Assessment of the value of ultrasound monitoring and doubling of insemination in clomiphene citrate stimulated IUI cycles

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1 Middle East Fertility Society Journal Vol. 9, No. 1, 2004 Copyright Middle East Fertility Society Assessment of the value of ultrasound monitoring and doubling of insemination in clomiphene citrate stimulated IUI cycles Hamdy Azab, M.D. * Nahed Afify, M.D. Saudi German Hospital, Aseer, Saudi Arabia ABSTRACT Objective: To compare the results of controlled ovarian stimulation and intra-uterine insemination using 4 protocols. Design: Prospective non randomized study. Setting: An assisted reproduction unit in a private hospital. Materials and methods: 91 couples with unexplained infertility and 79 couples with male subfertility. All women received clomiphene citrate 50 mg twice daily starting from the 3rd day of cycle for 5 days. Patients were classified into 4 groups. The 1st group (45 patients, 125 cycles) was monitored by transvaginal sonography. HCG was given when at least one follicle reaches a diameter of 17 mm or more. IUI was scheduled 36 hours after the HCG shot. The 2nd group (43 patients, 118 cycles) was also monitored by ultrasound and HCG was given as before, double insemination was done 20 hours and 40 hours after the HCG shot. In the 3rd group (42 patients, 112 cycles), monitoring of ovulation was done using commercial urinary LH detection kit, IUI was scheduled 24 hours after detection of LH. In the 4th group (40 patients, 108 cycles), monitoring of ovulation was done by urinary LH detection kit, double insemination was done 12 and 24 hours after detection of LH. Main Outcome measure: Clinical pregnancy rate (PR). Results: A total of 170 patients underwent 463 cycles with an average of 2.72 cycles per patient. The total number of pregnancies was 31 with an overall PR of 18% per patient and 7% per cycle. The overall pregnancies for groups I, II, III, and IV were 8 (18% per patient, 6% per cycle), 9 (21% per patient, 8% per cycle), 7 (17% per patient, 6% per cycle), and 7 (18% per patient, 6% per cycle), respectively. There was no statistically significant difference between any two groups. Patients with unexplained infertility and patients with infertility duration of less than 4 years had significantly higher PR than patients with male subfertility and patients of infertility duration more than 4 years respectively. Conclusion: Clomiphene citrate (CC) stimulated IUI cycles, self monitored by urinary LH kits and employing single insemination, appear to be a simple, relatively effective and inexpensive initial management for couples with unexplained infertility or mild male factor subfertility of less than 4 years duration. Controlled ovarian stimulation together with intrauterine insemination (COS/IUI) is a widely used practice for the management of infertility, particularly for couples with unexplained infertility, male factor infertility, or endometriosis (1-3). COS * Consultant of obstetrics and gynecology SGH-Aseer, Lecturer of obstetrics and gynecology, Kasr El-Ini, Cairo University. Consultant of clinical pathology SGH-Aseer, Assistant Professor of clinical pathology, Ain Shams University. plus IUI has been found to be more effective for treatment of infertility than either treatment alone (2, 4). Several studies documented that COS/IUI treatment is cost effective for subfertile couples before proceeding to the more invasive and expensive IVF procedures (1, 5). COS using clomiphene citrate (CC) is relatively simple, inexpensive, and safe. The PR per cycle in CC/IUI cycles varies from 6-26% (2, 3, 6). CC has been found to be as effective as gonadotropins for COS Vol. 9, No. 1, 2004 Azab and Afify U/S monitoring and doubling of insemination in CC stimulated IUI cycles 31

2 Table 1. Summary of patients' characteristics. Group I Group II Group III Group IV Statistics Number of patients Number of Cycles Mean (SD) Range (0.56) (0.54) (0.53) Age (years) Mean (SD) Range Infertility Duration Mean (SD) Range Infertility Etiology Unexplained Infertility Male subfertility 29(2.5) (1.2) (2.1) (1.2) (2.3) (1.1) (0.52) 29.1(2.8) (1.3) (Non Significant) in certain population of patients (7). In this study, we are trying to reach a simple and inexpensive protocol as an initial management of infertile couples. We are investigating the value of monitoring of ovulation using vaginal ultrasound versus self monitoring using urinary LH detection kits, at the same time we are checking the value of double insemination versus single insemination. MATERIALS AND METHODS Ninety one couples with unexplained infertility and 79 couples with male subfertility participated in this study during the period from April 2001 until December The hospital review board approved the protocol of the study. An informed consent was taken from the couples. The age of female partners ranged from years with a mean of 28.5 years. All couples had at least 2 years duration of infertility. They had undergone the basic infertility evaluation including history, clinical examination, mid luteal phase progesterone, prolactin assay, and semen analysis. Tubal patency was confirmed by either hysterography or laparoscopy. Women with tubal abnormality were excluded from the study. Unexplained infertility was considered if the results of basic infertility evaluation were normal. Male factor infertility was defined as sperm count < 20 millions/ml, normal morphology < 30 %, or progressive motility < 50 % before sperm preparation. Subjects' characteristics are summarized in Table 1. All women received CC 50 mg tablets twice daily for 5 days starting from the 3rd day of cycle. Women were classified into 4 groups. There was no significant difference among the 4 groups regarding, the age, the duration of infertility, the number of cycles per patient, or the distribution of patients with unexplained infertility and male infertility. In the 1st group monitoring of ovulation was done using transvaginal sonography (TVS) starting from the 10th day of cycle. HCG 10,000 IU was given when the mean diameter of at least one follicle is 17 mm. Single insemination was then done 36 hours after the HCG shot. The 2nd group was also monitored by TVS and HCG was given as before. Two inseminations were done 20 and 40 hours after the HCG shot. In the 3rd group monitoring of ovulation was done using urinary LH detection kits (Clear Plan) starting from the 10th day of cycle, single insemination was done 24 hours after detection of LH surge. The 4th group was monitored by LH detection kit and double insemination was done 12 and 24 hours after detection of LH surge. The choice of treatment for each couple was based on their 32 Azab and Afify U/S monitoring and doubling of insemination in CC stimulated IUI cycles MEFSJ

3 Table 2. PR according to cause of infertility Unexplained infertility Male subfertility Chi square P value PR/Patient 21/91 (23%) 10/79 (13%) () PR/Cycle 21/245 (9%) 10/218 (5%) () Non Significant preference. The same method was used if the couple had more than one cycle of treatment. Male partners were instructed to collect semen by masturbation after days of sexual abstinence. After liquefaction and initial semen analysis, suitable samples were prepared using the density gradient method. SupraSperm system from Medi-Cult (Copenhagen, Denmark) was used. 2 ml of the 55% SupraSperm were dispensed in a centrifuge tube, and then 2 ml of the 80% suprasperm were dispensed beneath the 1st solution. 1 ml of semen sample was added to the prepared gradient. The tube was then centrifuged for 20 minutes at 300g. The supernatant was carefully removed leaving the sperm pellet. The pellet is suspended in 2 ml sperm preparation medium (Medi-Cult) and Centrifuged for 10 minutes at 200g The supernatant was removed and the wash process was repeated. The pellet is then suspended in 0.5 ml of sperm preparation medium. If the count of motile sperms after preparation was less than 5 millions, these couples were excluded from the study and referred to either IVF or ICSI. IUI was done using Wallace (Wallace, Kent, U.K.) IUI catheters, with 1 or 2 ml syringe. With the patient in lithotomy position a speculum was inserted in the vagina. The cervix was cleaned by cotton swab. The IUI catheter was gently passed through the cervical canal ml of sperm Table 3. PR according to infertility duration Infertility < 4 ys Infertility > 4 ys Chi square P value PR/Patient 25/105 (24%) 6/65 (9%) * PR/Cycle 25/278 (9%) 6/185 (3%) * Significant p value suspension was slowly injected into the uterine cavity. The patients remained in a supine position for 15 minutes after the procedure. Clinical pregnancy was considered upon the visualization of an intrauterine pregnancy sac using TVS Data were presented in terms of mean, range, standard deviation, and percentage. Comparison between any two groups was done using the Chisquare test with or without Yates correction and Fisher exact test. One way ANOVA test and Chisquare test were used to check for any difference among the 4 groups. P values of less than 0.05 were considered significant. The SPSS (Chicago, IL, USA) and Microsoft Excel computer programs were used for statistical analysis. RESULTS A total of 170 patients underwent 463 cycles with an average of 2.72 cycles per patient. There were a total of 31 pregnancies with an average PR of 18% per patient and 7% per cycle. Of the 31 pregnancies; 27(87.1%), continued pregnancy beyond 16 weeks and 4 (12.9%) resulted in spontaneous abortion. There was only one set of twins (3.2%). There were no ectopic pregnancies. Couples with unexplained infertility had a higher PR (9%) compared to couples with male subfertility (5%). However, this was not statistically significant. Couples with infertility of less than 4 years duration had a significantly higher PR (9%) than couples with infertility of more than 4 years (3%). These data are summarized in Tables 2 and 3. The overall pregnancies for groups I, II, III, and IV were 8 (18% per patient, 6% per cycle), 9 (21% per patient, 8% per cycle), 7 (17% per patient, 6% per cycle), and 7 (18% per patient, 6% per cycle), respectively. These data are summarized in Table 4. The value of U/S monitoring versus self-lh monitoring was assessed by comparing the PR of the 1st and 3rd groups and the 2nd and the 4th groups. Although the women underwent U/S monitoring had a higher PR, yet the difference was not statistically significant. Similarly, double insemination did not yield a significant higher PR compared to single insemination, as evident by comparing Vol. 9, No. 1, 2004 Azab and Afify U/S monitoring and doubling of insemination in CC stimulated IUI cycles 33

4 Table 4. Pregnancy rate in the four groups Group Pregnant women Non pregnant women Total no. of patients No. of cycles PR/Patient PR/Cycle 1st group(us monitoring, single insemination) % 6% 2nd group (us monitoring, double insemination) % 8% 3rd group (LH monitoring, single insemination) % 6% 4th group (LH monitoring, double insemination % 6% Total % 7% the 1st and 2nd groups and the 3rd and 4th groups. These data are summarized in Tables 5 and 6. DISCUSSION COS and IUI is a widely used practice for management of infertility being simple and relatively inexpensive approach. In this study we are trying to reach a simple approach for the management of unexplained infertility and male factor subfertility. Patients with unexplained infertility have undergone basic infertility evaluation; however, not all of them had laparoscopy or analysis of the possibility of immunological factors. Based on this, the cause of unexplained infertility in some patients can be related to early stage endometriosis. We analyzed the value of U/S monitoring of ovulation versus self urinary LH monitoring and the value of increasing the frequency of insemination. Although the PR was higher with U/S monitoring, yet the difference was not statistically significant. Zreik et al, (8) have found that U/S monitoring and induction of ovulation using HCG did not yield a higher PR when compared to urinary LH monitoring, which is matching with our conclusion. In a retrospective study by Deaton et al, (9) they found that the success of IUI with CC is not dependent on the method used to establish the timing for the IUI. They concluded that U/S monitoring of ovulation has no advantage over urinary LH monitoring. Moreover, Martinez et al, (10) found that waiting for endogenous LH surge may have an advantage over triggering ovulation by HCG. They suggested that this allows full natural maturation to occur. However, Awonuga et al, (11) found no value for waiting spontaneous LH surge. Our results and the mentioned studies are in common suggesting that urinary LH monitoring is as effective as U/S monitoring in this population of IUI patients. There is controversy in the literature about the value of double insemination compared to single insemination. Silverberg et al, (12) were the first to address a significant value of double insemination in a prospective randomized study. Ransom et al, (13) in another prospective randomized study found that increasing the frequency of insemination does not provide a significant increase in cycle PR. Ragni et al, (14) found that two IUIs performed 12 hours and 34 hours after HCG administration is the most cost-effective regimen for women undergoing COH cycles with clomiphene citrate and gonadotropins. The authors suggesting value of double insemination refer this to optimizing the window of ovulation taking full advantage of sequential ovulation. In our study we used CC only for induction of ovulation so the value of sequential ovulation of multiple follicles is denied. We have found no significant value of double insemination which seems to be logic among this population of patients stimulated by CC. Our results demonstrated a significant increase in PR in women with infertility duration of less than 4 years (9%) compared to women with infertility of 4 years or more (3%). This is in accordance with the results of Nulsen et al, and Tomlinson et al (15-16). However, other studies found no relation between the duration of infertility and the likelihood of pregnancy (3, 17). Regardless of the variability in the literature, CC stimulated IUI cycles can not be recommended for women with long standing infertility. 34 Azab and Afify U/S monitoring and doubling of insemination in CC stimulated IUI cycles MEFSJ

5 Table. 5 The value of U/S monitoring versus self-lh monitoring 1st group 3rd group P value 2nd group 4th group P value Total patients No. of cycles PR/Patient (%) 8/45 (18%) 7/42 (17%) 1 () 9/43 (21%) 7/40 (18%) 0.8 () PR/Cycle (%) 8/125 (6%) 7/112 (6%) 1 () 9/118 (8%) 7/108 (6%) 0.8 () () Non Significant Table. 6 Double insemination compared to single insemination 1st group 2nd group P value 3rd group 4th group P value Total patients No. of Cycles PR/Patient (%) 8/45 (18%) 9/43 (21%) 0.8 () 7/42 (17%) 7/40 (18%) 1 () PR/Cycle (%) 8/125 (6%) 9/118 (8%) 0.8 () 7/112 (6%) 7/108 (6%) 1 () () Non Significant We found a higher PR in couples with unexplained infertility (9%) compared to couples with male factor subfertility (5%); however, the difference was not statistically significant. Previous studies showed a PR ranging from 6-26% in women with unexplained infertility (2, 3, 6) and a PR of 3-5% in couples with male subfertility (2, 18, 19). Several studies (20-23) achieved a higher PR in male subfertility. We applied post preparatory threshold value of 5 million motile sperms to be included in the study. The higher PR in these studies could be due to the use of a higher threshold total motile sperm count and/or the use of gonadotropins for stimulation. Finally, this study shows that women with unexplained infertility or mild male factor abnormality and of infertility duration less than 4 years will have a good chance with CC stimulated IUI cycles monitored by self urinary LH and employing single insemination. Couples with long standing infertility or severe male defect need a more aggressive approach. REFERENCES 1. Goverde AJ, McDonnell J, Vermeiden JP, Schats R, Rutten FF, Schoemaker J. Intrauterine insemination or in-vitro fertilization in idiopathic subfertility and male subfertility: a randomized trial and cost-effectiveness analysis. Lancet 2000; 355: Arici A, Byrd W, Bradshaw K, Kutteh WH, Marshburn P, Carr BR. Evaluation of clomiphene citrate and human menopausal gonadotropin treatment: a prospective randomized cross over study during intrauterine insemination cycles. Fertil Steril 1994; 61: Deaton JL, Gibson M, Blackmer KM, Nakajima ST, Badger GJ, Brumsted JR. A randomized controlled trial of clomiphene citrate and intrauterine insemination in couples with unexplained infertility or surgically corrected endometriosis. Fertil Steril 1990; 54: Guzick DS, Carson SA, Coutifaris C. Efficacy of superovulation and intrauterine insemination in the treatment of infertility. N Engl J Med 1999; 340: Zayed F, Lenton EA, Cooke ID. Comparison between stimulated in vitro fertilization and stimulated intrauterine insemination for the treatment of unexplained and mild male factor infertility. Hum Reprod 1997; 12: Karlstrom PO, Bergh T, Lundkvist O. A prospective randomized trial of artificial insemination versus intercourse in cycles stimulated with human menopausal gonadotropin or clomiphene citrate. Fertil Steril 1993; 59: Ecochard R, Mathieu C, Royere D, Blache G, Rabilloud M, Czyba JC. A randomized prospective study comparing pregnancy rates after clomiphene citrate and human menopausal gonadotropin before intrauterine insemination. Fertil Steril 2000; 73(1): Zreik TG, Garcia-Velasco JA, Habboosh MS, Olive DL, Arici A. Prospective, randomized, crossover study to evaluate the benefit of human chorionic gonadotropin-timed versus urinary luteinizing hormone-timed intrauterine inseminations in clomiphene citrate-stimulated treatment cycles. Fertil Steril 1999; 71(6): Vol. 9, No. 1, 2004 Azab and Afify U/S monitoring and doubling of insemination in CC stimulated IUI cycles 35

6 9. Deaton JL, Clark RR, Pittaway DE, Herbst P, Bauguess P. Clomiphene citrate ovulation induction in combination with a timed intrauterine insemination: the value of urinary luteinizing hormone versus human chorionic gonadotropin timing. Fertil Steril 1997; 68(1): Martinez AR, Bernadus RE, Voorhorst FJ, Vermeiden JP, Schoemaker J. A controlled study of human chorionic gonadotropin induced ovulation versus urinary luteinizing hormone surge for timing of intrauterine insemination. Hum Reprod 1991; 6(9): Awonuga A, Govindbhai J. Is waiting for an endogenous luteinizing hormone surge and/or administration of human chorionic gonadotropin of benefit in intrauterine insemination? Hum Reprod 1999; 14(7): Silverberg KM, Johnson LV, Olive DL, Burns WN, Schenken RS. A prospective, randomized trial comparing two different intrauterine insemination regimes in controlled ovarian hyperstimulation cycles. Fertil Steril 1992; 57: Ransom MX, Blotner MB, Bohrer M, Corsan G, Kemmann E. Does increasing frequency of intrauterine insemination improve pregnancy rates significantly during superovulation cycles? Fertil Steril 1994; 61(2): Ragni G, Maggioni P, Guermandi E, Testa A, Baroni E, Colombo M, Crosignani PG. Efficacy of double intrauterine insemination in controlled ovarian hyperstimulation cycles. Fertil Steril 1999; 72(4): Nulsen JC, Walsh S, Dumez S, Metzger JF. A randomized and longitudinal study of human menopausal gonadotropin with intrauterine insemination in the treatment of infertility. Obstet Gynecol 1993; 82: Tomlinson MJ, Amissah-Arthur JB, Thompson KA, Kasraie JL, Bentick B. Prognostic indicators of intrauterine insemination: statistical model for IUI success. Hum Reprod 1996; 11: Dodson WC, Haney AF. Controlled ovarian hyperstimulation and intrauterine insemination for treatment of infertility. Fertil Steril 1991; 55: Balasch J, Ballesca JL, Pimentel C, Creus M, Fabregues F, Vanrell JA. Late low-dose pure follicle stimulating hormone for ovarian stimulation in intrauterine insemination cycles. Hum Reprod 1994; Bolton VN, Braude PR, Ockenden K, Marsh SK, Robertson G, Ross LD. An evaluation of semen analysis and in vitro tests of sperm function in the prediction of the outcome of AIH. Hum Reprod 1989; 4: Miller DC, Hollenbeck BK, Smith GD, Randolph JF, Christman GM, Smith YR, Lebovic DI, Ohl DA. Processed total motile sperm count correlates with pregnancy outcome after intrauterine insemination. J Urol 2002; 60(3): Cohlen BJ, Te Velde ER, Van Kooij RJ, Looman CW, Habbema JD. Controlled ovarian hyperstimulation and intrauterine insemination for treating subfertility: a controlled study. Hum Reprod 1998; 13(6): Dickey RP, Pyrzak R, Lu PY, Taylor SN, Rye PH. Comparison of the sperm quality necessary for successful intrauterine insemination with World Health Organization threshold values for normal sperm. Fertil Steril 1999; 71(4): Khalil MR, Rasmussen PE, Erb K, Laursen SB, Rex S, Westergaard LG. Homologous intrauterine insemination. An evaluation of prognostic factors based on a review of 2473 cycles. Acta Obstet Gynecol Scand 2001; 80(1): Received on April 13, 2003; revised and accepted on August 19, Azab and Afify U/S monitoring and doubling of insemination in CC stimulated IUI cycles MEFSJ