Timing of hCG Administration Does Not Affect Pregnancy Rates in Couples Undergoing Intrauterine Insemination Using Clomiphene Citrate Paul A. Robb, MD; Jared C. Robins, MD; and Michael A. Thomas, MD Cincinnoti, Ohio Background: Therapeutic intrauterine insemination (IUI) combined with clomiphene citrate ovarian stimulation is widely used to improve pregnancy rates for a variety of disorders. The goal of this study was to elucidate whether hCG administration at 24 or 36 hours after clomiphene citrate stimulation impacts pregnancy rates. Methods: The study was conducted as a retrospective chart review of 182 clomiphene citrate/lUI cycles in 90 women at the Center for Reproductive Health at the University of Cincinnati Medical Center. Comparisons were made between lUls performed at 24 hours versus 36 hours after hCG. Clinical variables included age of the female partner, semen concentration and motility, and infertility diagnosis. Outcomes were pregnancy rates and live birth rates. Data analysis was performed using Chi square for proportions and Student's t-test for continuous varables. Results: The pregnancy rate was 7% in the 24-hour group and 15.9% in the 36-hour group (P=0.057). However, the live birth rate was 4.0% in the 24-hour group and 8.5% in the 36hour group (P=0.2).
Conclusions: There is no significant difference in pregnancy rates in couples utilizing clomiphene citrate and undergoing IUI, whether hCG is administered at 24 hours or 36 hours pror to the procedure. Key words: clomiphene citrate a intrauterine insemination * hCG
INTRODUCTION Therapeutic intrauterine insemination (IUI) combined with clomiphene citrate ovarian stimulation is widely used to improve pregnancy rates for a variety of disorders. Administration of human chorionic gonadotropin (hCG) can be performed at 24 or 36 hours prior to IUI for patient convenience. The choice of the two regimens at our institution was basically made on the grounds of patient preference. Those uncomfortable with giving their own injections were given their injection in the office on the morning of their visit, and their IUI was scheduled for 24 hours after the injection. Those who were comfortable receiving their injection at home with a friend or family member had their injection in the evening with their IUI scheduled 36 hours later. Previous investigators have demonstrated that follicular rupture takes place approximately 36-38 hours after hCG administration.' However, sperm can survive in the cervix for up to 80 hours after intercourse.2 It remains unclear from the literature whether there is a difference in pregnancy outcomes if IUI occurs 24 or 36 hours after hCG administration. Fuh and associates showed a nonsignificant trend toward higher pregnancy rates as the time interval between hCG and IUI increased from 48 hours (pregnancy rate 23%) in 436 gonadotropinstimulated cycles.3 The goal ofthis study was to elucidate whether hCG administration at 24 or 36 hours after clomiphene citrate stimulation plays a significant role in pregnancy rates.
MATERIAL AND METHODS
© 2004. From the Department of Obstetrics and Gynecology, University of Cincinnati Medical Center, Cincinnati, OH. Send correspondence and reprint requests for J Natl Med Assoc. 2004;96:1431-1433 to: Michael A. Thomas, Department of Obstetrics and Gynecology, 231 Sabin Way, ML 526, Cincinnati, OH 45267-0526; e-mail:
[email protected]
JOURNAL OF THE NATIONAL MEDICAL ASSOCIATION
A retrospective chart review of clomiphene citrate/IUI cycles undertaken at the Center for Reproductive Health at the University of Cincinnati Medical Center was performed on couples undergoing clomiphene/IUI between January 2000 and September 2001. Patients were stimulated with 50-100 mg of clomiphene citrate (82% received 100 mg) on cycle days 3 to 7 and then were administered hCG 7,500-10,000 IU, when one-to-three lead follicles VOL. 96, NO. 1 1, NOVEMBER 2004 1431
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reached a mean diameter of 18 mm. Sperm washing was done on all samples by mixing the semen specimen with MHTF media (InVitroCare: Frederick, MD) and centrifuged for 6 min. at 300 x g. The supernatant was discarded, the pellet resuspended in MHTF media, and centrifugation repeated. The subsequent pellet was then resuspended in MHTF media with 5% synthetic serum substitute (Irvine Scientific: Santa Ana, CA). A postwash sperm count and motility were performed on the washed specimen, and this value was used in reporting sperm parameters. IUI was then performed either 24 or 36 hours after the hCG dose based on patient preference. Clinical variables included age of the female partner, semen parameters (concentration and motility), and infertility diagnosis (ovarian reserve, male factor, unexplained, anatomic, anovulatory). All women with amenorrhea or .35 years of age underwent appropriate testing for FSH. Ovarian reserve issues included those patients with an elevated day-3 FSH concentration of .13 mIU. Male factor problems included the patients who had a male partner with abnormal semen parameters, or those who had no male partner and donor insemination was performed. Anatomic factors included those with fibroids or only one patent fallopian tube. Anovulatory patients included those with ovulatory dysfunction, most of whom had polycystic ovarian syndrome (PCOS). Outcomes were pregnan-
cy rates (positive hCG two weeks after exogenous hCG administration) and live birth rates. Data analysis was performed using Chi square for proportions and Student's t-test for continuous variables.
RESULTS A total of 90 women and 182 cycles were examined for the study. There were 100 cycles in the 24hour group and 82 cycles in the 36-hour group. The average number of cycles per woman was 1.8 in the 24-hour group and 1.6 in the 36-hour group. Thirtythree percent of women had cycles with IUI in both the 24-hour and 36-hour groups. The clinical variables are shown in Table 1 and Figure 1. There were no differences in age ofthe female partners or sperm parameters between the two groups as summarized in Table 1. However, the groups did differ in their infertility diagnosis as shown in Figure 1. In a subanalysis, only those couples with ovarian reserve issues showed a statistical difference between the number of couples with that particular diagnosis. The pregnancy rates and live birth rates are shown in Figures 2 and 3, respectively. The pregnancy rate in the 24-hour group was 7.0% and was not significantly different from the rate of 15.9% in the 36-hour group (P=0.057). The live birth rates were also not significantly different, with a rate of 4% in the 24-hour group and 8.5% in the 36-hour group (P=0.2).
Table 1. Couple Demographics (Female Partner Age and Sperm Concentration and Motility) in the 24-Hour and 36-Hour Groups
Demographics
Age of female partner (years) Sperm count (106/ML) Sperm motility (%)
24-Hour
36-Hour
P Value
33.8 ± 0.4 131.9 ± 13.6 53.9 ± 1.7
33.8 ± 0.6 109.5 ± 12.6 51.0 ± 1.8
P=0.95 P=O. 1 5 P=O.1 7
Figure 1. Infertility Diagnosis in Women in the 24-Hour (Filled) and 36-Hour Groups (Open): *PU 40r ~
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CONCLUSIONS This study showed no significant difference in pregnancy outcomes whether hCG was administered at 24 or 36 hours prior to IUI in clomiphene-stimulated cycles. The rate of positive hCG was 7.0% in the 24hour group and more than double that percentage at 15.9% in the 36-hour group. Though not statistically significant, there is a trend toward a higher pregnancy rate in the couples in the 36-hour group. However, no differences were noted in live birth rates (4% vs. 8.5%). The drop in statistical significance between the pregnancy rate and the live birth rate is a reflection of the number of pregnancy losses that occurred after the initial diagnosis. There were two biochemical pregnancies (29% of pregnancies), one ectopic (14% of pregnancies), and no miscarriages in the 24-hour group, while in the 36-hour group, there were four biochemical pregnancies (31% of pregnancies in the group), one ectopic (8% of pregnancies), and one miscarriage (8% of pregnancies). Therefore, the overall loss rates (biochemical pregnancies plus miscarriages, excluding ectopic pregnancies) were 29% in the 24-hour group and 38% in the 36-hour group. These loss rates are in the range of the 34% early-loss rate reported by others! Older age of women is a well-documented cause of increased pregnancy wastage. The women with losses in the 24-hour group had a mean age of 33 years (range 29-36), while those in the 36-hour group had a mean age of 35 years (range 27-42). The only patient characteristic that varied at the start ofthe study between the two groups was that of infertility diagnosis. The only diagnosis that differed between the two groups was that of decreased ovarian reserve. This diagnosis was present in 6% of the women in the 24-hour group and 1.2% of the women in the 36-hour group. A reanalysis, excluding those with ovarian reserve (n=7), failed to show a significant difference in live birth rates between the two Figure 3. Live Birth Rate (Live Delivered Infant per IUI) in the 24-hour (Filled) and 36-hour groups (open): P=0.2, 24-Hour vs. 36-Hour N=82 9 87-
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groups. This suggests that the lack of a difference was not related to differences in infertility diagnosis between the two groups. Pryor and colleagues showed an improved pregnancy rate when IUI was performed at 38-40 (60% pregnancy rate) compared to IUI at 32-34 hours (0% pregnancy rate) after hCG. However, the method of sperm preparation also differed between the two groups. While 54% of those in the 38-40-hour group had sperm prepared with a sperm swim-up technique, only 13% of those in the 32-34-hour group had this type of sperm preparation. Their patients also differed from the patients in the present study in that the males in the Pryor study were all quadriplegic and had sperm recovered via vibratory stimulation. The sperm counts were much lower than in the present study, and the sperm preparation method may have been more of a deciding factor than was the timing of the IUI and may have accounted for the difference in pregnancy rates. Though human menopausal gonadotropins were used for ovulation induction in 436 cycles, Fuh and associates found no significant differences in pregnancy rates as the time between hCG and IUI was lengthened from less than 28 hours to more than 48 hours? The main limitation of the present study is the small numbers and low overall pregnancy rates. In total, there were only 11 live births-four in the 24hour group, and seven in the 36-hour group. These small numbers may have precluded our ability to note a difference between the two groups. The other limitation is in the retrospective design that limited the variables that could be examined. We conclude that when counseling patients on hCG administration during clomiphene citrateinduced cycles, no difference appears to be found if the drug is administered for patient convenience at 24 or 36 hours. However, a study with larger number of patients may demonstrate different results.
ACKNOWLEDGEMENTS The authors would like to thank Dr. Anjana Patel for her help in collecting the data.
REFERENCES 1. Andersen AG, Als-Nielson B, Hornnes PJ, et al. Time interval from human chorionic gonadotropin (HCG) injection to follicular rupture. Hum Reprod. 1 995; 1 0:3202-3205. 2. Gould JE, Overstreet JW, Hanson FW. Assessment of human sperm function after recovery from the female reproductive tract. Biol Reprod. 1984; 31:888-894. 3. Fuh KW, Wang X, Norman RJ. Intrauterine insemination: effect of the temporal relationship between the luteinizing hormone surge, human chorionic gonadotropin administration, and insemination on pregnancy rates. Hum Reprod. 1997;12:2162-2166. 4. Yovich JL, Matson PL. The treatment of infertility by the high intrauterne insemination of husband's washed spermatozoa. Hum Reprod. 1988;3:939-943. 5. Pryor JL, Kuneck P, Blatz SM, et al. Delayed timing of intrauterine insemination results in a significantly improved pregnancy rate in female partners of quadriplegic men. FerfilSteril. 2001;76:1130-1135.E|
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