Treatment of infertile women with unilateral tubal occlusion by intrauterine insemination and ovarian stimulation

Available online at www.sciencedirect.com ScienceDirect Taiwanese Journal of Obstetrics & Gynecology 52 (2013) 360e364 Original Article Treatment of infertile women with unilateral tubal occlusion by intrauterine insemination and ovarian stimulation Ming-Huei Lin a,b,d, *, Yuh-Ming Hwu a,b,c, Shyr-Yeu Lin a, Robert Kuo-Kuang Lee a,d,e a Department of Obstetrics and Gynecology, Mackay Memorial Hospital, Taipei, Taiwan b Mackay Medicine, Nursing and Management College, New Taipei, Taiwan c Mackay Medical College, New Taipei, Taiwan d Department of Medical Research, Mackay Memorial Hospital, New Taipei, Taiwan e Department of Obstetrics and Gynecology, Taipei Medical University, Taipei, Taiwan Accepted 18 January 2012 www.tjog-online.com Abstract Objective: The aim of this study was to evaluate the value of intrauterine insemination (IUI) combined with ovarian stimulation in women with unilateral tubal occlusion detected on hysterosalpingography (HSG). Materials and Methods: A total of 703 patients undergoing IUI and controlled ovarian hyperstimulation were enrolled in this study. The study group consisted of 133 patients treated for unilateral tubal occlusion diagnosed by HSG during 2005e2011. The control group consisted of 570 patients with unexplained infertility treated during the same period. In all cases of the retrospective study, menstrual cycles were regular, basal serum follicle-stimulating hormone levels and sperm parameters were normal. Results: There were no significant differences in pregnancy rate per cycle between the study (17.3%) and control groups (18.9%). The pregnancy rate was higher in patients with proximal tubal occlusion (21.7%) compared with mid-distal tubal occlusion (12.5%) or unexplained infertility (18.9%), but the difference was not statistically significant. Conclusions: Infertile patients with only unilateral proximal tubal occlusion detected on HSG can be treated initially by IUI combined with ovarian stimulation. The cycle outcomes in patients with proximal tubal occlusion are similar to patients with unexplained infertility. However, the stimulated IUI might not be a good choice for patients with unilateral mid-distal tubal occlusion because of a lower success rate, although further evidence is needed. Copyright Ó 2013, Taiwan Association of Obstetrics & Gynecology. Published by Elsevier Taiwan LLC. All rights reserved. Keywords: infertility; intrauterine insemination; ovarian stimulation; unilateral tubal occlusion Introduction Tubal dysfunction with or without associated peritoneal pathology accounts for up to 35% of all infertility and represents more than 50% of the etiologies of female infertility [1e3]. It has become one of the most common causes of infertility and its incidence is increasing, primarily due to rising rates of sexually transmitted infection and resultant pelvic inflammatory disease. Risk factors for tubal disease including prior pelvic infection, intrauterine device usage, * Corresponding author. E-mail address: huei97@ms1.mmh.org.tw (M.-H. Lin). previous ectopic pregnancy, septic abortion, appendiceal disease, or diethylstilbestrol exposure should all prompt the physician to move quickly toward assessment of tubal function. Hysterosalpingography (HSG) and laparoscopy are two common methods used to assess the status of both tubal patencies. The HSG images display the contour of uterine cavity and the internal architecture of the tubal lumen that cannot be evaluated by laparoscopy. Furthermore, HSG is inexpensive and less invasive than laparoscopy and generally should be performed prior to the operative procedure. In addition, some investigators suggest using Chlamydia antibody as a screen test for tubal infertility [4,5]. 1028-4559/$ - see front matter Copyright Ó 2013, Taiwan Association of Obstetrics & Gynecology. Published by Elsevier Taiwan LLC. All rights reserved. http://dx.doi.org/10.1016/j.tjog.2012.01.037

M.-H. Lin et al. / Taiwanese Journal of Obstetrics & Gynecology 52 (2013) 360e364 361 In general, the treatment of infertile women with bilateral patent tubes or with bilateral obstructed tubes detected on HSG is clear and direct. However, no standard management is offered to patients with unilateral occlusion. There are four possible approaches for patients with unilateral tubal occlusion: (1) repeat HSG; (2) further evaluation and correction of tubal and pelvic lesions via laparoscopy or catheterization; (3) attempting to achieve pregnancy with controlled ovarian hyperstimulation (COH) and intrauterine insemination (IUI) through one patent tube; and (4) referring for in-vitro fertilization (IVF) to bypass the problem. The information available to date on the results after COH and IUI in patients with unilateral tubal occlusion diagnosed by HSG is sparse. The purpose of the present study was to investigate the role of stimulated IUI in these patients. Materials and methods Patient selection The study group consisted of the patients who received stimulated IUI at Mackay Memorial Hospital during 2005e2011 and met the following criteria: (1) age <40 years; (2) only unilateral tubal occlusion diagnosed by HSG; (3) regular menstrual cycles with normal basal serum follicle stimulating hormone (FSH), luteinizing hormone (LH), prolactin, and thyroid stimulating hormone; and (4) normal sperm parameters. The control group consisted of patients with unexplained infertility treated during the same period and met the same inclusion criteria, except for normal findings on HSG. All women of both groups were treated by one of three senior physicians with the same COH and IUI procedures. Data were collected retrospectively by chart review for selected patients. The Institutional Review Board of our hospital approved the use of patients medical records. Ovarian stimulation All IUI cycles were initiated on the Day 3 of menstrual cycle and were continued until ovulation. Ovarian stimulation was performed using recombinant FSH (Gonal F; Merck Serono, Geneva, Switzerland or Puregon; Oragnon International Inc., Roseland, NJ, USA), or human menopausal gonadotropin (Menopur; Ferring SAS, St Prex, Switzerland). The starting dose of gonadotropin was 75e150 IU according to the status of the patient. Follicular development was monitored by vaginal ultrasound and serum estradiol levels, and the dose of FSH or human menopausal gonadotropin was adjusted accordingly every 1e3 days. Ovulation was induced with 10,000 IU human chorionic gonadotropin (hcg, Profast; Merck Serono) when at least one follicle had a diameter of 18 mm. A single IUI was performed 36 hours after administration of hcg. If an LH surge was assumed by positive urine LH test on the triggering day, IUI was performed the day after hcg trigger. IUI and luteal support Semen was collected 2 hours prior to the insemination and after 48e72 hours of abstinence. Density gradient method (Sperm gradient kits; Cook Medical, Brisbane, Australia) was used for sperm preparation. A 2-week course of daily treatment with micronized progesterone (Utrogestan; Cassenne- Aventis, Paris, France) vaginally was prescribed for luteal phase support. Pregnancy was initially detected 16e20 days after administration of hcg. Ultrasound was performed at 6 weeks of gestation to confirm fetal viability. The presence of a gestational sac detected by ultrasound was defined as clinical pregnancy. Women with clinical pregnancy who miscarried prior to the Week 12 were defined as spontaneous abortion. Statistical analysis Results are presented as mean values standard deviation. The SPSS version 17.0 (SPSS, Inc., Chicago, IL, USA) was used for data management and analysis. Categorical variables were compared using a Chi-squared test, and continuous variables were analyzed using Student t test. A p value <0.05 was considered statistically significant. Results The initial sample consisted of 185 women with unilateral tubal occlusion and 588 women with unexplained infertility. In the unilateral tubal occlusion group, six patients whose age was 40 years underwent stimulated IUI twice and 46 patients had combined male and female causes. These 52 patients were excluded from this study. Among the unexplained infertility group, 18 patients who underwent stimulated IUI twice were also excluded due to old age (40 years). Finally, we studied a total of 703 IUI cycles in 703 patients including unilateral tubal occlusion group (n ¼ 133) and unexplained infertility group (n ¼ 570). No between-group differences in mean age, BMI, serum AMH, or sperm parameters were found (Table 1). However, previous abdominal surgery was significantly higher in Table 1 Comparison of basic clinical parameters between the two groups. Clinical parameters Unilateral tubal occlusion (n ¼ 133) Unexplained infertility (n ¼ 570) Age (y) 33.4 4.2 32.9 3.6 NS BMI (kg/m 2 ) 22.1 4.3 21.7 3.5 NS Serum AMH (ng/ml) 3.0 4.5 3.2 5.2 NS Previous abdominal surgery 38 (28.6) 28 (4.9) <0.001 Semen volume (ml) 3.2 1.5 3.3 1.7 NS Sperm concentration 68.0 46.0 77.8 51.4 NS (10 9 /L) Sperm motility (%) 59.2 15.4 60.8 18.1 NS Data are presented as mean standard deviation or n (%). AMH ¼ anti-müllerian hormone; BMI ¼ body mass index; NS ¼ not significant. p

362 M.-H. Lin et al. / Taiwanese Journal of Obstetrics & Gynecology 52 (2013) 360e364 patients with unilateral tubal occlusion than those with unexplained infertility (28.6% vs. 4.9%, respectively; p < 0.001). There were no significant differences in days of ovarian stimulation, total dose of gonadotropin injection, and number of follicle (16 mm) between the study and control groups (Table 2). The pregnancy rates after COH and IUI were 17.3% (23/133) in the study group, and 18.9% (108/570) in the control group ( p > 0.05). The pregnancy rate per cycle was lower in the patients with mid-distal occlusion than those with proximal occlusion, but was not statistically significant (12.5% vs. 21.7%, respectively; p > 0.05). Similarly, the patients with mid-distal occlusion had lower pregnancy rates than those with unexplained infertility (12.5% vs 18.9%, respectively; p > 0.05). There were no complications with pelvic inflammatory disease in either group. Discussion The HSG is valuable as a nonsurgical initial test for tubal patency. Although laparoscopy is important for diagnosing pelvic adhesions and endometriosis, a normal HSG result is followed by conception within 6 months in 30e50% of cases [6]. Diagnostic laparoscopy can be delayed or omitted if HSG findings are normal. If the HSG reveals bilateral tubal obstruction, however, either laparoscopy to confirm the diagnosis or IVF to skip the problem should be indicated. However, management of the patients with unilateral tubal occlusion diagnosed by HSG remains without consensus of opinion. Several possible approaches including repeat HSG, operative hystero-falloposcopy, ultrasound-guided tubal catheterization, selective salpingography, laparoscopy, stimulated IUI, and IVF have been recommended. A retrospective cohort study of 359 patients that evaluated the prognostic significance of HSG for fertility outcome found that the adjusted pregnancy rates were 0.81 (95% confidence interval, 0.47e1.4) for a one-sided tubal pathology, but only 0.30 (95% confidence interval, 0.13e0.71) for a two-sided pathology [7]. The authors concluded that unilateral tubal pathology detected on HSG has virtually similar fertility prospects to normal HSG and limited prognostic significance Table 2 Comparison of IUI cycle outcomes between the two groups. Clinical outcomes Unilateral tubal occlusion (n ¼ 133) Unexplained infertility (n ¼ 570) Days of ovarian stimulation 10.1 2.4 9.8 2.3 NS Total dose of gonadotropins (IU) 535 252 528 234 NS Number of follicles (16 mm) 2.7 1.6 2.8 1.4 NS Clinical pregnancy rate (%) 17.3 (23/133) 18.9 (108/570) NS Pregnancy rate of proximal 21.7 (15/69) a tubal occlusion (%) Pregnancy rate of mid-distal tubal occlusion (%) 12.5 (8/64) b Data are presented as mean standard deviation. NS ¼ not significant. a p > 0.05 compared with the unexplained group; b p > 0.05 compared with the proximal tubal occlusion and unexplained groups. p for fertility, whereas bilateral tubal pathology detected on HSG obviously reduced fertility prospects. Therefore, they suggested that the therapeutic strategy of patients with an HSG finding of unilateral tubal pathology should not differ from the therapeutic strategy in patients with a normal HSG, because these groups of patients have similar fertility prospects. By contrast, laparoscopy should be considered in patients with an HSG finding of bilateral tubal pathology, because one third of these patients may alter the original treatment plan from IVF to COH with IUI [8]. In our study, the pregnancy rates of single stimulated IUI in patients with unilateral tubal occlusion were similar to those with unexplained infertility. Furthermore, the subgroup of these women with proximal occlusion of a single tube has better pregnancy rates than those with unilateral mid-distal occlusion. Our results are in agreement with those of Farhi [9], which demonstrated that the cumulative pregnancy rate with three cycles of stimulated IUI was not significantly different between the unilateral tubal occlusion group (30.9%) and unexplained infertility group (42.6%), and was lower in mid-distal tubal occlusion (19%) than in proximal tubal occlusion (38.2%). A previous study also reported that the pregnancy rate after single stimulated IUI was similar in cases of unilateral proximal occlusion and unexplained infertility, but lower in cases of unilateral distal occlusion [10]. However, it was a small retrospective study and multiple types of ovarian stimulation were grouped together. Proximal tubal occlusion detected on HSG may be a falsepositive result that the tube is truly patent on subsequent testing. Several situations such as tubal spasm, temporary plugs of debris or amorphous material [11], and underfilling of the tube may cause a false finding of proximal occlusion. A false-positive rate as high as 15% for proximal tubal occlusion on HSG has been noted in the literature [12]. Indeed, a prospective study demonstrated that a repeat HSG achieved bilateral patency in 24 of 40 patients (60%) who were diagnosed with proximal tubal occlusion on initial HSG [13]. The second HSG can only improve the diagnosis of tubal patency, but unlike stimulated IUI that can treat the infertile patient with unilateral tubal occlusion as unexplained infertility with bilateral tubal patency. In our study, a higher pregnancy rate found in the unilateral proximal occlusion group may reflect the false positive reading of proximal occlusion on HSG. Laparoscopy is currently regarded as the most reliable tool in the diagnosis of tubal infertility. For clinical practice, laparoscopy can be delayed until tubal pathology is found on initial HSG. In patients with a normal HSG, laparoscopy is only performed in cases where infertility has persisted for a longer period time [14]. A meta-analysis study on the surgical treatment of proximal tubal disease showed that microsurgical anastomosis can achieve a near 50% pregnancy rate. Pregnancy rates in a selected series of transcervical tubal cannulation were similar to those reported in microsurgery. In addition, the authors suggested that macrosurgery was indicated only in cases of complete obliteration of the intramural fallopian tube because macrosurgery had a lower success rate than microsurgery [15].

M.-H. Lin et al. / Taiwanese Journal of Obstetrics & Gynecology 52 (2013) 360e364 363 For patients with distal tubal disease, a recent meta-analysis reported that there was no significant difference in pregnancy rates of patients with mild tubal disease between laparoscopy and conventional laparotomy group. However, the pregnancy rate of patients with severe tubal disease was significantly higher in the laparotomy group. Appropriate patient selection is the main factor affecting outcome in terms of fertility [16]. In a prospective study comparing results of laparotomy plus microsurgery and laparoscopy for the treatment of distal tubal occlusion, both methods were equally effective in restoring fertility in women with comparable tubal damage. As stated above, the severity of the tubal damage is a critical factor for the surgical outcomes [17]. In the pre-ivf era, surgical intervention of tubal disease was the only available treatment for tubal infertility. Thereafter, IVF has gradually replaced tubal surgery as the treatment of choice for tubal infertility and become the treatment of last resort for persistent infertility due to any cause. In contrast to tubal surgery, IVF cannot correct the tubal abnormalities, but can bypass the tubal problem and create a clinical pregnancy directly for patients with only tubal or combined with other associated infertility factors. Benadiva et al [18] demonstrated the Cornell experience that cumulative pregnancy rates in women with tubal infertility were >70% after four cycles of treatment with IVF, and were significantly higher than those after surgical correction, especially in older women. Other studies have also revealed that the cost effectiveness of reconstructive surgery in unselective patients with distal tubal occlusion is apparently lower than for IVF [19,20]. These findings indicate that laparoscopic surgery may be viewed as an alternative to IVF in younger women with mild distal tubal disease, but IVF will be the logical choice if the disease becomes severe or pregnancy is not achieved during the first postoperative year. In older women with any significant degree of tubal disease, IVF should be offered first because the fertility potential declines rapidly with advancing age and IVF is more efficient than tubal surgery. Unfortunately, to date, there are no studies designed to compare pregnancy rates or time to conception between stimulated IUI and surgical treatment in patients with unilateral tubal occlusion. IUI is often suggested to infertile couples in which the woman has at least one permeable fallopian tube and the man has mild to moderate male factor infertility. IUI combined with COH offers a number of advantages. It increases the number of oocytes that have the potential for fertilization. It raises the woman s hormone level, eliminates seminal plasma, and markedly increases the number of sperm reaching the uterine cavity. There are many protocols of ovulation induction provided for COH and IUI. Chung et al [21] suggested that combining low-dose recombinant FSH and clomiphene citrate might be an ideal treatment for IUI. However, the outcomes observed in a large case series strongly suggested that exogenous gonadotropin stimulation increases cycle fecundability in therapeutic donor insemination cycles, and cycle fecundability is more than twice that observed in clomiphene-stimulated cycles [22]. Meanwhile, the cycle fecundability observed in spontaneous and clomiphenestimulated therapeutic donor insemination cycles is similar, suggesting that clomiphene stimulation has little or no added value [23]. Thus, in this study, we used recombinant FSH without clomiphene for ovarian stimulation to avoid the adverse antiestrogen effects of clomiphene on endometrium. 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