Influence of Gynaecologic Adnexal Surgeries on Subsequent Ovarian Function and In Vitro Fertilization Treatment Outcome

Journal of Reproduction & Contraception doi: 10.7669/j.issn.1001-7844.2014.02.0072 2014 Jun.; 25(2):72-80 E-mail: randc_journal@163.com Influence of Gynaecologic Adnexal Surgeries on Subsequent Ovarian Function and In Vitro Fertilization Treatment Outcome Yao WANG 1,2, Yun SUN 1,2, Xiao-ming ZHAO 1,2, Su-ping FANG 1,2, Ning YAO 1,2, Yan HONG 1,2 1. Department of Reproductive Medicine, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200001, China 2. Shanghai Key Laboratory for Assisted Reproduction and Reproductive Genetics, Shanghai 200001, China Objective To investigate the correlation between gynaecologic adnexal surgery history and pregnancy outcome of in vitro fertilization (IVF) treatment. Methods A total of 810 women who were proceeded 810 IVF treatment cycles from October 2009 to March 2011 were recruited to this retrospective study, based on whether they had history of gynaecologic adnexal surgeries or not. Among 810 women, 587 women had no gynaecologic adnexal surgeries (group A), 223 women had gynaecologic adnexal surgeries (group B). Additionally, the group B was further divided into 4 subgroups based on their different gynaecologic adnexal surgery histories, such as tubal conservative surgery (group Ba1), unilateral salpingectomy (group Ba2), ovarian cyst ablation (group Bb1) and unilateral adnexal resection (group Bb2). The basal levels of FSH, antral follicle count (AFC), clinical pregnancy rate (CPR), embryos implantation rates (IR) and live birth rates (LBR) were compared. Results The levels of FSH and AFC were significantly different between groups A and B, respectively. Therefore, CPR, IR and LBR were significantly lower (P) in group B (30.9%, 17.8% and 25.1%) compared with group A (39.9%, 22.8% and 32.4%). Meanwhile, there was no significant difference between the patients who had tubal conservation surgery (group Ba1) and who had unilateral salpingectomy (group Ba2). However, in contrast to unilateral adnexectomy, ovarian cystectomy surgery influenced This work was supported by the National Natural Science Foundation of China (Grant No.81370762), the Key Program for Basic Research of the Science and Technology Commission of Shanghai Municipality, China (Grant No.12JC1405800) Corresponding author: Yan HONG; Tel: +86-21-20284547; E-mail: hongyjessica@163.com 72

FSH and AFC significant, even for the number of oocyte retrieved, but did not affect the IVF treatment outcome. Conclusion The previous history of gynaecologic adnexal surgeries may affect the subsequent ovarian function and also IVF outcomes. As for different operation methods, between tubal conservation surgery and unilateral salpingectomy, the IVF outcomes were not significantly different. The same result we found in different ovarian operation groups. Key words: gynaecologic adnexal surgery; oocyte function; clinical pregnancy rate (CPR); implantation rate (IR); live birth rate (LBR) Gamete quality is the principal factor that influences the consequence of in vitro fertilization (IVF). Surgery on the ovary may affect subsequent ovarian function, especially the outcome of ovarian stimulation and IVF. The adnexae includes ovary and fallopian tube. Damage to the fallopian tubes is a common cause of women having difficulty conceiving. Hydrosalpinges are relatively frequent in women with tubal disease infertility who are undergoing IVF. The prevalence of hydrosalpinges can range between 10% when diagnosed by transvaginal ultrasound, and 30% when either hysterosalpingography (HSG) or laparoscopy is used. In the majority of women with tubal ectopic pregnancy, laparoscopic surgery is the treatment of first choice [1]. So far, no consensus has been reached whether salpingotomy or salpingectomy leads to better fertility outcome [2]. However, the effects of salpingectomy on ovarian function remain unclear. Results of previous studies [2,3] in women undergoing IVF after laparoscopic salpingectomy have been mixed. Some investigators demonstrated [3,4] salpingectomy reduced number of dominant follicles and oocytes in the ipsilateral ovary, and reduced maximal levels of E2, as well as decreased antral follicle count, thus influence IVF outcome negatively, whereas other study showed salpingotomy does not significantly improve fertility prospects compared with salpingectomy [5]. As an approach for ovarian cysts, laparoscopy and laparotomy are both considered. Laparoscopy is used often owing to advantages including a shorter hospital stay and patient recovery, fewer adhesions, and less pain as compared with laparotomy. Thus, ovarian stripping remains the most frequently performed surgical technique for the treatment of ovarian cysts. A chief concern about the excision of ovarian cysts is the negative effect on ovarian reserve owing to follicle loss [4]. If surgery is undertaken, various techniques have been advocated to try to enhance the pregnancy rate. These include the use of magnification including microsurgical techniques, laparoscopic surgery, laser or electrodiathermy to minimise blood loss and scarring and positioning a prosthesis around the tube. 73

Despite the large consensus laparoscopy has gained among gynecological surgeons over the last two decades, residual ovarian function after operation remains an important unsolved topic. Surprisingly, this aspect has been poorly investigated in the past [6]. There is the same lack of information after laparotomy. Several retrospective studies have reported reduced responses to gonadotropin after cystectomy [7], and others reported a marked reduction in the number of both dominant follicles and retrieved oocytes in the operated ovary after cystectomy [8]. This study provides a description of the surgical challenges encountered with gynaecological adnexal surgery on subsequent ovarian function and outcomes from subsequent IVF cycles. Materials & Methods Subjects Data from IVF and intracytoplasmic sperm injection (ICSI) cycles performed at Department of Reproductive Medicine, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, between October 2009 and March 2011 were reviewed. Inclusion criteria were as follows: 1) fresh stimulation and transfer cycle; 2) agreement to be enrolled; 3) the first cycle after the adnexal surgery. Exclusion criteria were as follows: 1) known endocrine disease; 2) endometriosis; 3) postoperative pathologic diagnosis that was not benign ovarian cyst; clinical and sonographic suspicion of ovarian cancer; 4) oral contraceptive or IUD use 6 months before IVF treatment; 5) use donor egg; 6) a canceled cycle prior to human chorionic gonadotropin (hcg) administration. The selected women were identified 2 different groups: group A, women without gynaecologic adnexal surgery (control group); group B, women with gynaecologic adnexal surgery. The later group subsequently divided into 2 subgroups: group Ba, tubal surgery; group Bb, ovarian surgery. The two groups were further divided into 2 subgroups individually: group Ba1: the tubal conservative operation, which including oviduct fenestration, proximal tubal occlusion, salpingostomy and fimbrioplasty; group Ba2: unilateral salpingectomy. While Group Bb was divided into 2 subgroups: 1 for ovarian cyst ablation and 2 for unilateral adnexal resection. Approval for the study was obtained by the local institutional review board. All patients gave their informed consent to the use of their clinical data for research purposes. Methods This was a retrospective chart review. Only one cycle per patient was considered, the first cycle performed after surgery. The information regarding surgical technique was obtained from surgical and pathological records. 74

The pharmacological regimen for controlled ovarian hyperstimulation used was a daily 0.1 mg GnRH agonist (triptoreline, Decapeptyl, Ferring, United Kingdom). The stimulation protocol included the long and short down-regulation protocol. The long-term pituitary downregulation started from the late luteal phase. The short-term pituitary down-regulation began from the cycle day 2 or day 3. After that, 150 225 IU of FSH (Goanl-F, Serono, Switzerland) were administered daily. The dosage of recombinant FSH prescribed was decided based on age, hormonal tests, ultrasound characteristics of the ovaries. In all cases, follicular growth was monitored by serial transvaginal ultrasonography. Ovulation was triggered administering 6 000 U of hcg (chorionic gonadotrophin for injection, Lizhu, Inc, China) when 2 or more leading follicles had mean diameter 18 mm or greater. On the day of hcg administration, a transvaginal ultrasound scan was performed to record number and diameter of all the follicles. This information was recorded separately for each ovary. Transvaginal oocyte retrieval was performed 36 h after hcg administration and transfer of the embryos was undertaken 2 3 d later. The clinical pregnancy was defined as the ultrasonographic demonstration of an intrauterine gestational sac 4 weeks after embryo transfer. Patients were monitored by serial ultrasounds and serum estradiol measurements using Beckman DXI-800, immunology analyzer, USA. The levels of FSH, LH, E 2 were measured prior to the cycle initiation by a chemiluminescent assay obtained from Beckman corp. Primary outcome measures included the number of antral follicle, the previous cycle basal serum FSH, LH and E 2, the number of oocytes obtained at retrieval, fertilized oocytes, transfer embryos and achievement of an ongoing pregnancy (at least 1 normal fetal heart of sonography demonstration). Demographic data on each patient including age, body mass index (BMI) and infertility diagnosis were recorded. Additional variables observed were total quantity of FSH used for stimulation and details of stimulation protocol and dosage, pregnancy result, implantation result, miscarriage result and ongoing pregnancy rate. Statistical analysis The data were expressed as mean standard deviation (x s) or percentage (%) and analyzed by χ 2 tests, correlation coefficients, analysis of variance with correction for multiple comparisons, as appropriate. SPSS 16.0 software was used for statistical analysis. P was considered significant. Results Eight hundred and ten women were studied. Five hundred and eighty-seven had no history of surgery (group A), whereas the remainder was with surgery history (group B). Patients characteristics and outcomes are summarized in Table 1. Briefly, in group A, patients aged 22 44 (31.2 4.5) years. While in group B, the patients age was 22 44 75

(31.7 4.4) years. Other patients characteristics including precycle FSH, and antral follicle count are also shown in Table 1. These observations with their considerable variation reflect the demographics of our center s usual diverse patient population. There were no cancelled cycles in this cohort. FSH level was significantly higher in group B. The antral follicle count was less in group B, which means the ovarian function in group B was worse than that in group A (Table 1). For the IVF outcome, the clinical pregnancy rates were achieved to 39.9% vs 30.9% in group A vs group B (P). The implantation rates were 22.8% vs 17.8% (P), the live birth rates were 32.4% vs 25.1% (P)(Table 1). Table 1 Baseline and clinical characteristics of group A and group B (x s) Characteristics Group A Group B P n 587 223 Patients age (year) 31.2 4.5 31.7 4.4 Duration of infertility (a) 4.6 3.0 4.7 3.7 Day 3 serum FSH (IU/ml) 7.3 3.7 7.8 2.6 Antral follicle count (n) 11.7 4.7 8.4 5.0 Number of oocyte retrieval (n) 11.5 4.8 9.27 3.5 Number of embryo transfer (n) 2.1 0.1 2.1 0.0 Clinical pregnancy rate (%) Implantation rate (%) Live birth rate (%) 39.9 (234/587) 22.8 (624/2 740) 32.4 (417/1 287) 30.9 (69/223) 17.8 (83/467) 25.1 (56/223) In group Ba, the patients who had the history of tubal surgery before, were divided into two subgroups which were tubal conservative surgery (group Ba1) and unilateral salpingectomy (group Ba2). The baseline clinical characteristics and outcome treatment of IVF in these two groups are shown in Table 2. The clinical pregnancy rate in group Ba1 vs group Ba2 were 30.8% vs 31.5% (P). The implantation rates were 15.6% vs 18.1% (P> 0.05). The live birth rates were 23.1% vs 25.0% (P). All the data didn t show us significantly different, even which in group Ba2 were higher than those in group Ba1. In group Bb, as shown in Table 3, day 3 serum FSH was significantly higher in group Bb2 than in group Bb1 (7.7 2.3 IU/ml vs 8.8 1.1 IU/ml, P). AFC was also lower in group Bb2 than in group Bb1 (10.2 3.2 vs 6.0 2.9, P). The number of oocyte retrieved was significantly lower in group Bb2 (11.5 4.8 vs 9.3 3.5, P). In Table 3, the clinical pregnancy rates in group Bb1 vs group Bb2 were 30.2% vs 31.3% (P). The implantation rates were 19.1% vs 18.2% (P). Discussion This study showed the influence of gynaecologic adnexal surgery on stimulation for IVF. Furthermore, the study focused on the outcomes of different gynaecologic surgeries, which 76

Table 2 Baseline and clinical characteristics of groups Ba1 and Ba2 (x s) Characteristics Group Ba1 Group Ba2 P n 52 92 Patients age (year) 31.7 4.2 32.7 4.1 Duration of infertility (a) 5.2 4.4 3.9 3.5 Day 3 serum FSH (IU/ml) 7.9 2.9 7.7 2.6 Antral follicle count (n) 8.9 5.2 8.8 5.1 Number of oocyte retrieval (n) 10.6 6.5 9.4 6.2 Number of embryo transfer (n) 2.1 0.1 2.2 0.1 Clinical pregnancy rate (%) Implantation rate (%) Live birth rate (%) 30.8 (16/52) 15.6 (17/109) 23.1 (12/52) 31.5 (29/92) 18.1 (36/199) 25.0 (23/92) Table 3 Baseline and clinical characteristics of groups Bb1 and Bb2 (x s) Characteristics Group Bb1 Group Bb2 P n 63 16 Patients age (year) 32.4 5.0 34.1 3.2 Duration of infertility (a) 5.0 3.1 5.9 3.3 Day 3 serum FSH (IU/ml) 7.7 2.3 8.8 1.1 Antral follicle count (n) 10.2 3.2 6.0 2.9 Number of oocyte retrieval (n) 11.5 4.8 9.3 3.5 Number of embryo transfer (n) 2.1 0.1 2.1 0.0 Clinical pregnancy rate (%) Implantation rate (%) Live birth rate (%) 30.2 (19/63) 19.1 (24/126) 27.0 (17/63) 31.3 (5/16) 18.2 (6/33) 25.0 (4/16) compared within two different tubal surgeries and also within two different adnexal surgeries. As we all known, the age at IVF is a critical variable when dealing with ovarian reserve, produced almost identical results. In our data, the female age in all groups are highly similar. In which basal follicle stimulating hormone (FSH) levels measured on day 3 of the menstrual cycle is the most widely used ovarian reserve tests to assess the ovarian response to stimulation, for over two decades now. An increase in FSH levels occurs due to follicle depletion. While FSH levels alone may not be predictable of the ovarian response in such women. AFC is measured by transvaginal ultrasonography in the early follicular phase, by taking the mean of two perpendicular measurements. The numbers of follicles in both ovaries is added for the total AFC. AFC has long been used as a marker of ovarian reserve [9-11]. It is noteworthy that some of day 3 serum FSH and AFC which suggested the baseline ovarian reserve of the women are significantly different. In our study, the women who underwent gynaecologic adnexal surgery compared without surgery, had a higher FSH level and lower AFC, which means the ovarian function is influenced by the surgery. Moreover, the number of oocyte retrieved in unilateral adnexectomy group is obviously lower than ovarian 77

cystectomy group due to one side ovarian retrieved surgery. With regard to the outcome of IVF, there is a significant difference between with and without gynaecologic surgery groups. Somehow, comparing within two distinct tubal surgeries and two kinds of adnexal surgeries, even there are not alike, the IVF pregnancy consequence is a bitter higher in unilateral salpingectomy group and in ovarian cystectomy group, but no significantly different, which is in contrast to some prior studies [12]. As previously mentioned, the rate of fertility following salpingostomy and salpingectomy has been well documented [13,14]. Salpingostomy, on one hand, may allow spontaneous conception in selected cases with good prognosis and should not be performed in patients with a poor prognosis due to the high risk of recurrence [2,15]. Salpingectomy, on the other hand, possibly lead to blood flow changes, decreasing ovarian reserve [16]. It was observed a significant decrease in the ipsilateral ovarian response after salpingectomy, as reflected by the reduced quantity of developing follicles during COH for IVF [17]. Also it has been reported that a blind victimization of the fallopian tube should not be the rule [18]. Meanwhile, Almog et al. [3] concluded that salpingectomy does not influence ovarian response in COH. In the present study, salpingectomy is recommended as the preferred option [19]. The results of our study along with others would be helpful in counseling women before salpingectomy for hydrosalpinx or ectopic tubal pregnancy [3]. We also emphasizes, once again, a careful balance between the chances of spontaneous pregnancy and the risk of recurrences should be systematically considered. For the ovarian cyst, as suggested in the previous reports from Garcia-Velasco [20] and Marconi [21] that laparoscopic cystectomy of ovarian cyst did not affect ovarian response to gonadotropin stimulation, although the gonadotropin dose was higher in the cystectomy group. However, Exacoustos et al. [22] stated that removal of ovarian cysts has been associated with a poorer performance of IVF procedures, and a decrease in ovarian volume after surgery [23]. Compared with ovarian excision, the stripping technique is the preferred method for the surgical treatment of ovarian cysts. Although this technique has the lowest recurrence rates, it raises concerns about the loss of functional ovarian tissue also [24], which might further decrease ovarian reserve function (ORF) and pregnancy outcome [25]. Owing to this situation, surgeons must be aware of this fact when consulting patients about their future fertility. The possibility of reducing the ovarian reserve by the stripping procedure should be the main point of discussion before the procedure, and informed consent must be obtained. In contrast to some prior studies, in our view, unilateral adnexectomy will lose more follicles than ovarian cystectomy as a consequence, whereas the IVF outcome is the same regardless and the number of oocyte retrieved is significantly lower. The study has some strengths and some limitations that have to be considered. First of all, the study is retrospective and it is based on chart review. However, the dimension and the number of follicles are systematically recorded on the day of hcg administration, and all 78

ultrasound scans are performed by expert physicians who are unlikely to miss large follicles, similarly for day 3 antral follicle count. On the other hand, it is wise to note that although more than 2000 IVF-ICSI cycles per year are performed in our department. In this regard, it has to be recognized that the limited sample size represents a further limitation of the study. Inferences to the entire population of women with gynaecologic surgeries is limited. However, there is large individual variation in its onset. Our results, a need to be confirmed in larger studies. Thirdly, indeed, responsiveness to ovarian stimulation is considered the best surrogate way to estimate ovarian reserve [26]. Alternative tests such as day 3 serum FSH, LH, E2 could not be used in the present study because they did not consent to differentiate the separate contribution of the two gonads. Antral follicle count may be an option method because it allows the study of the gonads separately. Unfortunately, this variable was not systematically recorded in our study and we are thus unable to add this information. Finally, we excluded patients who has endometriosis, it is still possible that persistant mirror lesions were present, possibly impacting on ovarian reserve. Conclusion The present study supports the view that gynaecologic surgery influenced ovarian function and IVF outcome. As for effect on ovarian function, the tubal conservative surgery and unilateral salpingectomy are similar, while ovarian cystectomy and unilateral adnexectomy are not the same. However, for the IVF consequence, between two different tubal surgeries and two distinct ovarian surgeries are identical. Larger number of patients need to be studied to confirm our findings. In particular, the role of the surgical technique needs to be interpretated. The decipherment of this point may initiate new therapeutic controversy and may probably lead to more critical evaluation and selection of the surgical technique. References 1. Hajenius PJ, Mol F, Mol BW, et al. Interventions for tubal ectopic pregnancy. Cochrane Database Syst Rev, 2007(1):CD000324. 2. van Mello NM, Mol F, Opmeer BC, et al. Salpingotomy or salpingectomy in tubal ectopic pregnancy: what do women prefer? Reprod Biomed Online, 2010, 21(5):687-93. 3. Almog B, Wagman I, Bibi G, et al. Effects of salpingectomy on ovarian response in controlled ovarian hyperstimulation for in vitro fertilization: a reappraisal. Fertil Steril, 2011, 95(8):2474-6. 4. Vercellini P, Fedele L, Aimi G, et al. Reproductive performance, pain recurrence and disease relapse after conservative surgical treatment for endometriosis: the predictive value of the current classification system. Hum Reprod, 2006, 21(10):2679-85. 5. Mol F, van Mello NM, Strandell A, et al. Salpingotomy versus salpingectomy in women with tubal pregnancy 79

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