A systematic review of the effect of the distension medium on pain during outpatient hysteroscopy

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1 A systematic review of the effect of the distension medium on pain during outpatient hysteroscopy Natalie A. M. Cooper, M.B., Ch.B., a Paul Smith, B.Sci., M.B., Ch.B., b Khalid S. Khan, M.B., B.S., M.Sc., M.Med., c and T. Justin Clark, M.D. d a Clinical and Experimental Medicine, University of Birmingham; b Obstetrics and Gynaecology, West Midlands Deanery; c Obstetrics-Gynaecology and Clinical Epidemiology, Birmingham Women s Hospital, University of Birmingham; and d Birmingham Women s Hospital, Birmingham, United Kingdom Objective: To assess the effect of distension medium on pain during outpatient hysteroscopy. Design: Systematic review and meta-analysis. Setting: Outpatient hysteroscopy clinics. Patient(s): Women undergoing outpatient hysteroscopic examination. Intervention(s): Use of normal saline versus carbon dioxide as distension medium for outpatient hysteroscopy. Main Outcome Measure(s): Pain scores. Result(s): There was no statistically significant difference in pain scores when carbon dioxide or normal saline were used as the distension medium for outpatient hysteroscopy (standardized mean differences ¼ 0.05; 95% CI, 0.17 to 0.07; I 2 ¼ 92%). Conclusion(s): Carbon dioxide and normal saline are both suitable distending media for outpatient hysteroscopy as the procedural pain is comparable and the views obtained are satisfactory. However, normal saline does confer advantages that may make it more suitable for clinical use. (Fertil Steril Ò 2011;95: Ó2011 by American Society for Reproductive Medicine.) Key Words: Ambulatory, carbon dioxide, distension media, hysteroscopy, normal saline, office, outpatient, pain Hysteroscopy is one of the most common diagnostic tests in gynecology. The technique requires instillation of a distension medium to visualize the uterine cavity. A variety of media have been used: fluids such as normal saline, water, sorbitol, dextran, and glycine (1 4) and gases such as carbon dioxide (5, 6). More recently, miniaturization of endoscopy has facilitated the widespread use of hysteroscopy in an outpatient setting (7); however, as with any hollow viscus, distension of the uterine cavity causes pain (T12 L2 nerve roots). Moreover, spilling of distension medium into the abdominal cavity may be associated with referred pain to the shoulder tip, and cervical manipulation may cause vagal stimulation that results in fainting episodes (7). Image quality is an important consideration and may vary according to medium used. We conducted a systematic review to examine which distension medium causes the least amount of discomfort during outpatient hysteroscopy. MATERIALS AND METHODS We conducted the review prospectively, devising a protocol based upon widely documented methods (8, 9). Data Sources and Searches We conducted a comprehensive literature search to identify studies that evaluated pain associated with the use of differing distension media during outpatient hysteroscopy. The databases searched included MEDLINE (from 1950 to February 2009), EMBASE Received February 8, 2010; revised April 19, 2010; accepted April 30, 2010; published online June 23, N.A.M.C. has nothing to disclose. P.S. has nothing to disclose. K.S.K. has nothing to disclose. T.J.C. has nothing to disclose. Reprint requests: T. Justin Clark, M.D., Consultant Obstetrician and Gynaecologist and Honorary Senior Lecturer. Birmingham Women s Hospital, Birmingham, United Kingdom, B15 2TG ( justin.clark@ bwhct.nhs.uk). (from 1980 to February 2009), CINAHL (from 1981 to February 2009), and the Cochrane Library. A combination of the key words hysteroscopy, vaginoscopy, vaginoscop*, (uter* AND disten*), distension media, sodium chloride, normal saline, carbon dioxide, dextran, mannitol, and their associated medical subject headings were used to search MEDLINE, EM- BASE, and CINAHL. The Cochrane Library was searched using the key words hysteroscopy and distension. There were no limits or filters placed on the searches to ensure maximum sensitivity. We also checked the reference sections of selected original articles for relevant papers and retrieved any that we felt were relevant. Study Selection The following criteria were used to determine which studies were included in the review. The population was women undergoing diagnostic or operative hysteroscopy in the outpatient setting. The intervention was a comparison of the use of different distension media. The outcome was assessment of pain. The study design was randomized controlled trials. Abstracts were independently reviewed by two of the authors (N.A.M.C. and P.S.). The complete manuscripts of citations fulfilling the selection criteria were reviewed in full to reach the final decision on inclusion or exclusion. Any disagreements about study eligibility were resolved by consensus. Inter-rater agreement for study selection was assessed using the kappa statistic (10). Data Extraction Data were extracted from the selected studies in duplicate (by N.A.M.C. and P.S.) using piloted data extraction forms. Data were collected from each trial for study quality according to strict criteria (Table 1) for the technical aspects of the procedure, pain assessment, image quality, procedural time, and shoulder tip pain. Studies varied in how pain was assessed; when an overall pain score was given, this 264 Fertility and Sterility â Vol. 95, No. 1, January /$36.00 Copyright ª2011 American Society for Reproductive Medicine, Published by Elsevier Inc. doi: /j.fertnstert

2 was used for the meta-analysis, but when the individual steps were scored and no overall score was given, the score relating to inspection of the uterine cavity was used. We collected data regarding image quality as this may be adversely affected by the type of distension medium used. Normal saline has a higher refractive index than air, which causes magnification and reduces the visual field (3). Carbon dioxide does not create a lavage, so blood, mucus, and bubbles may obscure the image. The different mechanisms of administration (insufflators for carbon dioxide and pressure bags for normal saline) may affect the length of the procedure, which prompted the collection of data regarding procedural time. Data Synthesis Pain experienced during outpatient hysteroscopy was evaluated using standardized mean differences (SMD). This measure was chosen as it allowed comparison of outcome data from studies using different scales to quantify pain (11). Heterogeneity was assessed by examining the I 2 statistic, which if greater than 75% suggests considerable heterogeneity (11). Meta-analysis was performed for data regarding pain during the procedure and procedural time weighting the studies by the inverse of the variance and using the random effects models to give conservative estimates of effect (11). For dichotomous outcomes, we used the Peto method due to a low incidence of events in the studies (12). Analyses were performed using RevMan software (13). RESULTS Study Selection, Details and Quality The literature search yielded 703 citations, and 20 were retrieved for further evaluation. Eleven studies were rejected because they did not meet our inclusion criteria (1, 2, 4, 6, 14 20), and two were rejected as duplicates (21, 22). The seven remaining studies were selected as eligible for inclusion in the review (3, 23 28); however, it became apparent that two of these papers may have reported the same study (24, 27). The investigators were contacted to confirm this, but no answer was received. To prevent probable duplication of data, we used the earlier published paper only (24), resulting in six papers being eligible for the review (Fig. 1). The inter-rater reliability for the study selection was very good (kappa ¼ 0.85). Details of the study populations, interventions, outcome assessment and data reporting are shown in Table 2. The quality of the studies was poor, with only one considered to have adequate randomization and concealment (24) (see Table 1). Effect of Distension Medium on Pain All six studies reported data for pain when comparing normal saline versus carbon dioxide. Five studies used scales to collect the data (23 26, 28) and reported them as mean and standard deviation. One study reported the number of people selecting each of four numbered categories (0 ¼ none, 1 ¼ mild, 2 ¼ severe, and 3 ¼ pain that did not allow the procedure to continue) (3). We used the category number as a value and calculated a mean and standard deviation (29) for the pain experienced during the procedure. Meta-analysis showed that there was no statistically significant difference in pain scores when carbon dioxide or normal saline were used as the distension medium for outpatient hysteroscopy (SMD ¼ 0.05; 95% CI, 0.17 to 0.07; I 2 ¼ 92%) (Fig. 2). Shoulder Tip Pain Shoulder tip pain was reported by all six studies. One study used a visual analogue scale to assess the severity of the pain and reported a mean and standard deviation (24). The remaining five studies (3, 23, 25, 26, 28) reported the number of events or the percentage of women who experienced shoulder tip pain. If the number of events was not reported (25, 28), we calculated the value from the percentage. Meta-analysis of five studies found that shoulder tip pain was statistically significantly reduced when using normal saline as compared with carbon dioxide as the distension medium (OR ¼ 0.19; 95% CI, 0.09 to 0.40; I 2 ¼ 41%) (see Fig. 2). Vasovagal Episodes Vasovagal reactions were specifically reported by four studies (3, 24, 25, 30), one of which reported no vasovagal episodes (25). The remaining two studies reported symptoms that may be attributed to vasovagal episodes (nausea, dizziness, and hypotension) (23, 28) but did not specifically state them to be vasovagal reactions. We used the number of events from the three studies (3, 24, 26) that stated the patients had suffered vasovagal episodes for meta-analysis and found that there were statistically significantly fewer vasovagal episodes when using normal saline as the distension medium (OR ¼ 0.31; 95% CI, 0.12 to 0.82; I 2 ¼ 0%) (see Fig. 2). TABLE 1 Methodologic quality assessment of the studies included in the systematic review of the effect of the distension medium used on pain during outpatient hysteroscopy. Study Randomization sequence a Allocation concealment b Follow-up c Total adequate Brusco et al. (23) Inadequate Inadequate 100% 1 Lavitola et al. (24) Adequate Adequate 100% 3 Litta et al. (25) Inadequate Inadequate 100% 1 Nagele et al. (26) Inadequate Inadequate 100% 1 Paschopoulos et al. (3) Inadequate Inadequate 100% 1 Shankar et al. (28) Inadequate Inadequate 100% 1 a Randomization was considered adequate if it was a computer-generated random number sequence. b Concealment was considered adequate if it was a third party (e.g., pharmacy staff); the concealment was inadequate if sealed envelopes were used. c If all patients were accounted for, the follow-up evaluation was considered 100%. This is because if the patients did not have the procedure they would have been unable to contribute to the results; however, the investigators could explain why their data were missing. Fertility and Sterility â 265

3 FIGURE 1 Study selection process for systematic review of the effect of the distension medium used on pain during outpatient hysteroscopy. Potentially relevant citations identified and screened fo r retrieval Medline, EMBASE and CINAHL 685 Cochrane Library 18 Total n = 703 Citations retriev ed for more detailed evaluation Total n = 20 Publications selected for appraisal n = 6 Citations excluded Inappropriate population, inte r vention or outcome measure n=482 Duplicates n= 201 Total n = 683 Publications excluded Not randomized controlled trial n =11 Duplicates n = 3 Total n =14 Duration of Procedure Procedural time was reported by four studies (23 26) as mean and standard deviation. Meta-analysis found that outpatient hysteroscopy using normal saline was statistically significantly shorter than when using carbon dioxide (SMD ¼ 1.32; 95% CI, 1.48 to 1.17; I 2 ¼ 98%) (see Fig. 2). Image Quality Image quality was reported by four studies (23, 24, 26, 28). Three studies used scales with categories (e.g., 0 ¼ no view, 1 ¼ poor view, etc.) (23, 24, 26) and asked the operators to select the appropriate number. One study used these data to calculate a mean and standard deviation (26). The remaining two studies (23, 24) reported the number of operators selecting from certain categories but did not give data for all of the categories. The final study (28) used unnumbered categories (very satisfactory, satisfactory, and unsatisfactory) and asked the operators to select an appropriate one. We were not able to meta-analyze these data from the studies as they were not adequately reported and the outcome assessments were not comparable. Three studies reported no statistically significant difference in image quality between carbon dioxide and normal saline (23, 24, 26); however, one of these studies (26) reported changing the distension media from carbon dioxide to normal saline in eight (10.1%) patients. One study found a statistically significant increased risk of unsatisfactory view with the use of carbon dioxide (relative risk ¼ 4.75; 95% CI, 1.61, 16.4) (28), attributing it to bubbles and bleeding. Of the 19 patients who had an unsatisfactory view at hysteroscopy using carbon dioxide, 17 were changed to normal saline and an improved view was reported in 11 (64.7%). DISCUSSION Principal Findings of the Review This systematic review and meta-analysis finds that there is no statistically significant difference in the pain of outpatient hysteroscopy when using carbon dioxide or normal saline as the distension medium. However, meta-analysis found that vasovagal episodes, shoulder tip pain, and procedural time were all statistically significantly reduced when using normal saline. Image quality may be better with normal saline as it causes a lavage and thus prevents blood and bubbles from obscuring the view. Strengths and Limitations of the Review Many aspects of the review lead us to believe that our results are valid. First, we formulated a clinically focused question. We then performed comprehensive searches that encompassed multiple online databases as well as searching the articles reference sections for relevant studies. We did not restrict our search to the English language, and we used broad search terms to avoid making the question too specific to be adequately sensitive. We did not seek any unpublished data, so there is a risk of publication bias. All data were extracted in duplicate to avoid errors. Data were restricted to randomized controlled trials to minimize selection bias. There was considerable heterogeneity (I 2 ¼ 92%) in the meta-analysis of procedural pain. Because the random effects model gives more weight to small studies, we excluded one small study (23) with an outlying result to explore heterogeneity. As well as being small, this study used a vaginoscopic approach (without a speculum and tenaculum) in the normal saline group and a traditional approach with a speculum in the carbon dioxide group and so had more than one variable. Analysis without this study reduced the heterogeneity to 82% but still produced a nonsignificant result overall (SMD ¼ 0.06; 95% CI, 0.24 to 0.37). We were unable to identify any causes for heterogeneity, and it may be attributable to the small number of studies used for the meta-analysis. Heterogeneity was also high in the meta-analysis of procedural time (I 2 ¼ 98%), and again this was difficult to explain. All of the studies in this analysis found individual statistically significant results in favor of the use of normal saline, which was in keeping with our metaanalysis result. In contrast, heterogeneity was low in the metaanalyses exploring vasovagal episodes and shoulder tip pain. A weakness of our review is that it only contains six studies, five of which we assessed to be of low quality due to inadequate randomization and concealment, but these data reflect the totality of the published trials in this area. Although we found statistically significant results, we cannot assess whether they are clinically significant. Comparison with Other Studies There are no published systematic reviews that compare carbon dioxide to normal saline as the distension medium for outpatient hysteroscopy. A large case series of 5,000 patients found that carbon dioxide and normal saline were both feasible distending media, with no difference in success rate but that there were statistically significantly more vasovagal episodes and shoulder tip pain when carbon dioxide was used (14). This is in keeping with our findings. Clinical Implications of the Review Our review supports the use of both normal saline and carbon dioxide for outpatient hysteroscopy, as the pain experienced during the diagnostic procedure is comparable between media. However, 266 Cooper et al. Techniques and instrumentation Vol. 95, No. 1, January 2011

4 Fertility and Sterility â 267 TABLE 2 Characteristics of the selected studies included in the systematic review of the effect of the distension medium used on pain during outpatient hysteroscopy. Study Participants Intervention Comparison Outcome measures Data reported Brusco et al. (23) Lavitola et al. (24) Litta et al. (25) Women undergoing hysteroscopy at an artificial insemination and sterility clinic. Infertile women undergoing diagnostic outpatient hysteroscopy. Pre- and postmenopausal women undergoing diagnostic outpatient hysteroscopy. External genitalia cleaned with disinfectant. Outpatient hysteroscopy performed with a 4-mm rigid hysteroscope and a 7-mm operative sheath by a vaginoscopic approach. Normal saline delivered by a pressure bag (at 50 mm Hg) used to distend the uterine cavity. A paracervical block was used when necessary. N ¼ 45 Vaginoscopic hysteroscopy with a 30 continuous flow hysteroscope, using normal saline as the distension medium introduced by a pressure bag at mm Hg measured by a manomometer. An endometrial biopsy was taken when indicated. N ¼ 97 Speculum inserted into the Rigid, 2.9 mm, 30 hysteroscope introduced into canal into the uterine cavity, normal saline infused by a 100 mm Hg pressure bag. The hysteroscopy then continued as normal. Endometrial biopsies were taken when indicated. N ¼ 214 External genitalia cleaned with disinfectant. Outpatient hysteroscopy performed with a 4-mm rigid hysteroscope and a 7-mm operative sheath by a traditional approach using a speculum and tenaculum. Carbon dioxide delivered by a uterine insufflator at 40 ml/ min used to distend the uterine cavity. A paracervical block was used when necessary. N ¼ 29 Vaginoscopic hysteroscopy with a 30 continuous flow hysteroscope, using carbon dioxide as the distension medium introduced by uterine insufflator at a pressure of 100 mm Hg. An endometrial biopsy was taken when indicated. N ¼ 92 Speculum inserted in to the Rigid, 2.9-mm, 30 hysteroscope, introduced into canal into the uterine cavity carbon dioxide administered by a hysterosufflator with a pressure of 100 mm Hg and flow rate of 40 ml/min. The hysteroscopy then continued as normal. Endometrial biopsies were taken when indicated. N ¼ 201 Scale of 0 5 to score pain during the procedure, and presence of shoulder pain were recorded. Operators graded quality of image on a scale from 0 5 (5 ¼ good image quality). Time recorded from introduction of hysteroscope until removal at the end of procedure. VAS 0 10 used to score pain during progression of the scope through the canal, during inspection of the cavity, and the intensity of any shoulder pain. Image quality scored by the operator on a scale of 0 5 (5 ¼ excellent). Incidence of vasovagal episodes reported. VAS 0 10 reported, completed approximately 10 min after end of procedure to rate pain experienced. Procedure duration reported. Presence of shoulder tip pain reported. Pain and procedure time reported as mean and SD. Number and percentage of women experiencing shoulder tip pain reported. Image quality reported as percentages. Mean and SD reported for pain and procedural time, as well as number and percentage of women experiencing vasovagal episodes and examinations with mediocre image quality. Mean and SD reported for pain and procedural time as well as number and percentage of women experiencing shoulder tip pain.

5 268 Cooper et al. Techniques and instrumentation Vol. 95, No. 1, January 2011 TABLE 2 Continued. Study Participants Intervention Comparison Outcome measures Data reported Nagele et al. (26) Pre- and postmenopausal women undergoing diagnostic outpatient hysteroscopy. Paschopoulos et al. (3) Women admitted for total abdominal hysterectomy who agreed to undergo outpatient diagnostic hysteroscopy hours before surgery. Exclusions: suspicion of endometrial cancer. Speculum inserted into the Os probed and if thought to be tight, dilated under local anesthesia if required. Rigid, 5.5-mm (with sheath), 30 hysteroscope, introduced into canal into the uterine cavity, normal saline infused by a mm Hg pressure bag. The hysteroscopy then continued as normal. Targeted endometrial biopsies and minor surgical procedures were performed when indicated using a 7-mm operative sheath. N ¼ 78 Hysteroscopy performed with a 2.8-mm, 30, rigid hysteroscope by a vaginoscopic approach. Normal saline delivered by a pressure bag (40 80 mm Hg) used to distend the uterine cavity. N ¼ 35 Speculum inserted in to the Os probed, and if thought to be tight, dilated under local anesthesia if required. Rigid, 5.5-mm (with sheath), 30 hysteroscope, introduced into canal into the uterine cavity, carbon dioxide administered by a hysterosufflator at 100 mmhg with a variable flow rate up to 120 ml/min. The hysteroscopy then continued as normal. Targeted endometrial biopsies and minor surgical procedures were performed when indicated using a 7-mm operative sheath. N ¼ 79 Hysteroscopy performed with a 2.8-mm, 30, rigid hysteroscope by a vaginoscopic approach. Carbon dioxide was delivered by a microhysteroflator with a maximum pressure of 200 mm Hg and a flow rate of 25 ml/min to distend the uterine cavity. N ¼39 Abdominal pain and shoulder tip pain ranked on scale of 0 4 (0 ¼ no pain, 1 ¼ mild, 2 ¼ moderate, 3 ¼ severe, 4 ¼ very severe). Image quality graded on a scale of 0 4 (0 ¼ none, 1 ¼ good, 2 ¼ adequate, 3 ¼ poor, 4 ¼ very poor). Incidence reported of vasovagal episodes. Procedure duration reported. Completed a questionnaire after the hysteroscopy which asked patients to rate shoulder pain and pelvic pain on a 4-point scale (0¼ none, 1¼ mild, 2¼severe, 3¼ pain that did not allow the procedure to continue). Abdominal pain, shoulder pain, hysteroscopic vision, and procedural time reported as mean and SD. Number of women experiencing shoulder pain and vasovagal episodes also reported. Number of poor or very poor image examinations reported. Number and percentage of women in each group who selected each of the four categories. We allocated values to the categories (i.e., 0, 1, 2, and 3) and calculated the mean and SD.

6 Fertility and Sterility â 269 TABLE 2 Continued. Study Participants Intervention Comparison Outcome measures Data reported Shankar et al. (29) Pre- and postmenopausal women undergoing diagnostic outpatient hysteroscopy for abnormal uterine bleeding. Exclusions: procedure not feasible when unable to visualize the cervix or for severe cervical stenosis. Pelvic pain scored with VAS 0 10, and PPI. Shoulder tip pain scored with VAS Image quality ranked as very satisfactory, satisfactory, or unsatisfactory. Pelvic pain reported as mean and SD. Shoulder tip pain reported as percentage, with 95% CI. We converted percentages to numbers. Image quality reported as number of examinations falling into each category. [Group 1] Speculum inserted in to the vagina to visualize the cervix. Vulsellum applied. Cervix dilated if necessary. Rigid, 5.5-mm (with sheath), 30 hysteroscope introduced into the cervical os and along the canal into the uterine cavity, normal saline infused by a mm Hg pressure bag. The hysteroscopy then continued as normal. Endometrial biopsies were taken from all patients. N ¼ 100 [Group 2] Another saline group had lignocaine added to the distension medium. This group was not used in our analysis. N ¼ 100 Speculum inserted in to the Vulsellum applied. Cervix dilated if necessary. Rigid, 5.5- mm (with sheath), 30 hysteroscope introduced into canal into the uterine cavity, carbon dioxide, delivered by a hysteron-insufflator at a maximum pressure of 100 mm Hg with a variable flow rate of up to 100 ml/min. The hysteroscopy then continued as normal. Endometrial biopsies were taken from all patients. N ¼ 100 Note: CI ¼ confidence interval; PPI ¼ Present pain intensity scale (verbal descriptors of pain ranked from 0 5 on a numeric scale); SD ¼ standard deviation; VAS ¼ visual analogue scale.

7 FIGURE 2 Forest plots showing the results of meta-analysis of studies that examine the effect of the distension medium used on pain during outpatient hysteroscopy. normal saline is the distension medium of choice in the office setting because it is associated with statistically significantly fewer vasovagal episodes and incidences of shoulder tip pain. Furthermore, distension of the uterine cavity with normal saline as opposed to carbon dioxide results in a quicker hysteroscopic procedure, which is especially advantageous in conscious patients who are undergoing an invasive test. Although we could not adequately assess image quality, two of the studies reported changing from carbon dioxide to normal saline when the image was poor or obscured by blood (26, 28); this suggests that normal saline is a more practical medium and can cause an improvement in view over carbon dioxide. A further consideration is the specialist equipment that is required to use carbon dioxide to distend the uterus. A hysterosufflator is required to control insufflation of carbon dioxide into the uterus; however, normal saline can be administered simply with a giving set and gravity or a pressure bag, although this can result in leakage of fluid and a more messy procedure compared with carbon dioxide. Our review was not able to examine the cost effectiveness of the distension media, but the increased duration of the procedure and capital outlay for specialist equipment associated with the use of carbon dioxide, for no apparent benefit over normal saline, may not support the routine use of carbon dioxide in an outpatient setting from an economic perspective. A final, important consideration refers to the increasing use of therapeutic procedures in outpatient hysteroscopy. These procedures include the use of bipolar electrosurgery (7, 31) for removing fibroids, polyps, synechiae (32), and septae (33, 34), which require a conducting liquid medium (i.e., normal saline). Moreover, other office interventional procedures using mechanical equipment (35) or where there is a likelihood of endometrial fragmentation necessitate the use of a liquid distension medium to maintain visualization by clearing both blood and debris. Thus, performing a diagnostic hysteroscopy with normal saline will negate the need to change distending medium should a subsequent operative procedure be required (i.e., the see and treat ethos). 270 Cooper et al. Techniques and instrumentation Vol. 95, No. 1, January 2011

8 Unanswered Questions and Future Research An economic analysis should be performed to analyze whether there is any discrepancy regarding cost when either carbon dioxide or normal saline are used for outpatient hysteroscopy. From our experience, the majority of clinicians within the United Kingdom are using normal saline for their outpatient hysteroscopies, and it would be interesting to examine the reasons for this with qualitative research. REFERENCES 1. Amin HK, Neuwirth RS. Operative hysteroscopy utilizing dextran as distending medium. Clin Obstet Gynecol 1983;26: Taylor PJ, Lewinthal D, Leader A, Pattinson HA. A comparison of Dextran 70 with carbon dioxide as the distention medium for hysteroscopy in patients with infertility or requesting reversal of a prior tubal sterilization. Fertil Steril 1987;47: Paschopoulos M, Kaponis A, Makrydimas G, Zikopoulos K, Alamanos Y, O Donovan P, et al. Selecting distending medium for out-patient hysteroscopy: does it really matter? 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