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Oral Misoprostol Before Office Endometrial Biopsy

Perrone, Jack F. MD; Caldito, Gloria PhD; Mailhes, John B. PhD; Tucker, Angela N.; Ford, William R. MD; London, Steve N. MD

Original Research

OBJECTIVE To evaluate oral misoprostol use before office endometrial biopsy.

METHODS Forty-two nonpregnant women aged 35–77 years were randomized to a prospective, double-blind study to receive either 400 μg oral misoprostol or placebo 3 hours before office endometrial biopsy. Misoprostol effects were assessed by 1) cervical resistance, 2) ease of performing the endometrial biopsy, 3) success rate of obtaining an endometrial biopsy, 4) pain intensity associated with the endometrial biopsy, and 5) adverse clinical side effects.

RESULTS Patients in the misoprostol group experienced significantly (P < .01) more pain associated with the endometrial biopsy. The observed power to detect this difference in misoprostol-placebo comparison using the Wilcoxon rank sum test at 0.05 level of significance is 89%. In addition, significantly (P < .05) more patients had the adverse side effect of uterine cramping at 1.5 hours after medication ingestion in the misoprostol group. The observed power to detect this difference is 98%. There were no differences between the misoprostol and placebo groups in cervical resistance, ease of performing the biopsy, success rate for obtaining an endometrial biopsy, or adverse side effects at 3 hours post medication ingestion.

CONCLUSION Oral misoprostol 400 μg caused more uterine cramping and pain in nonpregnant women undergoing office endometrial biopsy when given 3 hours before biopsy attempt. No other cervical effects were noted.

Oral misoprostol causes more pain and uterine cramping in women undergoing endometrial biopsy than placebo.

Department of Obstetrics and Gynecology and Department of Biometry, Louisiana State University Health Sciences Center, Shreveport, Louisiana.

Address reprint requests to: Jack F. Perrone, MD, Louisiana State University Health Sciences Center, Department of Obstetrics and Gynecology, 1501 Kings Highway, PO Box 33932, Shreveport, LA 71130; E-mail:

Received August 28, 2001. Received in revised form October 30, 2001. Accepted November 1, 2001.

An endometrial biopsy is a common office procedure used for obtaining a pathologic diagnosis of the uterine endometrium in women presenting with abnormal uterine bleeding.1 Office endometrial biopsy is generally easily performed, but it does cause patients varying degrees of uterine or pelvic pain. In addition, occasionally an endometrial biopsy cannot be easily obtained secondary to anatomic cervical stenosis, scarring, or atrophy. These are two areas of concern, and it would be beneficial to our patients if the biopsy could be less painful. This issue is not new and has been approached previously with the use of either paracervical analgesic blocks or oral nonsteroidal anti-inflammatory drugs before biopsy attempt. Secondly, in difficult biopsy cases caused by cervical anatomic changes, it would be worthwhile if there was a way to intrinsically change the cervix to make the biopsy easier. Currently, the mechanical means to overcome anatomic cervical stenosis, scarring, and atrophy during endometrial biopsy is by direct cervical traction with a tenaculum and/or the additional use of a probe, dilator, or spreading clamp. These techniques usually are associated with increased pain and anxiety. They also do not always result in successful biopsies.

Misoprostol (Cytotec, G. D. Searle & Co., Chicago, IL) is a stable, synthetic prostaglandin estrone analogue available in 100-μg and 200-μg tablets. It has Food and Drug Administration approval for preventing nonsteroidal anti-inflammatory drug-induced gastric ulcers in patients at high risk for complications resulting from gastric ulcers.2 In the specialty of obstetrics and gynecology, misoprostol has been used off-label for cervical priming or ripening in pregnant patients, induction of labor in gravid patients, pretreatment of the cervix before suction curettage for pregnancy terminations, missed and elective medical abortions, and for preventing and treating postpartum hemorrhage.3–14

The off-label use of misoprostol for gynecologic indications has received less attention. Four studies involving cervical priming before hysteroscopy in nonpregnant women have been published.15–18 Three of these studies15–17 reported that oral or vaginal misoprostol resulted in greater cervical dilatation, decreased cervical resistance, and less need for mechanical dilatation before hysteroscopy. In contrast, the other reported study did not demonstrate a cervical priming effect from misoprostol before hysteroscopy.18 Thus, additional information is needed to further evaluate the clinical efficacy of misoprostol for gynecologic procedures. The objective of the present study was to further evaluate the clinical effects of misoprostol when used before attempted office endometrial biopsy.

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This research was approved by the Institutional Review Board of Louisiana State University Heath Sciences Center-Shreveport (LSUHSC-S). Eligible patients were nonpregnant women who had a medical indication for an office endometrial biopsy who presented to the out-patient gynecology clinics of LSUHSC-S during March 27, 2000, to January 17, 2001. They were offered participation in the study, and those choosing to participate were assessed according to the inclusion and exclusion criteria of the study protocol. Inclusion criteria included signing the informed consent form, agreeing to follow the study protocol, a medical indication for an endometrial biopsy, a negative urine pregnancy test, and no contraindications to misoprostol. Exclusion criteria were a positive history of inflammatory bowel disease and not meeting the inclusion criteria.

Forty-two women (21 in each group) aged 35–77 years were enrolled in this study. Each participant was randomly assigned to receive either oral misoprostol (400 μg) or oral placebo 3 hours before attempting an endometrial biopsy. To insure similar sample sizes between the two treatment groups, computer-generated randomization was performed in blocks of six (three to each study group) relative to the time that patients entered the study. Only the statistician and the designated pharmacy employee knew the randomization schedule. A designated LSUHSC-S pharmacy employee possessed the randomization schedule and distributed the assigned medication (misoprostol or placebo) accordingly on the day of endometrial biopsy in a sealed numbered envelope to the research associate. The patient then opened the envelope in the presence of the research associate only, who did not look at the actual pills ingested but was there to document the time and make sure the patient took the medication with water. The medication was not labeled so the patient could not know which medication was taken. Hence, the patient, the physician performing the biopsy, and the research associate did not know which medication was ingested by the patient.

Before pill ingestion, oral body temperature was taken. At 1.5 and 3 hours after pill ingestion, the patient was assessed for adverse side effects (body temperature change, nausea, vomiting, headache, diarrhea, vaginal bleeding, uterine cramping, and pelvic pain). Uterine length was recorded (cm), and each endometrial biopsy was performed by the principal investigator using a 3-mm endometrial biopsy pipet curet (Milex Pipet Curet, Milex Products, Chicago, IL). Although a 600-mg ibu-profen tablet was available for any patient who complained of excessive uterine cramping or pelvic pain, no patient requested the analgesic. If needed for biopsy, a single tooth tenaculum was applied to the anterior cervix for stabilization and counter-traction. A steel cervical dilator was also available and used. After the endometrial biopsy and completion of the pain intensity visual analogue scale, the participants were given follow-up appointments in the Women's Health Clinic of LSU-HSC-S to discuss the biopsy pathology results.

The efficacy of misoprostol as compared with placebo was assessed 3 hours after the medication ingestion by five outcome variables: 1) cervical resistance (peak compression force, kg), 2) ease of performing the endometrial biopsy (need for tenaculum and/or dilator usage), 3) success rate of obtaining a biopsy (yes or no), 4) pain intensity associated with the biopsy (evaluated by a visual analogue pain scale), and 5) adverse clinical side effects (evaluated by a visual analogue scale specific for the side effect of interest). Cervical resistance (peak compression force) was measured with a Series BG Digital Force Gauge (Cooper Instruments, Warrenton, VA) attached to the end of the 3-mm endometrial biopsy pipet curet. This measurement was the greatest point of cervical resistance encountered when the pipet curet initially passed through the external and internal cervical os. The visual analogue scales were measured on a millimeter scale ranging from zero to 100 with zero representing the least possible pain or no side effect and 100 representing the worst pain or side effect.19

Because of a non-normal distribution of the pain intensity and adverse clinical side effect data, the Wilcoxon rank sum test was used to compare the median values of the misoprostol and placebo groups. The two groups were also compared on cervical resistance (mean peak compression force) using the Wilcoxon rank sum test, and on having a successful biopsy and ease of performing the biopsy (need for instrument(s) use) using the χ2 test.

The demographic, historical, and clinical data included age, gravidity, parity, race, weight, height, menopausal status, current hormone usage, last menstrual period, indication for endometrial biopsy, prior cervical or uterine surgery, prior endometrial biopsy, and type of past obstetric deliveries. The Wilcoxon rank sum test was used to test for differences among quantitative variables, and the χ2 test was used to test for differences among qualitative variables. The SAS 8.1 software (SAS Institute Inc., Cary, NC) was used for all statistical calculations.

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Analysis of the demographic, historical, and clinical data show that patient weight was the only statistically significant (P < .05) difference between groups (Table 1). Analysis of the outcome variable data (Table 2) shows that patients in the misoprostol group experienced significantly (P < .01) more pain associated with the endometrial biopsy and significantly (P < .05) more adverse side effects of uterine cramping and pelvic pain 1.5 hours after medication ingestion than did patients in the placebo group. There were no other differences between the groups in adverse side effects at 1.5 hours after medication. At 3 hours post medication, no differences in adverse side effects were found between the groups. There were no differences found between the two groups in cervical resistance (mean peak compression force), success rate for obtaining an endometrial biopsy, and the ease of performing the biopsy (need for tenaculum and/or dilator). P values for these three outcome variables were not statistically significant (P < .05), although the power to detect a difference between these variables was inadequate.

Table 1

Table 1

Table 2

Table 2

Actual analysis of the observed power for the misoprostol-placebo comparison was also calculated for each of the five outcome variables (Table 2). There is adequate statistical power to declare a significant difference at 0.05 level of significance between the two groups with regard to pain intensity and the adverse side effect of uterine cramping 1.5 hours after the medication (89% and 98%). Despite the low power (47%) for pelvic pain comparison resulting from the large observed variability for this measurement, a significant difference is observed between the two groups with the misoprostol group experiencing more pelvic pain. The observed power for the nonsignificant variables of cervical resistance, ease of performing biopsy, and successful biopsy were also low at 6%, 45%, and 5%.

The data for the two outcome variables, ease of performing the biopsy, and pain associated with the endometrial biopsy, were analyzed for the effect of instrument(s) use. As shown in Table 2, there was no significant difference between the groups in the ease of performing the biopsy (P = .06). The need for the additional use of a tenaculum and/or dilator to obtain the biopsy was not statistically different between the groups. The effect of instrument (tenaculum and/or dilator) use on pain intensity scores was significant however. Pain intensity scores for patients who required the use of an instrument for obtaining a biopsy were significantly higher (P < .01) than for patients who did not require instrument usage (Table 3). When analyzed per treatment group, the use of instrument(s) during a biopsy resulted in significantly more pain within both the misoprostol and placebo groups. Furthermore, whether or not additional instruments were used, more pain was experienced in patients who took misoprostol as compared with placebo. There was a significant (P < .05) difference between groups on pain intensity when no instrument(s) were used, whereas, when an instrument(s) was used, no significant difference was shown (Table 4). There were no complications from the endometrial biopsy procedure in any patient.

Table 3

Table 3

Table 4

Table 4

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This randomized study was designed to evaluate cervical effects from a single 400-μg oral dose of misoprostol given 3 hours before office endometrial biopsy as compared with placebo. The sample of patients studied included premenopausal, perimenopausal, and postmeno-pausal women from a semidiverse urban and rural population. Cervical effect was assessed by five outcome variables which, in our opinion, are clinically relevant to the adequate performance of an office endometrial biopsy.

A 400-μg dose of oral misoprostol given 3 hours before endometrial biopsy was selected based on the results from a randomized controlled trial on the use of oral and vaginal misoprostol versus placebo for preoperative cervical dilatation11 and for enhanced patient compliance in our population with an oral medication and study participation limited to 4 hours. Ngai et al8 showed that a 400-μg oral dose of misoprostol was as effective as either a 200- or 400-μg vaginally administered tablet for cervical priming when given 3 hours before first-trimester vacuum aspiration. No significant differences were found between these groups. The misoprostol-treated patients had significantly (P < .01) increased baseline cervical dilatation and significantly (P < .05) decreased cumulative force required for cervical dilatation compared with the placebo group at the 3 hour pretreatment interval. Patients in the placebo group had significantly (P < .05) fewer adverse side effects than those in the misoprostol group, and there were no significant differences in side effects among patients who received misoprostol. Operative complications were not encountered in any of the patients. Because of the high inherent success rate for endometrial biopsy secondary to the small diameter pipet, we thought a minimal increase in dilatation of the cervix would be necessary to decrease pain associated with the biopsy, obtain the biopsy more easily, and increase the success rate in difficult cases secondary to anatomic changes. However, we acknowledged that there could possibly be a difference in effect with nonpregnant women.

In contrast to the obstetric literature, there are limited data available regarding the use of misoprostol in non-pregnant patients for gynecologic indications. The four studies that evaluated misoprostol for cervical priming before diagnostic and operative hysteroscopy reported different results.15–18 Preutthipan and Herabutya15,16 and Ngai et al17 showed that misoprostol significantly increased cervical dilatation and decreased both cervical resistance and the need for additional cervical dilatation before hysteroscopy. Conversely, Cooper et al18 found no significant difference in the cervical resistance between misoprostol and placebo when misoprostol was given as a 1000-μg vaginally placed tablet 2–4 hours before operative hysteroscopy in women treated with goserelin for 5 weeks preoperatively.

In two of these studies by the same authors, when 200 μg of misoprostol or placebo was placed vaginally 9–10 hours before hysteroscopy in nulliparous patients and cervical priming effects were then evaluated before diagnostic hysteroscopy15 and before operative hysteroscopy,16 misoprostol enhanced cervical dilatation, reduced the need for cervical dilatation before hysteroscopy, decreased the operating time, and reduced the frequency of complications (cervical tears). However, significant differences in side effects of mild lower abdominal pain and slight vaginal bleeding were also noted in the misoprostol groups. It is possible that the decreased complication rate after hysteroscopy in the misoprostol group and the relatively high complication rate (20.2% overall with 11.4% cervical tears) in the placebo group may reflect differences in surgical experience and technique. This complication rate was also noted by Scott and Magos (Letter to the Editor, Obstet Gynecol 2001;97: 641).

The efficacy of misoprostol for cervical priming was also supported by a randomized controlled study of nulliparous women who received 400-μg oral misoprostol 12 hours before diagnostic hysteroscopy.17 In that study, the authors found the cumulative force required to dilate the cervix was significantly less and the mean cervical dilatation was significantly greater in the misoprostol group. There were no differences in operating times, complication rates, or side effects between the misoprostol and control groups.17 In the three positive studies on preoperative misoprostol use,15–17 patients had a longer exposure to misoprostol (9–12 hours) than in our study.

In contrast, in the present study, we found no significant benefit for the oral administration of 400-μg misoprostol 3 hours before office endometrial biopsy. We were able to demonstrate with adequate power that patients in the misoprostol group experienced significantly more pain associated with the biopsy and significantly more uterine cramping at 1.5 hours after medication ingestion than did placebo. These two effects indicate that misoprostol had an effect on the uterus during this time frame. These are clinically relevant differences even though the uterine cramping did not require the use of an analgesic. The increase in pain associated with the endometrial biopsy from the misoprostol is increased discomfort to the patient. Both of these outcomes are in direct contrast to the desired effect to decrease pain with endometrial biopsy and use of misoprostol.

The visual analogue scale was used to measure the effects. This measurement has a subjective component, but no other objective measurement is available. The visual analogue scale measurement has been used in past and current studies and has been previously shown to be a valid instrument for the evaluation of pain.19 Because the patient was blinded to the drug she received, there is no bias in her individual measurement to assess her pain and discomfort.

We acknowledge that the observed power was inadequately low for the detection of the other three outcome variables secondary to the smaller sample size. The number of patients needed to satisfy adequate power for statistical significance for cervical resistance is 708 per group. This number of patients was beyond the intent of this study. However, there were no differences between the misoprostol and placebo groups in cervical resistance, ease of performance, and success rate. All these variables were objectively measured, and one physician, who was blinded to the medication, performed every biopsy. These data indicate that misoprostol is not useful for the difficult cases secondary to cervical anatomic changes. We conclude that misoprostol was not beneficial before office endometrial biopsy and do not recommend its use for this purpose.

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© 2002 The American College of Obstetricians and Gynecologists