Catheter type does not affect the outcome of intrauterine insemination treatment: a prospective randomized study

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1 TECHNIQUES AND INSTRUMENTATION Catheter type does not affect the outcome of intrauterine insemination treatment: a prospective randomized study Peter Fancsovits, M.Sc., Laszlone Toth, Akos Murber, M.D., Gyorgy Szendei, M.D., Zoltan Papp, D.Sc., and Janos Urbancsek, Ph.D. First Department of Obstetrics and Gynaecology, Semmelweis University Faculty of Medicine, Budapest, Hungary Objective: To compare the main outcome of IUI with the Gynetics catheter (Gynetics Medical Products, Hamont-Achel, Belgium) or the Makler cannula (Sefi-Medical Instruments, Haifa, Israel). Design: Prospective, randomized study. Setting: Infertility and endocrinology unit in a university hospital. Patient(s): Two hundred fifty-one infertile couples undergoing 784 consecutive IUI treatments. Intervention(s): Patients were randomly assigned to undergo IUI treatment with either the Gynetics catheter (124 patients) or the Makler cannula (127 patients). Main Outcome Measure(s): Primary outcome measures were pregnancy and cumulative pregnancy rates. Secondary outcome measures were the ease of introduction of the catheter, the presence of bleeding, and semen regurgitation after removal of the catheter. Result(s): The use of the Gynetics catheter resulted in similar pregnancy (10.4% vs. 9.7%) and cumulative pregnancy rates (27.9% vs. 26.4%) as compared with the Makler cannula. Difficult introduction of the catheter was more frequent in the Gynetics group than in the Makler group (19.4% vs. 8.0%, respectively), but the frequency of bleeding did not differ between groups. Sample regurgitation was observed more often in the Makler group than in the Gynetics group (49.9% vs. 17.9%, respectively). Conclusion(s): A lower frequency of sperm regurgitation and a higher frequency of difficult introduction was observed when the Gynetics catheter was used. However, there was no significant difference in pregnancy rates with use of either the Gynetics catheter or the Makler cannula. (Fertil Steril 2005;83: by American Society for Reproductive Medicine.) Key Words: Intrauterine insemination (IUI), Gynetics catheter, Makler cannula Homologue IUI is one of the oldest treatments for infertility, and it is still a widely used and cost-effective therapy. The aim of IUI with washed spermatozoa is to bypass the cervical mucus barrier and increase the sperm concentration at the site of fertilization. The pregnancy rate per IUI cycle varies between 6% and 22% (1 4). The main factors affecting the efficiency of IUI treatments are the woman s age, cause of infertility, sperm quality, and ovarian stimulation (1, 4 6). During the IVF treatments, the type of ET catheter has proved to have a considerable effect on treatment outcome (7, 8). The explanation for this difference is still unclear, but it might be associated with the traumatic effects of the Received May 19, 2004; revised and accepted August 8, Presented at the 18th Annual Meeting of the European Society of Human Reproduction and Embryology, Vienna, Austria, July 1 3, Reprint requests: Peter Fancsovits, M.Sc., First Department of Obstetrics and Gynaecology, Semmelweis University Faculty of Medicine, 27. Baross u., Budapest 1088, Hungary (FAX: ; fancsi@noi1.sote.hu). catheter during introduction into the uterine cavity (9, 10). Data are limited regarding comparisons between different types of IUI catheters, and the results do not confirm the hypothesis that the use of an insemination catheter with a soft tip has any beneficial effect on the outcome of IUI (11, 12). Various types of IUI catheters are commercially available. They vary in length, caliber, location of the distal port (endor side-loading), and degree of rigidity and malleability. All of them must meet the following criteria: [1] they are easy to use, [2] they are semirigid devices that follow the curvature of the uterus and minimize trauma to the cervix and endometrium, [3] they are made of nontoxic material, and [4] the intrauterine tip of the catheter occupies a small volume, to minimize reflux of the inseminated sample (13). During the past 5 years, we used a simple, semirigid, side-loading Gynetics catheter (Gynetics Medical Products, Hamont-Achel, Belgium) for IUI. In some cases, we had difficulty inserting the Gynetics catheter into the uterine cavity, and a stylet or tenaculum had to be used as an /05/$30.00 Fertility and Sterility Vol. 83, No. 3, March 2005 doi: /j.fertnstert Copyright 2005 American Society for Reproductive Medicine, Published by Elsevier Inc. 699

2 adjuvant. Occasionally, reflux of the sperm suspension was observed after removal of the catheter. It is important for the injected contents to be retained within the uterine cavity to maximize the chances of sperm getting to the site of fertilization. To minimize the occurrence of these problems, we considered introducing another IUI catheter into our practice. The Makler cannula (Sefi- Medical Instruments, Haifa, Israel) (14) is the only IUI catheter that is designed to minimize reflux of the inseminated sample. In reviewing the relevant literature, however, we did not find any clinical study comparing the incidence of regurgitation of inseminated sample between different IUI catheters. The Makler cannula is a side-loading IUI catheter that is shorter, thicker, and more rigid than the Gynetics catheter. Used together with the Makler insemination device, the flare base of the cannula can be pressed against the cervix and can retain the sperm suspension in the uterine cavity. The purpose of this prospective, randomized study was to evaluate the characteristics and the efficacy of the IUI procedure with either the Gynetics catheter or the Makler cannula. In particular, we were interested in the effect of these IUI devices on the ease of introduction of the catheter, the frequency of trauma and semen regurgitation after insemination, and the extent to which these characteristics affect the pregnancy rate of IUI treatments. MATERIALS AND METHODS Patients Two hundred fifty-one infertile couples undergoing 784 consecutive IUI treatments from March 2000 to July 2003, at the Division of Assisted Reproduction, First Department of Obstetrics and Gynaecology, Semmelweis University Faculty of Medicine (Budapest, Hungary), participated in this study. Infertility was defined as at least 1 year of unprotected intercourse without conception. The indications for IUI were male factor infertility, cervical factor infertility, unexplained infertility, and a combination of any of these indications. Couples were treated by IUI if the women were ovulatory and had at least one open fallopian tube, and progressive motile sperm were present in the semen sample after sperm preparation. The IUI treatment was repeated up to six times or until the first pregnancy resulting in live birth occurred. The study was approved by the institutional review board of the First Department of Obstetrics and Gynaecology, Semmelweis University Faculty of Medicine. Randomization All patients were prospectively randomized into two groups: 124 were inseminated with the Gynetics catheter and 127 with the Makler cannula. Each patient was randomized on the day of their first IUI treatment, and the same catheter was used for all further inseminations within the study period. Randomization was achieved by a computer-generated randomization table, which was known by the staff of the andrology laboratory only. Ovulation Induction Ovarian stimulation was achieved by combined clomiphene citrate and hmg therapy. On days 7 10 of the cycle, transvaginal ultrasound assessment and serum E 2 measurement were performed. Human chorionic gonadotropin (5,000 IU IM) was administrated when the mean diameter of up to three follicles was 18 mm. Intrauterine insemination was performed hours after hcg administration. Sperm Preparation Semen samples were obtained by masturbation into sterile containers after 5 days of sexual abstinence and were left to liquefy at room temperature. The volume of ejaculate was recorded. Sperm concentration and motility were determined by analysis of 5 L of semen in a Makler chamber (Sefi- Medical Instruments). Semen was prepared with a two-layer Puresperm (Nidacon International, Gothenburg, Sweden) density gradient column (90%, 45%). The lower gradient layer was washed twice, and the final pellet containing the motile sperm was diluted to 0.5 ml with in-house-made Whittingham s T6 medium supplemented with 1% human serum albumin (Vitrolife, Göteborg, Sweden). The sperm concentration and motility of the final sample were also recorded. Insemination Procedure The IUI was performed with the patient in the dorsal lithotomy position. A speculum was placed inside the patient s vagina, and the portio vaginalis uteri was cleaned with a sterile swab. Either the Gynetics catheter or the Makler cannula was attached to a syringe, and the sperm suspension was loaded into the catheter. The catheter was gently inserted through the cervix into the uterine cavity, and then the sperm suspension was slowly expelled through the catheter. If there was difficulty cannulating the cervix, a stylet or tenaculum was used as an adjuvant. After removing the catheter, the grade of difficulty in introducing the catheter, the presence of bleeding, and semen regurgitation from the cervix were recorded. When the Gynetics catheter was used, its tip was placed near the fundus of the uterus. After the sperm suspension was injected into the uterus, the catheter was slowly removed. The patient remained in the dorsal lithotomy position for 10 minutes and rested in a sitting position for 30 minutes after IUI. When the Makler cannula was used for IUI, the syringe was attached to the Makler insemination device. The cannula was introduced into the uterine cavity until the external os was completely obliterated by the flared base of the cannula. 700 Fancsovits et al. Comparison of two IUI catheters Vol. 83, No. 3, March 2005

3 TABLE 1 Patient characteristics and sperm parameters. Gynetics catheter Makler cannula P a No. of patients No. of cycles No. of cycles per patient Patient age (y) Sperm number ( 10 6 /ml) Progressive motility (%) Total progressive motile sperm count in the ejaculate ( 10 6 ) Total progressive motile sperm count in the inseminated sample ( 10 6 ) Note: Data are presented as n or mean SD. a Student s t-test. The spring of the device was clamped to the outer brim of the speculum by which the cannula was kept in place. The flared base of the cannula was pressed against the cervix by the spring and acted as a retainer for minutes. Then the cannula was slowly removed, and the patient rested in a sitting position for 30 minutes. If menstruation was delayed after IUI, a urinary pregnancy test was performed. All positive tests were recorded as a pregnancy. Cumulative pregnancy rate was calculated by dividing the number of patients who became pregnant during the study period by the total number of patients. Statistical Analysis The statistical analysis was performed with commercial software (Statistica; StatSoft, Tulsa, OK). The variables selected for the initial analysis were female age, number of cycles per patients, sperm number, progressive motile sperm number (World Health Organization A B) and motility in the native semen sample, and progressive motile sperm number in the prepared sample. These variables were analyzed by Student s t-test. Differences in the circumstances of the insemination and the pregnancy and cumulative pregnancy rates between the groups were analyzed by 2 test. The chosen level of significance was P.05. RESULTS A total of 251 infertile couples were enrolled in the study and assigned to either the Gynetics catheter or the Makler cannula during their IUIs. Five patients were excluded because of procedural error during the study period. Three other patients were withdrawn from the study because it was not possible to cannulate the cervix with the chosen catheter. Thus, the analyzed group consisted of 243 couples: 122 assigned to receive the Gynetics catheter and 121 assigned to receive the Makler cannula. Demographics and sperm parameters of the study patients are shown in Table 1. The groups did not differ significantly in terms of age, number of cycles, and semen characteristics. Characteristics of the insemination procedures are shown in Table 2. The frequency of difficult inseminations (i.e., when instrumental help [stylet or tenaculum] was needed) was significantly higher in the Gynetics group than in the Makler group (77 of 396, 19.4%, vs. 28 of 351, 8.0%, respectively; P.0001). The presence of blood on the catheter was similar in both groups (Gynetics: 66 of 396, 16.7%, vs. Makler: 68 of 351, 19.4%; P.66). Introduction of the Makler cannula without any instrumental help resulted in bleeding more often (52 of 323, 16.1%) than introduction of the Gynetics catheter without instrumental help (18 of 319, 5.6%; P.0001). However, the frequency of bleeding was comparable when a stylet and/or tenaculum was used during the introduction of either the Gynetics catheter or the Makler cannula (Table 3). The frequency of IUI cycles with regurgitation of inseminated fluid was significantly higher when the Makler cannula was used (Gynetics: 71 of 396, 17.9%, vs. Makler: 167 of 311, 49.9%; P.0001). The pregnancy rate was similar in the Gynetics and Makler groups (10.4% vs. 9.7%, respectively; P.76). The cumulative pregnancy rate was 27.9% in the Gynetics catheter group and 26.4% in the Makler cannula group, and the difference was not significant (P.72) (Table 4). DISCUSSION Intrauterine insemination combined with controlled ovarian hyperstimulation is a commonly used and cost-effective Fertility and Sterility 701

4 TABLE 2 Characteristics of inseminations with Gynetics catheter or Makler cannula. Gynetics Makler P a No. of cycles Ease of introduction.0001 No instrumental help needed 319 (80.6) 323 (92.0) Stylet 16 (4.0) 13 (3.7) Tenaculum 22 (5.6) 8 (2.3) Stylet tenaculum 39 (9.8) 7 (2.0) Bleeding.66 Absent 330 (83.3) 283 (80.6) Insignificant bleeding 44 (11.1) 49 (14.0) Small bleeding 20 (5.1) 18 (5.1) Considerable bleeding 2 (0.5) 1 (0.3) Regurgitation of the inseminated sample.0001 Not present 325 (82.1) 176 (50.1) Present 71 (17.9) 175 (49.9) Note: Numbers in parentheses are percentages. 2 test. method for the treatment of infertility. It is mainly used to treat male factor, cervical factor, or unexplained infertility cases. The pregnancy rate per cycle varies extremely: very low (4%) or high (40%) pregnancy rates have been published (15, 16). The great variation in pregnancy rate by IUI treatment might be due to different characteristics of the study populations, different ovarian stimulation protocols, and different insemination technique. In this randomized study, we attempted to discover the influence of the type of insemination catheter used on the efficacy of the IUI treatment. In our study the overall pregnancy rate per cycle was 10.0%, and the cumulative pregnancy rate was 27.2%. These results are comparable with the 6% 22% pregnancy rates per cycle (1 4) and 19% 48% cumulative pregnancy rates (1, 6, 17, 18) reported in other studies. Only limited data are available regarding analyses of the effect of the IUI catheter type on pregnancy rate (11 13). These studies compared IUI catheters with soft and hard tips to test the hypothesis that a catheter with soft tip results in a higher pregnancy rate than a catheter with a hard tip. None of these studies pointed out any significant increase in pregnancy rate. However, Lavie et al. (13) used transvaginal ultrasound to evaluate endometrial changes and found that a catheter with soft tip is significantly less traumatic to the endometrium than a catheter with hard tip. Similar studies comparing ET catheters showed that the choice of catheter might affect the success of IVF-ET cycles (7, 8) because the softer catheter might be less traumatic to the endometrium. This finding was confirmed in a study by Tomás et al. (19), who showed that difficult ETs (which more often result in trauma to the endometrium) resulted in a lower pregnancy rate than easy or intermediate transfers. This might also be important in causing endometrial trauma during IUI. TABLE 3 Relationship between methods of catheter introduction and bleeding. Use of instrumental help Bleeding in Gynetics group Bleeding in Makler group P a Not needed 18/319 (5.6) 52/323 (16.1).0001 Needed 48/77 (62.3) 16/28 (57.1).63 Note: Numbers in parentheses are percentages. a 2 test. 702 Fancsovits et al. Comparison of two IUI catheters Vol. 83, No. 3, March 2005

5 TABLE 4 Cycle outcome of IUI in the Gynetics catheter and Makler cannula groups. Gynetics Makler P a Pregnancy rate (per cycle) 41/396 (10.4) 34/351 (9.7).7621 Cumulative pregnancy rate (per patient) 34/122 (27.9) 32/121 (26.4).7165 Note: Numbers in parentheses are percentages. 2 test. The Makler cannula used in our study has a harder tip than the Gynetics catheter. This difference between the two catheters resulted in the need for instrumental help more often in the Gynetics group than in the Makler group. However, more frequent use of a stylet or tenaculum did not result in a higher frequency of bleeding in the Gynetics group than in the Makler group. On the other hand, if we analyze those cycles in which no instrumental help was needed, the frequency of bleeding was higher in the Makler group than in the Gynetics group. The reason for this phenomenon could be that the rigidity of the Makler cannula facilitates penetration of the cervix without instrumental help but at the same time might cause injuries to the cervix or the endometrium more easily than the softer Gynetics catheter. Several studies have pointed out that IUI with a lower sperm number in the inseminated sample resulted in a lower pregnancy rate (1, 20). We believe that if a part of the injected sperm suspension regurgitates through the cervical canal, this decreases the sperm number at the site of fertilization. On the basis of these assumptions, we hypothesized that it is the regurgitation of the inseminated sample that might be responsible for the lower pregnancy rate in IUI treatment. The Makler IUI cannula and the Makler insemination device are designed to retain the sperm suspension in the uterus and cervix (14). In our study, when the Makler cannula was used, we saw sperm regurgitation more often than with the Gynetics catheter. The reason for this surprising difference in sperm regurgitation between the two catheter types is not clear. Possible explanations are that [1] the intrauterine volume of the Makler cannula is bigger than that of the Gynetics catheter, and it therefore pushes out a part of the sperm suspension from the uterine cavity, or [2] the longitudinal groove on the outer surface of the Makler cannula allows a larger volume of sperm suspension to pass from the uterine cavity to the cervical canal. Both factors might result in backflow of sperm suspension after removal of the catheter from the cervix. Despite finding differences in the frequency of sperm regurgitation between the two catheters, there were no significant differences between the two groups in terms of pregnancy rates. In the Gynetics catheter group the pregnancy rate was 10.4% per cycle, and the cumulative pregnancy rate was 27.9%. 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