In this large retrospective study, the impacts of interventional embolization of hydrosalpinx on the pregnancy outcomes were investigated in women undergoing FET with high-quality embryo transfer. Our results indicated that, based on a freeze-all policy, interventional embolization of hydrosalpinx could achieve the same live birth rate as hydrosalpinx-free obstruction with less risk, less pain and less cost. However, significant reduction was found in the implantation rate (35.81% [obstruction group] vs 32.24% [embolization group]; P = 0.004). Although the endometrial receptivity of hydrosalpinx patients was different from that of hydrosalpinx-free obstruction patients, the implantation rate was lower and the live birth rate was not affected in the embolization group. This suggests that embolization of hydrosalpinx is a preferred clinical treatment for hydrosalpinx.
Current treatments for hydrosalpinx mainly include ultrasound-guided hydrosalpinx aspiration, fimbria salpingostomy, proximal tubal ligation, and tubectomy before IVF-ET. Simple hydrosalpinx aspiration usually fails to improve the clinical pregnancy rate, implantation rate and parturition rate of IVF-ET, but may cause hydrosalpinx relapse [16, 17]. Salpingostomy often causes a high rate of hydrosalpinx recurrence in a short period and high incidences of abortion and ectopic gestation [13]. Tubectomy and proximal tubal ligation can significantly improve the clinical pregnancy rate and reduce the ectopic pregnancy rate. However, they are easy to cause damage to the mesovarium artery arches, which affects the ovarian blood supply and reduces the ovarian reserve function and superovulation response [8]. In the interventional embolization, microcoil is placed between the interstitial section and the isthmus of fallopian tube. The mechanism of action may be as follows: (1) mechanically complete partition of tubular lumina and (2) alkaline phosphatase released from the mildly mechanical necrotic tissues can benefit lymphocytic aggregation and proliferation of vascular tissues, which increases the embolization of tubular lumina [14]. A mechanical method in the interventional embolization of fallopian tube has no effect on the ovarian function.
Hydrosalpinx has an adverse effect on the outcomes after IVF-ET [18, 19]. To date, there is no consensus regarding the best surgical management for hydrosalpinx before IVF-ET. In the present study, the live-birth outcomes after FET were compared between hydrosalpinx patients treated with interventional embolization and hydrosalpinx-free obstruction patients. Compared with interventional embolization group, significantly higher implantation rate and clinical pregnancy rate were observed in the hydrosalpinx-free obstruction group. The flow of hydrosalpinx liquid may affect embryo implantation by mechanically flushing the uterine cavity. In addition, there are micro-organisms, toxic debris, lymphocytes, cytokines, prostaglandins, and other agents in the hydrosalpinx fluid. These may also transfer directly to the uterine cavity, exerting deleterious effects on the embryos or endometrium [20,21,22]. Based on our results, the significantly higher implantation rate and clinical pregnancy rate may be related to more embryos transferred at blastocysts stage (day 5) in the control group (17.71% vs 9.22%, P < 0.05). The endometrial receptivity of patients with interventional embolization was not different from that of patients with hydrosalpinx-free tubal infertility.
Moreover, there were no significant differences in the rates of ongoing pregnancy and live birth in patients with interventional embolization for hydrosalpinx. Both groups had similar live birth rate. After adjustment for confounding factors, compared to the embryos transferred in the blastocysts stage (day 5), the live birth rate significantly decreased after transfer with cleavage stage (day 3). Women with thicker endometrium on the day of transfer and more embryos transferred had a significantly higher live birth rate. For the baseline characteristics, significant difference was noted in cause of infertility. After adjustment for confounding factors, compared with the tubal factor, there were no impact on the live birth and clinical outcomes in case of high-quality embryo transferring. For patients with polycystic ovary syndrome (PCOS) or premature ovarian failure, the protocol and dose of drugs in egg retrieval cycle may be completely different. However, in the FET cycle, we usually use the letrozole ovulation protocol to prepare the endometrium in patients with PCOS. In a study of Di Paola et al. they calculated the follicle-stimulating hormone (FSH) starting dose according to the nomogram [23]. Their results indicated nomogram in intrauterine insemination (IUI) cycles could lead to a more tailored FSH starting dose and improve cost-effectiveness, especially in the expected hyper-response patients, which may reduce hyper-response and cancellation rate, and increase optimal follicle retrieval. The menstrual cycle is short and the basic FSH is high for patients with premature ovarian failure, and therefore hormone replacement treatment is preferred. Seckin et al. concluded that low-dose gonadotropin treatment was advised for women with PCOS, and there was no significant difference in pregnancy rates of non-obese patients with PCOS having IUI whether rFSH was started at 37.5 or 75 international units (IU) [24]. In addition, there is evidence showing that obese women require significantly larger amounts of gonadotropins to achieve similar IVF success rates as normal weighting women [25]. The pregnancy outcomes are not affected in case of high-quality embryos transferred [12]. It has been reported that interventional embolization can prevent tubal fluid flowing toward the cavity and improve the pregnancy outcomes of IVF [26]. Interventional embolization of hydrosalpinx can achieve the same live birth rate as hydrosalpinx-free obstruction with less risk, less pain and less cost.
In the salpingectomy, chronically infected tissues are removed, which limits the risk of subsequent abscess formation or torsion, as well as improves the access to the ovaries during the egg retrieval in the IVF [27]. However, laparoscopy is an invasive procedure, which may be infeasible in the presence of dense adhesions. In addition, laparoscopy has the risk of damaging major organs or vessels, especially in patients with previous abdominal/pelvic surgery, severe endometriosis or inflammatory bowel disease. In the study, the interventional embolization combined with ultrasound-guided hydrosalpinx puncture has been a routine treatment of hydrosalpinx in our center. If hydrosalpinx is identified on ultrasonography before transplantation, hydrosalpinx will be routinely punctured under ultrasound examination 2 days before transplantation. If the hydrosalpinx recurs on the day of transplantation, it is punctured again. If the hydrosalpinx is mild, hydrosalpinx is punctured on the day of transplantation, but uterus puncturing should be avoided, in order to not induce uterine contraction, or it will affect transplantation. Currently, the success rate of FET with the guidance of transvaginal or transabdominal ultrasound is controversial [28, 29]. In a recent study, Cozzolino et al. found a moderate quality of evidence supporting the beneficial effects of transabdominal guidance during embryo transfer compared with conventional clinical touch in clinical pregnancy and ongoing or live birth rates; quality of evidence supporting the equivalence of transvaginal vs transabdominal approach in clinical pregnancy and ongoing or live birth rates to be low [28]. Larue et al. found transvaginal ultrasound guidance of the transfer significantly increased the percentage of pregnancies per transfer compared with transfers performed under transabdominal ultrasound guidance; transvaginal ultrasound facilitated the performance of difficult transfers and in particular achieved outcomes in the situations that are not significantly different from those of easy transfers [29]. In the present study, FET was conducted under the guidance of transabdominal ultrasound. This procedure is minimally invasive, and easy and quick to perform. In addition, the retrograde flow of the hydrosalpingeal fluid, a factor related to the perturbed uterine environment, is eliminated by this procedure, and the integrity of ovarian blood supply is maintained. However, the interventional embolization is associated with ongoing pelvic pain secondary to the pressure and the diseased tube, and has risks of adnexal torsion and subsequent need for adnexal surgery [30]. Moreover, it has reported the clip migration and chronic pelvic pain post procedure [27]. In this study, there were no pelvic inflammation attack, accessory torsion and accessory abscess during pregnancy after interventional embolization. Therefore, the long-term safety during pregnancy after interventional embolization should be further investigated in studies with large sample size. The embolization may cause aseptic inflammation around the microcoil to block the accumulation of hydrosalpinx. In the present study, the ectopic pregnancy rate in the interventional embolization group was similar to that in the hydrosalpinx-free group, indicating that interventional embolization of hydrosalpinx before IVF-ET can reduce the ectopic pregnancy rate. Salpingectomy may also increase the risk of interstitial pregnancy (IP) (pregnancy within the fallopian tube that is located in the uterine wall and connects with the remainder of the tube to the endometrial cavity) in patients when the transection of the fallopian tube is close to the cornua. In a study of Wang et al. among 43 patients with IP, 71% underwent bilateral salpingectomy before IVF [31]. A corneal suture placed on laparoscopic salpingectomy has been shown to reduce the risk of IP, increasing the intrauterine pregnancy rate, ongoing pregnancy rate and live birth rate as compared to those without placement of a corneal suture [32]. In this study, ectopic pregnancy was noted in 14 patients and cornual pregnancy in 2 patients with tubal embolization. The ectopic pregnancy was found at the affected side in 1 patient. Three patients with ligation of oviduct developed ectopic pregnancy at the fallopian tube. There was no IP in the patients receiving interventional embolization for hydrosalpinx. The causes of ectopic pregnancy in hydrosalpinx patients are still unclear and may include the placement of microcoil, drop of microcoil, and hysteroscopy. Interventional embolization is considered as an alternative management, especially in patients with distorted pelvic anatomy or severe pelvic adhesions. At present, torsion during pregnancy and pelvic inflammation were not found in the patients of present study. One patient had ectopic microcoil. Polyethylene terephthalate fibers, which run through the inner coil of the Essure® device, may cause tissue reaction, resulting in tubal occlusion when the coil has been inserted. A systematic review of 11 studies (115 women who received Essure®) has shown successful placement in 96.5% of patients and the tubal occlusion was observed in 98.1% of patients [9]. With subsequent IVF, a reasonable pregnancy rate of 38.6% and live birth rate of 27.9% were achieved, and investigators concluded that Essure® is effective for the management of hydrosalpinx in women before IVF, when operative treatment is limited by pelvic adhesions. Compared with Essure®, microcoil is used for interventional embolization in HX, with a failure rate of < 5%. The microcoil used in the present study was made of titanium alloy. It can induce the oviducal inflammation, resulting in the oviducal obstruction, which avoids the flow of fluid in the hydrosalpinx into the uterus and therefore increases the success rate. However, a two-center randomized controlled trial (RCT) (involving 85 women) shows that, before IVF/ICSI, hysteroscopic tubal occlusion is inferior to laparoscopic salpingectomy; the ongoing pregnancy rate per patient following proximal interventional embolization with intratubal devices is 26.2% as compared to 55.8% following laparoscopic salpingectomy [33]. Furthermore, a systematic review involving more than 3000 patients shows that management of hydrosalpinx by hysteroscopic placement of Essure® devices before IVF produces lowers clinical pregnancy rate and live birth rate than those by laparoscopic salpingectomy and laparoscopic proximal tubal occlusion [26]. These results are inconsistent with our findings. Therefore, we recommend interventional embolization of hydrosalpinx as a treatment for hydrosalpinx. The adverse effects of hydrosalpinx on the uterine milieu during the implantation window have been well described. Current guidance supports the use of interventional embolization for tubal occlusion in women with hydrosalpinx before IVF or ICSI, as there is higher rate of successful treatment and the pregnancy rate is improved. Individualized care, based on woman's risk profile and preferences, is required to help make clinical decision, considering the full range of treatment options.
Our study shows that interventional embolization followed by IVF-ET can effectively improve the adverse effects of hydrosalpinx on the embryos and significantly increase the clinical pregnancy rate of IVF-ET while reducing the ectopic pregnancy rate. This is consistent with clinical findings after IVF-ET with ultrasound-guided aspiration of hydrosalpinx during the controlled ovarian hyperstimulation. The effects of interventional embolization on the IVF-ET before and after controlled ovarian hyperstimulation remain to be further studied. In our center, the interventional embolization is generally performed after controlled ovarian hyperstimulation.
There were several limitations in the present study. It was a retrospective study, the database was screened with strict inclusion criteria, and only patients receiving first embryo transfer cycle in our center were included for analysis. Additionally, the vast majority of patients in the present study received transfer of two cleavage-stage embryos, rather than single blastocyst transfer. Chinese legislation limited the proportion of blastocyst transfer cycles within 7%, aiming to control the male birth. Thus, the transfer of two cleavage-stage embryos remains a priority in Chinese IVF centers [34, 35]. In addition, the number of patients with the drop of microcoil, which needs to be removed by hysteroscopy, was not determined in the present study.
The present study had several strengths. To the best of our knowledge, this is a study with the largest sample size that evaluates the impact of hydrosalpinx on the reproductive outcomes. A number of potential confounders that may bias the results are controlled in the present study. Furthermore, all the data are from a single center, and thus the practice consistency can be assured. Except for the type of culture medium, all other IVF procedures and laboratory conditions remain unchanged during the study period.
