accuracy. However, pain encountered
at the time of procedure is a major limitation and at times lead to incomplete procedure. The
variables that influence women's experience of pain during these procedures are nulliparity,
menopausal status, pre-existing anxious state, use of tenaculum, presence of synechiae in the
cervical canal, and duration of procedure.

The average pain score recorded at the end of procedures when OH and EMB were performed
simultaneously was 7 on a 10 cm VAS scale (Visual analogue scale) 5 among pre and post
menopausal women who received pre-procedure analgesia in the form of oral Non-Steroidal Anti
Inflammatory drug (NSAID) and application of local anesthetic gel. Among patients where only
intracervical topical anesthetic injection was used, the pain score at the end of OH and EMB
was 9.22 (low pain) and 11.52 (moderate pain), respectively, on a 20cm VAS. Most women
describe EMB as "moderately" or "severely" painful6. A significant source of pain during
endometrial sampling is placement of tenaculum on the cervix. Interventions that have been
studied to reduce pain with EMB include misoprostol for cervical ripening, intrauterine
lidocaine infusion, paracervical block, and pre-procedure NSAIDs. The results are variable
with modest benefit on pain with only an intrauterine lidocaine infusion with or without
NSAID or/and misoprostol. Similarly, during OH also, there are multiple points where women
experience pain. It can be during tenaculum placement, introduction of the hysteroscope,
distension of uterine cavity, intrauterine procedures, and withdrawal of scope. Out of many
interventions evaluated, local anesthesia via paracervical block provided consistent
decreases in intraoperative and postoperative pain scores. There were mixed data on efficacy
of intracervical blocks and no evidence to support the use of intrauterine anesthesia or
topical gels, sprays, or creams. Premedication with opioid analgesics or NSAIDs do not confer
benefit in pain management during office hysteroscopy. Misoprostol for cervical ripening
prior to diagnostic hysteroscopy neither reduce pain nor facilitate the procedure for
hysteroscopes with diameters of less than 6 mm in premenopausal women, but there may be a
benefit in postmenopausal women. In contrast, another systematic review examining use of
misoprostol before hysteroscopy found that misoprostol given to premenopausal women reduced
the need for cervical dilatation and the incidence of cervical laceration.

Misoprostol is a prostaglandin E1 analog that was first marketed in the 1980s to prevent
gastric ulcer. It can be administered sublingually, orally, vaginally, or rectally. Peak
serum levels are achieved after vaginal administration. The plasma concentration increases
gradually after vaginal administration, reaching its maximum level after 70-80 minutes.
Misoprostol is commonly used in gynecology for inducing dilatation of the cervix for
termination of pregnancy and removing retained products of conception. It helps in
non-pregnant women to dilate the cervix and provides easy access to the uterine cavity for
transcervical procedures such as hysteroscopy and intrauterine device placement. To evaluate
the optimal dose of vaginal misoprostol for cervical priming before operative hysteroscopy,
low dose (200mcg) and high dose (400 mcg) misoprostol was compared in a recent randomized
control trial. They found no difference in perioperative dilatation time, and subjective
difficulty of cervical dilatation assessed by surgeons. However, the incidence of misoprostol
related adverse events such as abdominal pain, pre-insertion nausea and cramping were less in
the group who received 200 mcg misoprostol. But it is important to note that even 200 mcg
misoprostol is associated with 50% incidence of abdominal cramping. Since we would be
conducting outpatient diagnostic procedures only, we propose that use of 50 mcg misoprostol
would lead to adequate cervical dilatation to successfully complete the OH and EMB with lower
incidence of associated complications (abdominal cramping, vaginal bleeding, and nausea).
Moreover, it is important to note that the standard operating procedure of the fibroid and
endometriosis center has been the administration of 50 mcg misoprostol to patients undergoing
simultaneous OH and EMB. This practice that has been ongoing for over 12 months has provided
very favorable results. No other study has evaluated the efficacy of such a low dose and it
would be interesting to explore the minimal effective dose, which can be used for
simultaneous OH and EMB to yield effective results in terms of lower pain scores and lower
incidence of associated complications. As mentioned previously, studies evaluating the role
of misoprostol in alleviating overall pain during OH and EMB had mixed reviews. But those
studies have been performed in the general population. It is important to note that there are
subgroups of women (previous cesarean section, nulliparous, postmenopausal, previous loop
surgery) who more often need dilatation of the cervix to facilitate passage of the
hysteroscope. Therefore, this trial will focus on these subgroups to assess whether the use
of prostaglandin analogue provides clinically significant reduction in pain, reduces the need
for dilatation and incidence of genital trauma and whether these benefits outweigh the
potential harms (bleeding, laceration, abdominal cramping, fever etc.)

Inclusion Criteria:

All consecutive female patients aged 18-70 years presenting to the Center for successive OH
and EMB with the ability to provide written informed consent and meets at least one of the
criteria mentioned below:

- Previous cesarean section

- Nulliparous

- Postmenopausal

- Previous loop electrosurgical excision procedure (LEEP) or cone biopsy

- Previous myomectomy

Exclusion Criteria:

Premenopausal multiparous women with no prior surgeries performed on the uterus.

- Patients unable to provide informed consent

- Patients visiting the fibroid and endometriosis center with abnormal uterine bleeding,
infertility or for preoperative evaluation; however, OH and EMB is not required for
their evaluation based on their providers' clinical judgment.

- Patients with genital tract lesions.