Clomiphene citrate monitoring for intrauterine insemination timing: a randomized trial

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1 OVULATION INDUCTION Clomiphene citrate monitoring for intrauterine insemination timing: a randomized trial Vivian Lewis, M.D., a John Queenan Jr., M.D., a Kathleen Hoeger, M.D., a Joanne Stevens, R.N., Ph.D., a,b and David S. Guzick, M.D., Ph.D. a a Department of Obstetrics and Gynecology, University of Rochester School of Medicine and Dentistry, Rochester, New York; and b Department of Nursing, State University of New York at Brockport, Brockport, New York Objective: To compare pregnancy rates with two different methods of intrauterine insemination (IUI) timing in patients treated with clomiphene citrate (CC). Design: Prospective, randomized trial. Setting: Academic medical center. Patient(s): One hundred fifty ovulatory, infertile women. Intervention(s): Patients were randomized into a luteinizing hormone (LH) surge group or a follicle monitoring/ human chorionic gonadotropin (hcg) group. All patients underwent baseline ultrasound, and took clomiphene citrate, during days 5 9. Patients in the LH surge group underwent IUI on the day after a home test for the LH surge was positive, whereas those in the hcg group received hcg according to ultrasound parameters and underwent insemination hours later. Patients remained in the same study group for up to three cycles. Main Outcome Measure(s): Pregnancy rates per cycle and per patient. Result(s): No significant differences were found between groups in pregnancy rates per patient or per cycle. The LH surge group underwent IUI significantly later than the hcg group. Cancellation rates were significantly higher for the LH surge group (31% vs. 11%) and attributable mainly to failure to detect an LH surge. The majority of pregnancies in both treatment groups occurred in the first cycle. Conclusion(s): The decision to use hcg for IUI timing should be influenced by factors other than pregnancy rates. (Fertil Steril 2006;85: by American Society for Reproductive Medicine.) Key Words: Clomiphene citrate, intrauterine insemination, unexplained infertility, ovulation predictor kits, ultrasound monitoring, LH surge Clomiphene citrate (CC) and intrauterine inseminations (IUI) are frequently used to enhance the monthly probability of pregnancy for couples with unexplained or male factor infertility because of relative ease of use, favorable risk profile, and proven efficacy (1, 2). The two most widely used methods to determine the time of ovulation are home monitoring of urinary LH for a spontaneous LH surge or human chorionic gonadotropin (hcg) administration to trigger ovulation on the basis of ultrasound parameters. Home monitoring for the LH surge is inexpensive and noninvasive, but false negatives occur in up to 25% of cycles and false positives are seen in up to 4% of cycles (3 5). Ultrasound monitoring is thought by some to be associated with better Received August 27, 2004; revised and accepted July 13, Supported in part (product donation) by Serono, Inc., Rockland, Massachusetts. Presented in part at the 58th Annual Meeting of the American Society for Reproductive Medicine, Seattle, Washington, October 12 17, Reprint requests: Vivian Lewis, M.D., University of Rochester School of Medicine and Dentistry, 601 Elmwood Avenue, Box 668, Rochester, New York (FAX: ; vivian_lewis@urmc. rochester.edu). timing of the IUI. Several prospective, randomized studies have demonstrated that ultrasound monitoring and hcg administration to patients taking clomiphene citrate for IUI timing is associated with higher pregnancy rates than IUI in unstimulated cycles (1, 2). Few studies have compared hcg administration to spontaneous LH surge in clomiphene citrate-treated women undergoing IUI. At least one retrospective study, however, suggests no improvement in pregnancy rates with hcg use (6). Data on pregnancy rates from prospective, randomized trials have been inconsistent (7, 8). We asked whether pregnancy rates would be different in patients given hcg to time IUI than in those who timed IUI by their LH surge. MATERIALS AND METHODS We recruited ovulatory patients who had infertility, defined by at least 1 year of unprotected intercourse without pregnancy, or three failed cycles of donor intrauterine insemination. All patients had at least one normal, patent fallopian tube and a functional ipsilateral ovary. Women were as /06/$32.00 Fertility and Sterility Vol. 85, No. 2, February 2006 doi: /j.fertnstert Copyright 2006 American Society for Reproductive Medicine, Published by Elsevier Inc. 401

2 sumed to have ovulatory cycles if they had monthly menses and biphasic basal body temperature charts, or a history of positive ovulation predictor kits, or midluteal serum progesterone levels in the ovulatory range. Women with elevated FSH levels on day 3 of the cycle were excluded, as were those with severe endometriosis, recurrent pregnancy loss, or previous use of superovulation and IUI. Male partners underwent a screening semen analysis. World Health Organization (WHO) reference ranges were used for sperm count and motility (9). Because the most recent WHO publication did not include a reference range for normal morphology, we used the reference range provided by the laboratory performing the semen analysis. If there was at least one abnormal semen parameter (concentration, motility, or morphology), and if there were at least 4 million motile sperm with normal morphology in the ejaculate, patients were included in the study and classified as having male factor infertility. The cutoff for number of motile sperm was used to exclude couples with severe male factor infertility who would be unlikely to conceive with IUI (10, 11). Threshold levels for normal sperm morphology are not consistent, although morphology may also be an important prognostic indicator for fertility (12 14). Patients who met entry criteria could complete up to a maximum of three cycles of clomiphene citrate/iui. Upon entry into the study, each patient was randomized to undergo IUI timed according to the LH surge (surge group) or hcg administration (hcg group). Randomization order was assigned by computer program and took place at the time of the baseline ultrasound visit. Treatment group assignment was not known to the patient or treating physician until after informed consent was obtained and the baseline ultrasound was performed. Patients remained in their assigned treatment group for the duration of the study for purposes of data analysis and treatment. The University of Rochester Research Subjects Review Board, which is the institutional review board (IRB) for the medical center, approved the study. Protocol Women in both groups were seen during the first 5 days of the first cycle for transvaginal ultrasound to assure normal appearing ovaries. Clomiphene citrate (Serophene; Serono Inc., Rockland, MA) was given in a dose of 100 mg from day 5 through day 9, and monitoring began on day 12. For women in the surge group, a home ovulation predictor kit (Assure; Conception Technologies, San Diego, CA) was used once a day, in the afternoon, starting on day 12. Patients were instructed to follow the manufacturer s instructions. Insemination was scheduled for the morning after the first positive test. Women in the hcg group were seen on day 12 for an ultrasound. We used transvaginal ultrasound to measure the two largest diameters of each follicle in the same plane. The endometrium was scanned in a longitudinal plane and the maximum diameter at the fundus. The endometrial pattern was classified as layered (e.g., inner hyperechoic and outer echogenic), partially layered (e.g., scattered areas), or absence of layering. If there was at least one follicle of 20 mm mean diameter and the endometrial thickness was at least 8 mm with at least partial layering, hcg (10,000 units) was given that evening, and the insemination was performed hours later. If the mean follicle diameter was between 17 mm and 19 mm, the patient was seen daily until criteria for hcg administration were met or an LH surge occurred. If the mean diameter of the largest follicles was between 14 and 16 mm, the next visit was scheduled in 2 or 3 days. The next visit was scheduled in 3 5 days for patients whose only follicles were 14 mm. If the physician deemed the risk of hyperstimulation or multiple birth was too great ( 4 follicles 20 mm mean diameter by ultrasound), hcg was withheld. Any patient who did not satisfy criteria for hcg administration was instructed to perform home monitoring for an LH surge until her next ultrasound, and to schedule an insemination if her ovulation predictor kit gave a positive result. For all patients, if menses did not occur by 14 days after the IUI, a serum pregnancy test was performed. If positive, the beta hcg level was quantitated and repeated in 2 days. A pregnancy was defined by rising concentrations of hcg. Biochemical pregnancies were those that never progressed to the point of ultrasound visualization of a fetal sac. Viable pregnancies were those in which a fetal pole with cardiac activity was noted by ultrasound. If the patient did not conceive in cycle 1, cycles 2 and 3 were conducted in the same manner. Patients in the surge group were dropped from the study if they failed to detect the LH surge. Patients in the hcg group were dropped from the study if they failed to meet criteria for hcg administration and they did not detect an LH surge. Statistics The study was designed to test the null hypothesis that the pregnancy rate per cycle among couples treated with clomiphene citrate and IUI would be equivalent for the two study groups. To determine sample size, we assumed 0.05, and 0.20 (80% power). On the basis of a prior study (7) and our own center s unpublished data, we chose a sample size that could detect differences in cumulative pregnancy rates of 22% vs. 49% after three cycles for the hcg and surge groups, respectively. Under these assumptions, 75 women would be needed in each group. Data Analysis Comparisons between groups with respect to pregnancies per cycle were made by chi-square or Fisher s exact test. Comparisons of mean group values were assessed by independent t-tests. A P value of.05 was considered statisti- 402 Lewis et al. 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3 TABLE 1 Patient diagnoses. LH surge hcg Unexplained Male factor 9 10 Mild endometriosis 5 9 Cervical factor 5 1 Tubal/pelvic factor 7 7 Note: LH luteinizing hormone; hcg human chorionic gonadotropin. cally significant. The Kaplan Meier method of survival analysis was used to compare the cumulative pregnancy rates in the two groups. This procedure included the log-rank statistical test, as previously applied to infertile populations (15). RESULTS We randomized 75 patients to each group, 129 of whom completed at least one cycle of treatment (58 in the surge group and 71 in the hcg group). Patients ranged in age from 23 to 42 years. The mean age of patients in the surge group, years ( 3.93 standard deviation), was not significantly different from that of the patients in the hcg group, years ( 3.91). Racial and ethnic backgrounds were similar in the two groups: the majority of patients (87%) were Caucasian, 9% were African-American, 3% were Hispanic, and 1% were Asian. The majority of patients in both groups had a diagnosis of unexplained infertility. Similar proportions of couples had male factor infertility (12% and 15% of the surge group and hcg group, respectively). The diagnoses for all patients are listed in Table 1. There were 40 pregnancies: 17 in the surge group and 23 in the hcg group. The cumulative pregnancy rates for both groups are plotted in Figure 1 and Figure 2. Using an intention to treat analysis, the cumulative pregnancy rate over three cycles for patients in the surge group was 25%, which was not significantly different than the 31% pregnancy rate for patients in the hcg group (Fig. 1, log rank test). Nor was there a significant difference detected between groups for any given cycle. Considering only completed cycles, plotted in Figure 2, the cumulative pregnancy rates were not significantly differ- FIGURE 1 Cumulative pregnancy rates in the intention to treat population. Kaplan Meier life-table lists the percentage of all enrolled patients who achieved pregnancy during the course of three cycles of clomiphene citrate and IUI. The difference between groups is not significant. Fertility and Sterility 403

4 FIGURE 2 Cumulative pregnancy rates in patients who completed treatment. Kaplan Meier life-table lists the percentage of those patients who completed at least one cycle and achieved pregnancy. Patients who were dropped from the study without undergoing IUI are excluded in this analysis. The difference between groups is not significant. ent: 31% and 33% for the surge group and the hcg group, respectively (log rank test). A completed cycle was considered as one in which the patient took the clomiphene citrate and underwent IUI. Pregnancy rates per cycle were similar for both groups (11.1% for the surge group and 12.9% for the hcg group). Combining the two treatment groups, pregnancy rates were significantly higher in the first cycle than in cycles 2 and 3 (19.3% vs. 6.1% per cycle, respectively, P.001, chi-square). Pregnancy outcomes did not differ between groups. The majority of pregnancies in both groups were viable intrauterine pregnancies. Sixty-six percent of the pregnancies in the surge group and 82% of pregnancies in the hcg group were viable, a difference that was not statistically different (chisquare). Five multiple pregnancies occurred: two in the surge group and three in the hcg group, a difference that was not statistically significant. One patient became pregnant during a rest cycle (LH surge group). The mean cycle day of insemination was ( 1.50) for the surge group and ( 1.39) for the hcg group (P.012). A comparison between all patients who conceived and those who did not indicated no significant difference in the cycle day of ovulation ( vs ). Among all patients who conceived, those in the surge group tended to ovulate slightly later than those in the hcg group. The mean cycle day of insemination was ( 1.25) for women in the surge group who conceived compared with ( 1.27) for those in the hcg group who conceived (P.070). The number of follicles over 18 mm mean diameter was 2.17 ( 1.01) for patients who conceived and 1.84 ( 1.00) for those who did not, a difference that was not significant. Sixteen patients in the hcg group experienced an LH surge and underwent insemination before ultrasound criteria were met for hcg administration during 22 cycles. During those cycles, follicular development was reasonable, with all patients having at least one follicle of 16 mm diameter before the LH surge (range 1 4), but the endometrium remained thin. Only one patient who experienced an LH surge before meeting ultrasound criteria for hcg administration conceived (6.3%). In contrast, 42.3% of patients who consistently achieved follicular maturation with optimal endometrial morphology became pregnant (P.007, Fisher s exact test). Study dropout rates were much higher in the surge group than in the hcg group (31% vs. 11%, P.002), with failure 404 Lewis et al. Clomiphene citrate and insemination timing Vol. 85, No. 2, February 2006

5 TABLE 2 Reasons for study dropouts. LH surge hcg No LH surge detected 17 0 Personal or scheduling 1 4 conflict Medication side effects 0 1 Abnormal bleeding 2 0 Elevated FSH level b 0 1 Changed mind: 2 1 unspecified reason Unknown: lost to 1 1 follow-up Total (%) 23 (31%) 8 (11%) a Note: LH luteinizing hormone; hcg human chorionic gonadotropin; FSH follicle-stimulating hormone. a P.002, chi-square. b Pre-study evaluation showed a normal FSH level. The repeat level, which was done at the subject s request on the day of her entry into the study, was slightly elevated. to detect the LH surge as the most common reason for dropping out. Personal reasons, especially time commitment related to study visits, were the most common reasons for dropping out of the hcg group (Table 2). DISCUSSION The method of timing IUI does not significantly affect pregnancy rates in ovulatory patients treated with clomiphene citrate for superovulation. The majority of pregnancies occurred during the first cycle, after which pregnancy rates declined substantially for both groups. Patients in the surge group were much more likely to drop out of the study than those in the hcg group. Patients in the hcg group who became pregnant using this therapy were more likely to develop at least one large follicle and a favorable endometrial pattern before experiencing an LH surge. Few studies have prospectively examined the question of whether IUI is best timed by a natural LH surge or hcg administration. Martinez et al. published a prospective, randomized trial comparing urinary LH surge, as measured by trained laboratory staff, to hcg timing, on the basis of ovarian follicle size (7). The group using the urinary LH surge had a 20% per cycle pregnancy rate, whereas the rate for the hcg group was 9%, a difference that was not statistically significant. Zreik et al. published the other prospective, randomized comparison of IUI timing methods in clomiphene citrate-treated women. They found no difference between groups in pregnancy rates (8). However, their population differed in that 25% of their patients had ovulatory dysfunction, and they might be less likely to experience or detect an LH surge. Finally, retrospective data do not suggest a benefit of hcg use for this group of women, but these data are clearly influenced by practitioner and patient preference, and possibly by insurance considerations (6, 16). Patients in the surge group were far more likely to drop out of the study than those in the hcg group. Despite having ovulatory cycles, 23% of women in this group failed to detect their LH surge. These actual-use data are similar to previous studies in which as many as 32% of ovulatory women failed to detect their LH surge (3, 4). Many ovulatory women have cycles in which the duration of the LH surge is too short to be easily detected or the concentration of LH is below the limit of detection because of hydration (8). Although home ovulation predictor kits are clearly convenient and inexpensive, the substantial failure rate in actual use should be considered when counseling patients. In our study, patients in both treatment groups were far more likely to conceive in the first month of treatment, after which incremental increases in pregnancy rates were modest. Comparison to other studies is difficult as most used a crossover study design (2, 8, 17). In a study of 58 patients, Ecochard et al. used a crossover design and life-table analysis to compare women treated with two cycles of clomiphene citrate followed by two cycles of gonadotropins with those treated with gonadotropins followed by clomiphene citrate (17). The cycle fecundity rate was actually higher during the second clomiphene citrate cycle. In a retrospective study of over 3,000 cycles of clomiphene-citrate- and IUI-treated patients, Berg et al. found relatively stable cycle fecundity rates (5.3% 9.1%) over 8 cycles of treatment, after which pregnancy rates were generally 3% per cycle, with very small numbers of patients extending beyond 10 cycles (18). Our patient population may have been slightly older, which could have contributed to the rapid decline in pregnancy rates. Finally, many of the patients in our study used clomiphene citrate without IUI before entering the study, which could have eliminated some patients who would otherwise conceive over the course of three cycles. For couples experiencing secondary infertility who are still relatively young, it might be worthwhile to complete a few cycles of this treatment despite the drop-off in pregnancy rates because the risk of multiple births is much higher with gonadotropin therapy or IVF. Nonetheless, some authors have advocated a speedier transition to other therapies for older women, an approach supported by our data (19). We found a small but significant difference in the day of insemination between groups. The difference was smaller than that found by Martinez et al., possibly because our protocol required endometrial end points as well as follicle size for hcg administration (7). Unlike Dickey et al., we found no difference in the number of large follicles in conception Fertility and Sterility 405

6 cycles compared with nonconception cycles (20). Several investigators have noted that the antiestrogenic effect of clomiphene citrate on the endometrium has a negative impact on the chances of pregnancy (21 23). This may explain why the pregnancy rates were lower in cycles in which the endometrium failed to develop in synchrony with the follicles, such that patients experienced an LH surge before achieving ultrasound criteria for hcg. Our data indicate that the use of ultrasound monitoring to time IUI has no significant effect on the chance of pregnancy in patients with unexplained infertility. Patient preference and difficulties with ovulation predictor kits might be other reasons to select ultrasound monitoring. For patients who use the ovulation predictor kits, these data provide reassurance that pregnancy rates are not compromised. Acknowledgments: We gratefully acknowledge the assistance of William R. Phipps, M.D., who helped with data collection, Martha O Connor, R.N., who helped with subject recruitment, Wanda Rivers, who helped with data management, and Kenneth Edell who provided statistical assistance. REFERENCES 1. Guzick DS, Sullivan MW, Adamson GD, Cedars MI, Falk RJ, Peterson EP, et al. Efficacy of treatment for unexplained infertility. Fertil Steril 1998;70: Arici A, Byrd W, Bradshaw K, Kutteh WH, Marshburn P, Carr BR. Evaluation of clomiphene citrate and human chorionic gonadotropin treatment: a prospective, randomized, crossover study during intrauterine insemination cycles. Fertil Steril 1994;61: Miller PB, Soules MR. The usefulness of a urinary LH kit for ovulation prediction during menstrual cycles of normal women. Obstet Gynecol 1996;87: Nielsen MS, Barton SD, Hatasaka HH, Stanford JB. Comparison of several one-step home urinary luteinizing hormone detection test kits to OvuQuick. Fertil Steril 2001;76: Guermandi E, Vegetti W, Bianchi MM, Uglietti A, Ragni G, Crosignani P. Reliability of ovulation tests in infertile women. Obstet Gynecol 2001;97(1): 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: Martinez AR, Bernadus RE, Voorhorst FJ, Vermeiden JP, Schoemaker J. A controlled study of human chorionic gonadotrophin induced ovulation versus urinary luteinizing hormone surge for timing of intrauterine insemination. Hum Reprod 1991;6: 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: World Health Organization laboratory manual for the examination human semen and sperm-cervical mucus interaction. 4th ed. Cambridge: Cambridge University Press, Horvath PM, Bohrer M, Shelden RM, Kemmann E. The relationship of sperm parameters to cycle fecundity in superovulated women undergoing intrauterine insemination. Fertil Steril 1989;52: Van Voorhis BJ, Barnett M, Sparks AET, Syrop CH, Rosenthal G, Dawson 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: Burr RW, Siegberg R, Flaherty SP, Wang XJ, Matthews CD. The influence of sperm morhpology and the number of motile sperm inseminated on the outcome of intrauterine insemination combined with mild ovarian stimulation. Fertil Steril 1996;65: Van Waart J, Kruger TF, Lombard CJ, Ombelet W. Predictive value of normal sperm morphology in intrauterine insemination (IUI): a structured literature review. Human Reprod Update 2001;7: Guzick DS, Overstreet JW, Factor-Litvak P, Brazil CK, Nakajima ST, Coutifaris C, et al. Sperm Morphology, Motility, and Concentration in Fertile and Infertile Men. N Engl J Med 2001;345: Guzick DS. Basic statistical testing, including interim analysis. Semin Reprod Endocrinol 1996;14: Agarwal SK, Buyalos RP. Corpus luteum function and pregnancy rates with clomiphene citrate therapy: comparison of human chorionic gonadotrophin-induced versus spontaneous ovulation. Hum Reprod 1995;10: 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: Berg U, Brucker C, Berg FD. Effect of motile sperm count after swim-up on outcome of intrauterine insemination. Fertil Steril 1997; 67: 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: Dickey RP, Taylor SN, Lu PY, Sartor BM, Rye PH, Pyrzak R. Effect of diagnosis, age, sperm quality, and number of preovulatory follicles on the outcome of multiple cycles of clomiphene citrate-intrauterine insemination. Fertil Steril 2002;78: Fleischer AC, Pittaway DE, Beard LA, Thieme GA, Bundy AL, James AE, Jr, et al. Sonographic depiction of endometrial changes occurring with ovulation induction. J Ultrasound Med 1984;3: Eden JA, Place J, Carter GD, Jones J, Alaghband-Zadeh J, Pawson ME. The effect of clomiphene citrate on follicular phase increase in endometrial thickness and uterine volume. Obstet Gynecol 1989;73: Biljan MM, Mahutte NG, Tulandi T, Tan SL. Prospective randomized double-blind trial of the correlation between time of administration and antiestrogenic effects of clomiphene citrate on reproductive end organs. Fertil Steril 1999;71: Lewis et al. Clomiphene citrate and insemination timing Vol. 85, No. 2, February 2006