Comparison of the effectiveness of single intrauterine insemination (IUI) versus double IUI per cycle in infertile patients

Transcription

1 FERTILITY AND STERILITY VOL. 80, NO. 3, SEPTEMBER 2003 Copyright 2003 American Society for Reproductive Medicine Published by Elsevier Inc. Printed on acid-free paper in U.S.A. Comparison of the effectiveness of single intrauterine insemination (IUI) versus double IUI per cycle in infertile patients Saeed Alborzi, M.D., Shahdokht Motazedian, M.D., Mohammad E. Parsanezhad, M.D., and Sima Jannati, M.D. Division of Infertility and Endoscopy, Department of Obstetrics and Gynecology, Shiraz University of Medical Sciences, Shiraz, Iran Objective: To compare a single periovulatory intrauterine insemination (IUI) with a regimen based on double IUI, performed during preovulatory and periovulatory periods, in patients undergoing controlled ovarian hyperstimulation (COH). Design: Prospective, randomized study. Setting: Infertility and endocrinology units of a medical university. Patient(s): One hundred ten patients with male, cervical, and unexplained infertility who were undergoing 486 cycles of COH with IUI. Intervention(s): The patients were randomly divided into two groups. One group underwent single IUI in the first cycle and double IUI in the second cycle; this alternating pattern was continued up to six cycles unless pregnancy occurred. For patients in the second group, double IUI was performed in the first cycle and single IUI in the second cycle; this pattern was repeated as in the first group. Main Outcome Measure(s): Relationship of single and double IUI to rates of clinical pregnancy and abortion. Result(s): Forty-two women became pregnant, with an overall pregnancy rate per cycle of 8.6% and pregnancy rate per couple of 38.2%. Pregnancy rate per cycle was 7.9% in single IUI cycles and was 9.4% in double IUI cycles; these findings were not statistically significant. Conclusion(s): Among patients undergoing COH-IUI, results of single and double IUI do not statistically differ. (Fertil Steril 2003;80: by American Society for Reproductive Medicine.) Key Words: Intrauterine insemination, superovulation, double insemination Received July 11, 2002; revised and accepted February 21, Reprint requests: Saeed Alborzi, M.D., P.O. Box , Shiraz, Iran (FAX: ; alborzis@sums. ac.ir) /03/$30.00 doi: /s (03) Artificial insemination is one of the oldest treatments for infertility and remains one of the most commonly used therapies (1). Controlled ovarian hyperstimulation (COH) combined with intrauterine insemination (IUI) of capacitated sperm has been used to treat several fertility disorders (2). Data are limited on the optimum timing of IUI and the number of inseminations needed to improve pregnancy rates. The three randomized studies in the literature comparing single and double IUI regimens report conflicting results (1 3). Because double IUI is more expensive than single IUI, it is crucial to confirm whether it is associated with improved pregnancy rates. We sought to prospectively compare standard single preovulatory IUI with two double IUI regimens performed at the preovulatory and periovulatory stages and to compare pregnancy and abortion rates in these patients. We used consecutive cycles in which each patient acted as her own control, in an effort to decrease bias. MATERIALS AND METHODS The study was performed from January 1999 to June 2002 in 110 infertile couples undergoing COH-IUI cycles. The couples had been referred to the infertility and endocrinology units of Shiraz University of Medical Sciences. The protocol and consent forms were 595

2 approved by the Institutional Review Board of Shiraz University of Medical Sciences. The mean duration of infertility was 5.2 years (range, 3 to 12 years). The patients median age was 27.4 years (range, 18 to 37 years). After major pathologic conditions were excluded, the patients were classified into three groups according to their infertility diagnosis: unexplained (n 36), male (n 30), and cervical infertility (n 44). A couple was considered as having unexplained infertility when the results of semen analysis, postcoital testing, hormonal assay, endometrial biopsy, hysterosalpingography, and laparoscopy were normal. Male infertility was diagnosed on the basis of abnormal findings in semen analysis according to the World Health Organization criteria (4): in brief, volume less than 2 ml, count less than 20 million/ml, motility less than 50%, and normal shape less than 30% were considered as abnormal. Semen analysis was performed at least twice with an interval of 3 months between tests. We performed IUI for patients with male infertility if the total motile sperm count was 5 million/ml or greater (5). If sperm quality was sufficiently poor, other therapeutic options, such as IVF or intracytoplasm sperm injection (ICSI), were used. If semen analysis was normal and repeated postcoital testing showed no sperm, dead sperm, or shaking movement despite the presence of good mucus, patients were classified as having cervical infertility. All patients were asked to undergo six cycles of insemination unless pregnancy occurred. After we matched patients for age and duration of infertility, we randomly divided them into two groups using computer-generated random number table. Patients in the first group underwent a single insemination in the first cycle and a double insemination in the second cycle; this alternating pattern continued for six cycles. Patients in the second group underwent a double insemination performed in the first cycle and a single insemination in the second cycle; this pattern was repeated as for the first group. The patients underwent 486 COH cycles with IUI, (180 cycles in patients with cervical, 141 cycles in those with male, and 165 cycles in those with unexplained infertility). Single IUI was done in 253 cycles and double IUI in 233 cycles. The patients underwent an ovulation induction protocol with clomiphene citrate and hmg. Clomiphene citrate (Iran Hormon, Tehran, Iran), 100 mg/d, was administered orally for 5 days starting on day 5 of the cycle, and hmg (Organon, Oss, The Netherlands), 150 IU/d, was injected intramuscularly from day 8 of the cycle. Follicular monitoring by transvaginal ultrasonography was performed on day 10 or 11 of the cycle, and according to the size and number of stimulated follicles, hmg administration was continued until at least two dominant follicles 18 mm or larger were present. Then, 5,000 to 10,000 IU of hcg (Organon) was injected. Semen specimens were obtained by masturbation into a sterile jar after 2 to 3 days of abstinence and a few hours before the scheduled time of insemination. After liquefaction for approximately 20 to 30 minutes, the specimen was mixed and diluted with 2 ml of buffer medium (Ham s F-10; Sigma, St. Louis, MO). The mixture was centrifuged at 300 g for 5 to 10 minutes, and the supernatant was discarded. Then, 2 ml of Ham s F-10 medium was added and mixed, the specimen was centrifuged again for 5 minutes at 300 g, and the supernatant was discarded. After carefully overlaying with 0.5 to 0.7 ml of Ham s F-10 media, the tube was tilted at a 45-degree angle and was incubated for 30 to 45 minutes at 37 C. The most active motile sperm would rise or swim up into the buffer phase; these sperm were isolated by aspiration and used for insemination. Insemination was performed by using an IUI catheter (Devon Innovations Ltd, Bangalore, India) that was inserted through the cervix and its tip was placed near the uterine fundus. Insemination volume was typically 0.5 to 0.7 ml, and women had bed rest for 30 minutes after IUI. In the single insemination cycles, IUI was performed 34 hours after the hcg injection. In the double insemination cycle, the first IUI was performed 12 hours and the second IUI 34 hours after administration of hcg. If the patients missed a menstrual period 16 to 18 days after the final insemination, a quantitative -hcg assay was performed. If this assay was positive, it was repeated 2 to 4 days later and, if an appropriate increase in hcg level was detected, transvaginal ultrasonography was performed 3 weeks later. Only clinical pregnancies that were diagnosed by transvaginal ultrasonography were considered in the current analysis. The data were analyzed by using the 2 test and Fisher s exact test. P.05 was considered statistically significant. RESULTS Single insemination was performed in 91 cycles and double insemination in 89 cycles of patients with cervical infertility, 77 and 64 cycles for patients with male infertility, and 85 and 80 for those with unexplained infertility. Forty-two women became pregnant, yielding an overall pregnancy rate of 38.2%. Twenty of 42 pregnancies occurred in a single IUI cycle (47.6%), yielding a pregnancy rate per cycle of 7.9%, whereas 22 pregnancies occurred in a double IUI cycle (52.4%), resulting in a pregnancy rate per cycle of 9.4%. This latter rate was not statistically significant (P.05). Tables 1 and 2 show the pregnancy rate per cycle and per couple in single and double IUI, according to cause of infertility. Thirty-four of the 42 pregnancies were term pregnancies, and eight abortions occurred (19%). Seven of the 596 Alborzi et al. Single and double IUI Vol. 80, No. 3, September 2003

3 TABLE 1 Results of single IUI, by cause of infertility. Variable Unexplained infertility Male Cervical FIGURE 1 Clinical pregnancy rates after single and double IUI in patients with unexplained infertility (hatched bars), cervical infertility (gray bars), or male infertility (white bars). No. of patients No. of cycles No. of pregnancies Pregnancy rate per patient (%) Pregnancy rate per cycle (%) Abortion rate (%) Twin rate (%) 21 latter 8 patients aborted in the first trimester. Two patients had twin pregnancy, of whom 1 aborted in the first trimester. Although no significant difference was seen between patients with cervical infertility and the other two groups, the percentages indicated an increase in the number of pregnancies in patients with cervical using single or double IUI compared with patients with male and unexplained infertility (P.05). The pregnancy rates obtained with single and double IUI cycles differed between male and unexplained infertility, albeit nonsignificantly (P.05) (Table 1, Table 2, Fig. 1). Figure 2 shows the number of pregnancies with respect to number of cycles, for all patients and according to cause of infertility. Most pregnancies occurred in the first two cycles, regardless of whether single or double IUI was used and regardless of cause of infertility. The rates of miscarriage and twin pregnancy were similar in single and double IUI cycles (miscarriage rate, 20% and 18.2%, respectively; twin rate, 4.5% and 5%). These rates were not statistically significant (P.05). Pregnancy rates among patients undergoing single or double IUI did not statistically differ with respect to patient TABLE 2 Results of double IUI, by cause of infertility. Variable Unexplained infertility Male Cervical No. of patients No. of cycles No. of pregnancies Pregnancy rate per patient (%) Pregnancy rate per cycle (%) Abortion rate (%) Twin rate (%) 10.3 age, duration of infertility, number of stimulated follicles, or thickness of endometrium (all P.05). No complications, such as infection, extrauterine pregnancy, or severe ovarian hyperstimulation syndrome, were observed. DISCUSSION Controlled ovarian hyperstimulation combined with IUI has been used to treat infertile couples for many years, mainly because it is cost effective (2, 3, 6). This regimen is now used as the first-line therapy before more expensive and invasive procedures, such as IVF or GIFT, that are used to treat unexplained, male, or cervical infertility (1). Because initiation of pregnancy depends on the number and quality of sperm at the site of fertilization (6), assessment of the optimal method of insemination would be beneficial. In our randomized study, the overall pregnancy rate per couple was 38.2%, with 80.9% proceeding to term pregnancy; the pregnancy rate per cycle was 8.6%. This compares favorably with pregnancy rates reported in other studies, ranging between 11.9% and 33.3% (6 10). Most of our pregnancies occurred in the first two cycles of treatment, both with single and double IUI (Fig. 2). Data are limited on the optimal timing of IUI and the number of IUIs needed to improve pregnancy rates. The two randomized studies reported in the literature comparing single and double IUI regimens produced conflicting results, even though in both studies the double IUI was performed during the preovulatory and periovulatory periods (1, 2). FERTILITY & STERILITY 597

4 FIGURE 2 Number of pregnancies by treatment with single IUI (diamonds) or double IUI (squares) in all patients. Another study showed significant increases in the chance of pregnancy if IUI was performed during the preovulatory and periovulatory periods, but not the postovulatory period (3). We performed IUI during the preovulatory and periovulatory periods. Using the study by Silverberg et al. (1) as our reference, we found that pregnancy rates did not differ between single and double IUI in our 110 patients who underwent 486 treatment cycles, with a study power of 80% and 95% confidence. The pregnancy rates per cycle were 8.6% in single IUI cycles and 9.4% in double IUI cycles, results that were not significant (P.05). Our results are similar to those of Ransom et al. (2) and contrast with those of Silverberg et al. (1), and Ragni et al. (3), who found more significant pregnancy rates in double IUI cycles than in single IUI cycles. Those who advocate double IUI suggest that the second IUI might improve the chance of conception because of the unsynchronized ovulation pattern in COH. Because the multiple ovulations in COH are sequential over at least several hours, the first insemination would provide sufficient motile spermatozoa before the first ovulated oocyte. The second insemination may provide additional sperm to fertilize these oocytes that were subsequently released (2, 3). Insemination also bypasses cervical mucus, which ordinarily acts as a reservoir for sperm at mid-cycle; thus, a single IUI may miss oocytes that are released later (1, 3). Another explanation is that patients receiving two inseminations had a significantly greater number of spermatozoa inseminated, which may be an important (1, 3). In both of our samples, which appear similar to each other with respect to cycle performance variables and total number of motile spermatozoa inseminated, we found no difference in conception rates in favor of double IUI. Some possible explanations exist for the discrepancies in results among different reports. Silverberg et al. (1) used frozen donor sperm in approximately one quarter of their patients undergoing single IUI, whereas we did not. It is generally agreed that use of cryopreserved semen yields lower pregnancy rates than does use of fresh semen (2), and this undoubtedly contributed to the relatively lower cycle fecundity among Silverberg et al. s (1) patients. In addition, the sample size differed among the studies. We included 110 patients with 486 treatment cycles, with a study power of 80% and 95% confidence. Since the most frequent criticism applied to trials of IUI is lack of a control group, we designed our study so that each patient served as her own control. We understood that occurrence of pregnancy would interfere with several s, and the similarity of the control and study group should decrease investigation bias. The data obtained from natural cycles suggest that fertility is maximal on the day of LH peak just before ovulation. It seems that the optimal time for IUI in natural cycles is 10 to 20 hours after detection of the LH surge. This would suggest that preovulatory IUI is more important in natural cycles (1). Moreover, ovulation should rarely occur earlier than 36 hours after the hcg injection. Ragni et al. (3) 598 Alborzi et al. Single and double IUI Vol. 80, No. 3, September 2003

5 showed decreased pregnancy rates in patients with male infertility who underwent IUI 34 hours and 60 hours (after ovulation) compared those who had IUI with 12 and 34 hours after hcg injection. In our study, in the double IUI group, the first insemination was performed 12 hours after hcg injection, during the preovulatory period, and the second insemination was performed 34 hours after hcg injection, during the periovulatory period. The overall results of our treatment showed that IUI may provide a good pregnancy rate in patients with cervical infertility. Patients with hostile mucus generally had better pregnancy rates than did the other groups with both methods of IUI; however, the difference was not significant (P.05). This finding is similar to those of Kirby et al. (11). In our study, the pregnancy rate in patients with male infertility decreased with double IUI and increased in patients with unexplained infertility, although the differences were not statistically significant (P.05). In general, our results are better than those found by Stone et al. (6) who demonstrated pregnancy rates of 13.2% in patients with unexplained infertility, 10.7% in those with cervical infertility, and 8.4% in those with male infertility. It is essential to know which s are important in determining the outcome of COH-IUI. Several studies report significant decreases in pregnancy rate with advancing age (6, 12, 13). Guzick et al. (14) reported that pregnancy rates decrease with increasing duration of infertility, but others reported that duration of infertility is not important (8, 13). Melis et al. (15) found that a greater number of follicles did not substantially improve pregnancy results. However, in several other studies, significantly better results were achieved with greater numbers of follicles (6, 16, 17). Gerlie et al. (18) showed that inadequate endometrial development may negatively affect the outcome of implantation. We focused mainly on the number of inseminations and found no difference on that basis. In our study, the overall rate of miscarriage was 19% (20% in single IUI cycles and 18.2% in double IUI cycles). Other studies have demonstrated abortion rates of 20% to 29% (9, 14). The incidence of multiple pregnancy may increase with ovulation induction IUI. We found an overall incidence of twin pregnancy of 4.8% (5% in single IUI cycles and 4.5% in double IUI cycles; P.05). Other studies showed twin pregnancy rates of 1.5% to 30% (13, 14). In conclusion, we found that increasing use of double rather than single inseminations did not improve the pregnancy rate. Pregnancy rates obtained with single or double IUI did not significantly differ among patients with cervical, male, or unexplained infertility. References 1. Silverberg KM, Johnson JV, Olive DL, Burns W, Schenken RS. A prospective, randomized trial comparing two different intrauterine insemination regimens 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: Ragni G, Maggioni P, Guermandi E, Testa A, Baroni E, Colombo M, et al. Efficacy of double intrauterine insemination in controlled ovarian hyperstimulation cycles. Fertil Steril 1999;72: Collection and examination of human semen. In: WHO laboratory manual for the examination of human semen and semen-cervical mucus interaction. Fourth edition. Cambridge (UK): Cambridge University Press, 1999: 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: Stone BA, Vargyas JM, Ringler GE, Stein AL, Marrs RP. Determinants of the outcome of intrauterine insemination: analysis of outcomes of 9963 consecutive cycles. Am J Obstet Gynecol 1999;180: Berg U, Bruker C, Berg FD. Effect of motile sperm count after swim-up on outcome of intrauterine insemination. Fertil Steril 1997;67: Zreik TG, Garcia-Velasco JA, Habboosh MS, Olive DL, Arici A. Prospective, randomized, cross over study to evaluate the benefit of HCG-timed versus urinary luteinizing hormone-timed IUI in clomiphene citrate stimulated treatment cycles. Fertil Steril 1999;71: Dodson WC, Haney AF. Controlled ovarian hyperstimulation and intrauterine insemination for treatment of infertility. Fertil Steril 1991; 55: van der Westernlaken LA, Naaktgeboren N, Helmerhost FM. Evaluation of pregnancy rates after intrauterine insemination according to indication, age, and sperm parameters. J Assist Reprod Genet 1998;15: Kirby CA, Warnes GM, Flaherty SP, Matthews CD, Godfrey BM. A prospective trial of intrauterine insemination of motile spermatozoa versus timed intercourse. Fertil Steril 1991;56: Agarwal SK, Buyalos RP. Clomiphene citrate with intrauterine insemination: is it effective therapy in women above the age of 35 years? Fertil Steril 1996;65: Van Voorhis BJ, Barnett M, Sparks AE, Syrop CH, Rosenthal G, Daveson J. Effect of the total motile sperm count on the efficacy and cost effectiveness of intrauterine insemination and in vitro fertilization. Fertil Steril 2001;75: Guzick DS, Carson SA, Coutifaris C, Overstreet JW, Factor-Litvak P, Steinkampf MP, et al. Efficacy of ovulation and intrauterine insemination in the treatment of infertility. N Engl J Med 1999;340: Melis GB, Paoletti AM, Strigini F, Fabris FM, Canale D, Fioretti P. Pharmacologic induction of multiple follicular development improves the success rate of artificial insemination with husband s semen in couples with male related or unexplained infertility. Fertil Steril 1987; 47: Martinez AR, Bernardus RE, Voorhorst FJ, Vermeiden JP, Schoemaker J. Intrauterine insemination does and clomiphene citrate does not improve fecundity in couples with infertility due to male or idiopathic s: a prospective, randomized, controlled study. Fertil Steril 1990; 53: Khalil MR, Rasmussen PE, Erb K, Laursen SB. Homologous intrauterine insemination. An evaluation of prognostic s based on a review of 2473 cycles. Acta Obstet Gynecol Scand 2001;80: Gerli S, Gholami H, Manna A, Di Frega AS, Vitiello C, Unfer V. Use of ethinyl estradiol to reverse the antiestrogenic effects of clomiphene citrate in patients undergoing intrauterine insemination: a comparative, randomized study. Fertil Steril 2000;73:85 9. FERTILITY & STERILITY 599