ovarian hyperstimulation (COH) and intrauterine

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1 No difference in cycle pregnancy rate and in cumulative live-birth rate between women with surgically treated minimal to mild and women with unexplained infertility after controlled ovarian hyperstimulation and intrauterine insemination Erika Werbrouck, M.D., Carl Spiessens, Ph.D., Christel Meuleman, M.D., and Thomas D Hooghe, M.D., Ph.D. Leuven University Fertility Centre, University Hospital Leuven, Leuven, Belgium Objective: The association between infertility and minimal to mild is controversial and poorly understood. The clinical pregnancy rate (PR) per cycle after controlled ovarian hyperstimulation (COH) with or without intrauterine insemination (IUI) is reportedly lower in women with surgically untreated minimal to mild than in women with unexplained infertility. It is possible that prior laparoscopic removal of has a positive effect on the clinical PR after COH and IUI. Therefore, we tested the hypothesis that after COH and IUI the PR per cycle and the cumulative live-birth rate (CLBR) are equal or higher in women with recently surgically treated minimal to mild when compared with women with unexplained infertility. Design: A retrospective, controlled cohort study. Setting: Leuven University Fertility Centre, a tertiary academic referral center. Patient(s): One hundred seven women treated during 259 cycles with COH and IUI including patients with (n 58, 137 cycles) and unexplained infertility (n 49, 122 cycles). All patients with had minimal (n 41, 100 cycles) or mild (n 17, 37 cycles) disease that had been laparoscopically removed within 7 months before the onset of treatment with COH and IUI. Intervention(s): Controlled ovarian hyperstimulation using clomiphene citrate (23 cycles) or gonadotrophins (236 cycles) in combination with IUI. Main Outcome Measure(s): Clinical PR per cycle and CLBR within four cycles of treatment with COH and IUI. Result(s): The clinical PR per cycle was comparable in women with minimal or mild (21% or 18.9%, respectively) and in women with unexplained infertility (20.5%). The CLBR within four cycles of COH and IUI was also comparable in women with minimal, mild, and unexplained infertility (70.2%, 68.2 %, 66.5%, respectively). Conclusion(s): The data from our study suggest that COH and IUI shortly after laparoscopic excision of is as effective as COH and IUI in patients with unexplained subfertility. (Fertil Steril 2006;86: by American Society for Reproductive Medicine.) Key Words: Intrauterine insemination, controlled ovarian hyperstimulation, minimal to mild, unexplained infertility Until today, the association between minimal to mild (American Society for Reproductive Medicine [ASRM] [1]) and subfertility has been controversial. In a recent prospective cohort study (2), the probability of conceiving naturally and carrying a pregnancy beyond 20 weeks was approximately 50% lower in women with surgically untreated minimal to mild (15.7%) than in women with unexplained infertility (23.6%). In addition, other retrospective studies have indicated a lower monthly Received September 13, 2005; revised and accepted January 23, Reprint requests: T. D Hooghe, Leuven Unversity Centre, UZ Gasthuisberg, Herestraat 49, B-3000 Leuven, Belgium (FAX: ; thomas.dhooghe@uz.kuleuven.ac.be). fecundity rate (MFR) in women with minimal to mild than in women with unexplained infertility (3). Although more prospective studies are needed to confirm and understand the mechanism of subfertility associated with minimal to mild, many investigators have now accepted this association and have tested the hypothesis that -related infertility can be treated by surgery or by nonspecific fertility-enhancing therapy, including controlled ovarian hyperstimulation (COH) and intrauterine insemination (IUI). The hypothesis that surgical removal of minimal to mild improves fecundity has been confirmed by some (4, 5) but not by all (6, 7) investigators in mostly 566 Fertility and Sterility Vol. 86, No. 3, September /06/$32.00 Copyright 2006 American Society for Reproductive Medicine, Published by Elsevier Inc. doi: /j.fertnstert

2 retrospective controlled studies. Recently, in a randomized, controlled Canadian trial, the hypothesis was confirmed that laparoscopic resection or ablation of minimal to mild and associated adhesions enhances fecundity (8). In this study, the MFR and clinical pregnancy rate (PR) after 36 weeks were twice as high after surgical removal of the and associated adhesions (4.7% and 30.7%, respectively) than after diagnostic laparoscopy (2.4% and 17.7%, respectively). According to two prospective, randomized controlled trials, nonspecific fertility enhancement using COH and IUI reportedly improves the monthly live-birth rate (11%) when compared with expectant management (2%) in women with minimal to mild (9, 10). However, not all women had received an ablation of the endometriotic lesions before COH and IUI, and treatment with COH and IUI did not restore normal fertility in these women. In contrast, recently randomized, controlled trials indicated that the clinical PR after COH and IUI (11) or after COH only (12) was significantly lower in women with minimal to mild (13% and 6.5%, respectively) than in women with unexplained infertility (32% and 15%, respectively). However, in both randomized trials, had not been treated surgically before the onset of treatment with COH and IUI. It is possible that treatment with COH and IUI after surgical removal of may result in a higher clinical PR after COH and IUI than treatment with COH and IUI in women with surgically untreated. Therefore, the aim of the present study was to test the hypothesis that the clinical pregnancy (live-birth) rate per cycle, and the cumulative pregnancy (live-birth) rate after COH and IUI are similar or higher in patients with previously surgically removed minimal to mild when compared with women with unexplained infertility. MATERIALS AND METHODS Patient Selection All couples with unexplained infertility or minimal to mild who participated in our program of COH and IUI between 1994 and 2002 were identified from the database of the Leuven University Fertility Center (LUFC). Because the study was of a retrospective nature and all files were searched electronically, it was not necessary to ask for Institutional Review Board (IRB) approval according to the guidelines of the Commission for Medical Ethics in our hospital. In all patients, a complete workup, including surgery, was performed within a period of 3 to 4 months after the initial visit and before the waiting period of 6 to 12 months, allowing spontaneous conception before the onset of treatment with COH and IUI. The complete infertility investigation at LUFC included a semen analysis; basal body temperature records; basal hormonal analysis between day 3 and day 5 of the cycle for FSH, LH, E 2, prolactin, TSH, and androgens; midluteal endometrial biopsy or P analysis; hysteroscopy; and laparoscopy. Three patients had received 1 treatment cycle with COH and IUI in another fertility center before being fully investigated at LUFC. Patients with unexplained infertility were defined as couples with infertility associated with normal results for all previously mentioned diagnostic investigations, with the exception of luteal insufficiency. Patients with minimal to mild were similar to patients with unexplained infertility, except for the presence of endometriotic lesions that were staged as minimal to mild according to the ASRM classification system (1). Patients with minimal or mild had a score of 1 5 or 6 15 points, respectively, as defined in the revised ASRM classification (1).These endometriotic lesions were all excised or destroyed by laser surgery during the diagnostic laparoscopy. Histological confirmation of (i.e., presence of endometrial glands and stroma) was confirmed in all patients in 1 biopsy. Luteal insufficiency was present if the histological dating of the endometrial biopsy was 2 days out of phase (13) or if midluteal P concentration was 10 ng/ml. Patients who conceived naturally after laparoscopy and therefore did not participate in the program of COH and IUI were not followed up in our center; thus, their number is not known. Exclusion criteria included abnormal tuboovarian anatomy compromising tubal transport of gametes or embryos or fimbrial oocyte pickup function (dense adnexal and/or ovarian adhesions due to pelvic inflammatory disease because of previous pelvic surgery for the treatment of moderate or severe ), abnormal ovulatory function (anovulation or oligoovulation due to polycystic ovary syndrome, hyperprolactinemie, thyroid dysfunction, or luteinized unruptured follicle syndrome), abnormal implantation due to endometrial polyps or submucosal myomas, and male factor infertility (semen analysis with 50% progressive motility and/or spermatozoa/ml and/or 10% normal sperm morphology, according to previously reported guidelines (World Health Organization [WHO] [14, 15]). In contrast with the male exclusion criteria, no hard cutoff values were used for the female exclusion criteria because they were based on the medical diagnosis for each patient immediately after the infertility investigation including hysteroscopy and laparoscopy. This diagnosis was based on generally accepted causes for female infertility (16). Using the previously mentioned inclusion and exclusion criteria, we identified 107 patients who were treated during 259 cycles of COH with IUI. Because this was a retrospective cohort study evaluating pregnancy outcome after fertility treatment, neither specific approval by the IRB nor informed consent by the patients was needed. The detailed characteristics of patients and cycles are presented in Table 1. Fertility and Sterility 567

3 TABLE 1 Patient characteristics. Characteristic Minimal Mild Unexplained infertility No. of patients Age (y) No. of insemination cycles No. with primary subfertility (%) 82 (82) 33 (89) 72 (59) No. with secundary subfertility (%) 18 (18) 4 (11) 50 (41) No. with LI Time interval between cycles (years) Duration of subfertility (years) Time interval laparoscopy/first IUI (years) No. of CC cycles Start-dose (mg) No. of hmg cycles Start-dose (N ampuls 75 IU per day) No. of follicles Endometrial thickness (mm) Note: Values are means SD. CC clomiphere citrate; hmg human menopausal gonadotropin; LI luteal insufficiency. Werbrouck. COH and IUI are effective in. Fertil Steril Controlled Ovarian Hyperstimulation The COH in preparation for IUI was performed either with clomiphene citrate (CC), in a dose of 50 or 100 mg/d from day 3 to day 7 of the menstrual cycle (n 23 cycles), or with human menopausal gonadotropin (hmg) in a dose of 75 or 150 IU IM/d (Humegon, Organon, Oss, the Netherlands or Metrodin HP, Serono, Geneva, Switzerland) starting day 2 of the cycle (n 236 cycles). Ovarian response was monitored by ultrasound and blood sampling for E 2, P, LH, and FSH. Human chorionic gonadotropin in a dose of 5,000 or 10,000 IU IM was administered when the leading follicle had reached an average diameter of mm. An IUI was performed approximately 38 hours later. When the women had two or more mature follicles ( 14 mm) at the time of hcg injection, selective follicle aspiration was offered to them, and usually one or two mature follicles were left intact after this procedure. Sperm Analysis and Preparation The semen was collected by masturbation after 3 to 5 days of sexual abstinence. A semen analysis was performed following the WHO guidelines (14, 15). After liquefaction, sperm samples were centrifuged over a discontinuous two-layer density gradient (40%/80%) (Percoll, Amersham Pharmacia Biotech SA, Uppsala, Sweden or PureSperm, Nidacon International AB, Göteborg, Sweden) followed by one wash with HEPES-buffered Earle s Balanced Salt Solution supplemented with 0.3% human serum albumin (Sigma Chemical Co., St Louis, MO) and a second wash using IVF medium (MediCult, Copenhagen, Denmark). The samples were resuspended in IVF medium and subsequently incubated at 37 C and 5% CO 2. After 1 hour, the motility was evaluated and the sperm count was determined. The samples were centrifuged just before insemination, and the pellets were resuspended in a volume of 0.25 ml IVF medium. Intrauterine Insemination The IUI was performed using an intrauterine catheter (Kremer Delafontaine; Prodimed, Neuilly-en-Thelle, France) with a 1- or 2-mL syringe. The catheter was gently passed through the cervical canal, and the sperm suspension was expelled into the uterine cavity. Insemination volumes ranged from ml. The women remained supine for 20 minutes after IUI. A pregnancy test on blood was performed 12 days after IUI. If the test was positive, the pregnancy was confirmed by ultrasonography 3 weeks later. Pregnancies were followed up for the occurrence of miscarriage, ectopic pregnancy, multiple pregnancy, and live birth. Statistical Analysis On the cycle level, pregnancy outcome was defined as clinical PR (presence of a gestational sac on ultrasound at 7 weeks of amenorrhea), implantation rate (number of embryos with positive fetal heart rate on ultrasound), and livebirth rate per cycle of COH and IUI. Differences in these endpoints between groups were statistically evaluated by the 2 test. The cumulative live-birth rate (CLBR) within four 568 Werbrouck et al. COH and IUI are effective in Vol. 86, No. 3, September 2006

4 FIGURE 1 Classification of patients with minimal to mild. Werbrouck. COH and IUI are effective in. Fertil Steril cycles of COH and IUI was analyzed using life table analysis, and subgroups were compared using Kaplan-Meier analysis. RESULTS General Patient Characteristics General patient group characteristics (107 women, 259 cycles) and the distribution of scoring points (5) among the patients with minimal to mild are listed in Table 1 and Figure 1, respectively. The subgroups with minimal, mild, and unexplained infertility were similar, except for the duration of infertility, which was significantly lower in women with unexplained infertility compared with women with minimal (P.0053). None of the patients developed ovarian hyperstimulation. Cycle Level The average clinical PR per cycle was 20.4% and was similar in women with minimal (21%), mild (18.9%), and unexplained infertility (20.5%) (Table 2). The results were also similar between groups for all the other clinical outcome data (Table 2). Life Table Analysis The cumulative live-birth rate within four cycles was similar in patients with minimal (70.2%), mild (68.2%), and unexplained infertility (66.5 %) (Fig. 2). A spontaneous pregnancy occurred during the time interval between two treatment cycles with COH and IUI in six couples with minimal (n 3), mild (n 1), and unexplained infertility (n 2). These pregnancies were not included in the life table analysis. DISCUSSION The results of our study confirm our hypothesis that, after COH and IUI, the clinical PR and CLBR are similar in women with recently surgically treated minimal to mild and in women with unexplained infertility. These data are in contrast with earlier reports that demonstrated a significantly lower PR after COH, with or without IUI, in patients with surgically untreated minimal to mild when compared with those with unexplained infertility (11, 12). Furthermore, in our study, the 20% PR per cycle after COH and IUI in women with minimal to mild was higher than the 6% (11) or 13% (12) PRs reported previously. The fact that there was no surgical treatment of before therapy with COH and IUI in these studies (11, 12) could contribute to these lower PRs. Collectively, these data suggest that surgical treatment before COH and IUI restores the clinical PR after COH and IUI in women with minimal to mild to the same level as reached in women with unexplained infertility. To our knowledge, only one other investigation (17) has evaluated the outcome of superovulation and IUI in patients with treated minimal to mild compared with those with unexplained infertility, but it concluded that women with had lower PRs than those with unexplained infertility. However, that study (17) cannot be compared with our study because the patients were older (average age, 37.4 years) than in our study and included not only patients with minimal or mild but also a subgroup with mild adnexal disease, including distal tubal disease and adnexal adhesions, which are known to cause a less favorable fertility prognosis (3). In our study, no statistical difference was found between the cumulative live-birth rate of patients with minimal and mild and unexplained infertility (70.2%, 68.2%, and 66.5%, respectively). In another retrospective cohort study performed at LUFC (18), a lower CLBR of 52.8% was found within four cycles of COH and IUI in couples with normozoospermia. A possible explanation for the discrepancies in results is the difference in patient selection in the study. The previously published trial (18) evaluated the CLBR in a group of women whose male partners had normozoospermia, but the group was heterogeneous with respect to the severity of, abnormal ovulatory function, abnormal tuboovarian anatomy, and other factors (18). A longer duration of infertility (Table 1) was observed in patients with minimal when compared with couples with unexplained infertility. This may be explained by our policy of expectant management (after full infertility workup before surgery) during 6 to 12 months after surgical treatment of to allow spontaneous conception; it was demonstrated in a multicenter, Canadian randomized controlled study that surgical removal of endometriotic lesions and -related adhesions in women with minimal to mild increased the spontaneous PR (8). This longer duration of infertility in the group when compared to the unexplained infertility group is unlikely to have influenced the results significantly. Indeed, any bias introduced would have favored a lower PR in the group than in the unexplained infertility group Fertility and Sterility 569

5 TABLE 2 Clinical PR and live-birth rate per cycle after treatment with COH and IUI in women with and women with unexplained infertility. Characteristic Total Minimal mild Minimal Mild Unexplained infertility Patients Cycles No. of pregnancies/no. 20% 20% 21% 19% 20% of cycles (53/259) (28/137) (21/100) (7/37) (25/122) No. of implantations/ 23% 23% 25% 19% 23% no. of cycles (60/259) (32/137) (25/100) (7/37) (28/122) No. of multiple pregnancies/no. of 11% 14% 19% 0 12% clinical pregnancies (6/53) (4/28) (3/21) (0/7) (3/25) Twins 0/7 3/25 Triplets 2/21 0/7 0/25 1/21 a No. of miscarriages/ no. of clinical 11% 11% 19% 0 12% pregnancies (6/53) (3/28) (3/21) (0/7) (3/25) Ectopic pregnancies/ 4% 4% 5% 0 4% clinical pregnancies (2/53) (1/28) (1/21) (0/7) (1/25) No. of live births/no. of 85% 85% 81% 100% 84% pregnancies (45/53) (24/28) (17/21) (7/7) (21/25) No. of multiple live births/no. of live 11% 7% 9% 0 12% births (5/45) (2/28) (2/21) (0/7) (3/25) a Single delivery was achieved after embryo reduction of a triplet pregnancy. Werbrouck. COH and IUI are effective in. Fertil Steril FIGURE 2 Cumulative birth rate. because it is well known that the PR after fertility treatment is negatively correlated with the duration of infertility. In our study, the implantation rate per cycle was 23%; it was similar in women with and in women with unexplained infertility. In contrast, a higher implantation rate of 44% was observed in patients with unexplained infertility in a randomized prospective trial (11) because the multiple pregnancy rate per cycle was much higher in that study (11) than in our study (11%). The multiple pregnancy rate in our study is comparable to the rate reported in our previously published study (18), still higher than in our current practice (19), but lower than what is generally reported after COH with gonadotrophins and IUI (20 22). This observation, together with the high cumulative livebirth rate of nearly 70% within four cycles, suggest that COH and IUI should be a first line of treatment in patients who have not become pregnant within 6 months to 1 year after surgical treatment of minimal to mild and who have no other fertility reducing factors. Werbrouck. COH and IUI are effective in. Fertil Steril REFERENCES 1. American Society for Reproductive Medicine. Revised American Society for Reproductive Medicine classification of : Fertil Steril 1997;67: Bérubé S, Marcoux S, Langevin M, Maheux R, and the Canadian Collaborative Group on Endometriosis. Fecundity of infertile women with minimal or mild and women with unexplained infertility. Fertil Steril 1998;69: Werbrouck et al. COH and IUI are effective in Vol. 86, No. 3, September 2006

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