Anna C. Nackley, M.D. and Suheil J. Muasher, M.D.

FERTILITY AND STERILITY VOL. 69, NO. 3, MARCH 1998 Copyright 1998 American Society for Reproductive Medicine Published by Elsevier Science Inc. Printed on acid-free paper in U.S.A. MODERN TRENDS The significance of hydrosalpinx in in vitro fertilization Anna C. Nackley, M.D. and Suheil J. Muasher, M.D. The Jones Institute for Reproductive Medicine, Department of Obstetrics and Gynecology, Eastern Virginia Medical School, Norfolk, Virginia Objective: To review the effects of hydrosalpinx on IVF/ET and the role of salpingectomy. Design: The literature on hydrosalpinx, IVF/ET, embryotoxicity, and salpingectomy for hydrosalpinx was identified through MEDLINE searches and reviewed. Result(s): Hydrosalpinx has been associated with poor fertility prognosis. IVF/ET is a better alternative to tubal surgery for those patients with severe distal tubal disease, and it is also more cost effective. However, the presence of hydrosalpinx has a negative effect on IVF/ET by decreasing the pregnancy rates and implantation rates compared with patients undergoing IVF/ET for tubal disease but without hydrosalpinx. The hydrosalpingeal fluid has been demonstrated to be embryotoxic to developing embryos, thus leading to increased early pregnancy losses. Poor endometrial receptivity has also been demonstrated in the presence of hydrosalpinges. Removal of the hydrosalpinges leads to improved IVF/ET rates comparable to those patients without hydrosalpinx. Therefore, salpingectomy has been recommended for patients with hydrosalpinx who will be undergoing IVF/ET. Conclusion(s): The presence of hydrosalpinx has a negative effect on IVF/ET because of the suspected embryotoxicity of the hydrosalpingeal fluid. Surgical removal of the hydrosalpinx has been shown to improve IVF/ET rates. (Fertil Steril 1998;69:373 84. 1998 by American Society for Reproductive Medicine.) Key Words: Hydrosalpinx, IVF/ET, salpingectomy, embryotoxicity, infertility Received July 28, 1997; revised and accepted September 17, 1997. Reprint requests: Suheil J. Muasher, M.D., The Jones Institute for Reproductive Medicine, 601 Colley Avenue, Norfolk, Virginia 23507-1627 (FAX: 757-446-8998). 0015-0282/98/$19.00 PII S0015-0282(98)00484-6 Tubal disease is one of the major causes of female infertility (1). In vitro fertilization/embryo transfer was first introduced as a method to overcome tubal infertility (2). In most centers, tubal factor still remains the main indication for IVF/ET. Tubal disease includes an array of disorders including blockage, both proximally and distally, peritubal adhesions, and hydrosalpinx. Pelvic inflammatory disease, previous ectopic pregnancy (EP), endometriosis, previous sterilization, previous surgery, and a history of peritonitis can cause such conditions leading to tubal infertility. Severe tubal disease, specifically distal tubal obstruction leading to hydrosalpinx, is associated with a poor fertility prognosis (3, 4). The purpose of this article is to review the literature involving hydrosalpinx and IVF/ET and the role of salpingectomy. DIAGNOSIS OF HYDROSALPINX The presence of hydrosalpinx can be diagnosed by hysterosalpingogram (Fig. 1) or by laparoscopy with or without chromopertubation. A meta-analysis of all the studies comparing hysterosalpingography to the gold standard of laparoscopy with chromopertubation showed the hysterosalpingogram to have a sensitivity of 65% in the diagnosis of tubal obstruction and a specificity of 83% (5, 6). Transvaginal ultrasonography (US) has also been used to evaluate pelvic structures. Normal fallopian tubes can only be recognized in the presence of pelvic fluid. In some patients, hydrosalpinx can be diagnosed by transvaginal ultrasonography (Fig. 2). It is recognized by its location separate from the ovary, its tubular appearance, and occasional longitudinal folds in the ampullary portion of the fallopian tube (7). Transvaginal US is very specific in the diagnosis of hydrosalpinx, but its sensitivity is poor. A study by Atri et al. (8) evaluated the accuracy of endovaginal sonography in the detection of fallopian tube blockage and found the specificity of transvaginal US to be 100% with a sensitivity of only 34%. Atri et al. also 373

FIGURE 1 Hydrosalpinges diagnosed by hysterosalpingogram. demonstrated an increase in sensitivity (91%) of transvaginal US in the diagnosis of hydrosalpinx by scanning the tubes immediately after hysterosalpingography, thus providing tubal distention making the hydrosalpinx more evident. Methods using the passage of air or fluid to visualize FIGURE 2 Hydrosalpinx diagnosed by transvaginal ultrasonography. Note the adjacent ovarian cyst. the tubes sonographically have also been described. The same principle makes sonohysterosalpingography a useful tool in the diagnosis of hydrosalpinx (9 11). Color Doppler ultrasonography has also been used in evaluating tubal patency and diagnosing hydrosalpinx (12, 13). Other diagnostic methods include salpingoscopy or falloposcopy (14 16). RESULTS OF SURGICAL TREATMENT ALONE FOR HYDROSALPINX Surgical repair of the damaged tubes can offer some hope; however, patients with severe pathology, particularly hydrosalpinx, have very disappointing results. Boer-Meisel et al. (17) determined the importance of five factors in an effort to differentiate patients in whom tubal surgery had little chance of success and in whom it was expected to be successful. The prognostic factors included 1) the extent of adhesions, 2) the nature of the adhesions, 3) the diameter of the hydrosalpinx, 4) the macroscopic condition of the endosalpinx, and 5) tubal wall thickness. Patients with good, intermediate, or poor prognosis were classified into three groups on the basis of calculated scores. The condition of the endosalpinx and extent of adhesions were found to be the two most important prognostic factors. The probability of a successful intrauterine pregnancy in the group with poor prognostic factors was only 3% after tubal surgery versus 77% and 21% in the good and intermediate groups, respectively. It is selection rather than surgical technique that determines the success of reconstructive tubal 374 Nackley and Muasher The significance of hydrosalpinx in in vitro fertilization Vol. 69, No. 3, March 1998

surgery. This finding suggests that IVF/ET is a better alternative to tubal surgery for patients with severe tubal disease. The same group at a later date added three factors derived from hysterosalpingogram findings and used them in conjunction with the established laparoscopic findings to enhance decision making when deciding between surgery versus IVF. The prognostic factors detected by hysterosalpingography involved the nature of tubal mucosal patterns, the diameter of the hydrosalpinx, and the expandability of the ampullary region (18). Donnez and Casanas-Roux (19) observed 275 women with distal tubal occlusion who had undergone either microscopic fimbrioplasty or salpingostomy. These women were classified as degree I to IV based on extent of occlusion, morphology, ampullary dilatation, fimbrial cell percentage, and tubal wall thickness in an attempt to determine prognostic factors for fimbrial microsurgery. Fimbrial reconstruction was performed on those with degree I disease, whereas terminal salpingostomy was performed on those with degree II IV disease. Those with mild disease (degree I) had a term pregnancy rate of 60% with an ectopic pregnancy rate of only 2%. Those with severe disease (degree IV) or hydrosalpinx, defined as distal occlusion with ampullary distention more than 25 mm, had a significantly decreased term pregnancy rate of 22% with an ectopic pregnancy rate of 12%. A decreased fimbrial ciliated cell percentage was noted in those with hydrosalpinx (degree IV) further proving its role in ovum transport. Mage et al. (20) proposed a method based on hysterosalpingogram and initial laparoscopic findings to determine the success after terminal salpingostomy on patients with different grades of tubal damage. Classification was based on patency, ampullary tubal mucosa, wall thickness, and peritubal adhesions. Adhesions were also classified as none, mild, moderate, or severe. An intrauterine pregnancy rate of 58% and an ectopic pregnancy rate of 8% were found in patients with tubal grade I disease. A 38.8% pregnancy rate and a 16.6% ectopic rate were noted in patients with mild adhesions. Patients with tubal grade III disease and moderate to severe adhesions had a higher ectopic rate of 14.2% and an intrauterine pregnancy rate of 9.5%. Those with severe adhesions had a 5.5% intrauterine pregnancy rate and a 16.6% ectopic pregnancy rate. Those with tubal grade IV disease had no successful pregnancies. Mage et al. (20) concluded that IVF should be considered a better alternative to microsurgery in distal occlusion for patients with poor prognostic factors on the basis of tubal damage and adhesive disease. Schlaff et al. (21) reviewed pregnancy outcomes in 95 women with distal tubal obstruction who underwent microsurgical terminal neosalpingostomy. Pregnancy success was inversely related to the extent of tubal disease, which was based on dilation, rugal integrity, and fimbrial status. Pregnancy rates in those with severe disease were 12% intrauterine and 4% ectopic compared with 70% intrauterine and 10% ectopic in those with mild disease. In conclusion, they encouraged those with severe disease to pursue IVF/ET because of the poor results after neosalpingostomy. Weidemann and Hepp (22) compared microsurgery to IVF/ET in patients with tubal disease and concluded that patients with thick-walled hydrosalpinx or combined proximal and distal tubal disease would benefit more from IVF/ET. These five studies by Boer-Meisel, Donnez, Mage, Schlaff, and Weidemann and their colleagues, all suggest IVF as a better alternative to tubal surgery for severe distal tubal disease. Table 1 shows the results of surgery for varying degrees of tubal disease. Gocial (23) compared the cost of surgery versus IVF in patients with severe tubal disease. The overall success rate for natural conception after tubal reconstruction at his center was less than 30%. He noted that although the cost of IVF per cycle is more than 75% the cost of tubal surgery, the eventual success rate of IVF is much better than that of tubal surgery. The cost per baby delivered was about 10% lower for those who proceed with IVF rather than tubal surgery. Another study evaluating the cost effectiveness of surgery versus IVF/ET in patients with severe tubal disease was published by Van Voorhis et al. (24). IVF/ET resulted in a 22.2% delivery rate at an average cost of $43,138 per delivery. Tubal surgery, which involved a neosalpingostomy by laparotomy, yielded a 12.5% delivery rate at a cost of $76,232 per delivery. HYDROSALPINX AND IVF/ET IVF/ET was developed to overcome mechanical obstruction attributable to tubal disease. However, severe tubal disease (specifically hydrosalpinx) has been found to also affect the success of IVF/ET. Englert et al. (25) discovered that patients with tubal infertility have lower IVF/ET success rates than those with male infertility or idiopathic cases. Van Rysselberge et al. (26) noted high IVF cancellation rates in those patients diagnosed with tubal infertility and found the main reason to be low estrogen response. Sims et al. (27) were the first to study the effect of hydrosalpinx on IVF outcome. A retrospective case-controlled study was conducted involving 118 patients with hydrosalpinx undergoing 283 stimulations and 823 patients with tubal factor infertility but without hydrosalpinx undergoing 1,431 stimulations. A lower clinical pregnancy rate of 18%, and a higher miscarriage rate of 42% resulting in a lower ongoing pregnancy rate of 10% was discovered compared to the control group whose rates were 26%, 23%, and 19%, respectively. They FERTILITY & STERILITY 375

TABLE 1 Results of surgery for tubal disease. Author (reference) Tubal disease status No. of intrauterine pregnancies/ no. of patients (%) No. of ectopic pregnancies/ no. of patients (%) Boer-Meisel et al. (17) Good prognosis 21/27 (77) 1/27 (4) Poor prognosis 1/37 (3) 6/37 (16) Donnez and Casanas-Roux (19) Degree I 79/132 (60) 2/132 (2) Degree IV 9/40 (22) 5/40 (12) Mage et al. (20) Grade I tubal disease 7/12 (58) 1/12 (8) Grade IV tubal disease 0/13 (0) 0/13 (0) Severe disease 7/56 (12.5) 2/56 (4) Note. Good prognosis was defined as few or no loose adhesions, 1 cm in diameter of hydrosalpinx, normal macroscopic condition of endosalpinx, thin tubal wall. Poor prognosis was defined as many fixed dense adhesions, 3 cm in diameter of hydrosalpinx, poor macroscopic condition of endosalpinx, thick and edematous tubal wall. Degree I was defined as patent fallopian tube with evidence of conglutination of the fimbrial folds. Degree IV was defined as occlusion with ampullary distention of 25 mm per hydrosalpinx. Grade I was defined as partial tubal occlusion with normal ampullar tubal mucosa by hysterosalpingography (HSG) and by laparoscopy. Grade IV was defined as total occlusion with abnormal ampullar tubal mucosa by HSG and laparoscopy. Mild disease was defined as absent or small hydrosalpinx, inverted fimbria, no significant adhesions and presence of rugae. Severe disease was defined as large hydrosalpinx of 30 mm in diameter, no fimbria, dense adhesions, and frozen pelvis. suggested treatment of the hydrosalpinx before IVF such as laparoscopic removal or peritransfer antibiotic coverage. Strandell et al. (28) conducted a retrospective study involving 254 women with definite tubal disease determined by hysterosalpingogram or laparoscopy/laparotomy, or a combination of tests, to determine whether the presence of hydrosalpinx influenced pregnancy outcome after IVF/ET. Forty-five patients had hydrosalpinx and underwent 91 ET. Their results were compared to 173 patients with minimal disease who underwent 1,285 ET. The pregnancy rate for those patients with unilateral or bilateral hydrosalpinx was 13% using fresh embryos with a delivery rate of 7% compared to the 26% pregnancy rate and 18% delivery rate in those patients with minimal adhesive disease and no evidence of hydrosalpinx. Strandell et al. (28) concluded that persistent hydrosalpinx was associated with a reduced implantation rate and increased risk for early pregnancy loss. It was hypothesized that the removal of the hydrosalpinx by salpingectomy or salpingostomy would normalize the IVF/ET rates in this group. Andersen et al. (29) reported a marked reduction in implantation rates when hydrosalpinx was visible on US. The IVF/ET results of 741 patients were reviewed. Sixty-two patients had hydrosalpinx, 493 had tubal disease but no hydrosalpinx, and 178 had unexplained infertility. They found the rates of implantation, pregnancy, early pregnancy loss, and delivery per aspiration were significantly reduced despite a comparable number of aspirated oocytes and embryos transferred. In those patients with tubal disease but without hydrosalpinx the pregnancy rate per transfer was 36% compared with 22% in the hydrosalpinx group and 33% in the unexplained fertility group. The implantation rates were 2.9%, 10%, and 10% in the hydrosalpinx group, the nonhydrosalpinx group, and the unexplained fertility group, respectively. Early pregnancy loss was calculated to be 70% for the hydrosalpinx group compared with 36% in those without hydrosalpinx and 36% in those with unexplained infertility. Vandromme et al. (30) confirmed Strandell s findings of IVF failure in patients with the diagnosis of hydrosalpinx despite adequate ovarian response, retrieval of the normal number of oocytes compared to the overall IVF population, and normal fertilization rates. Comparisons were made in a retrospective study analyzing 37 patients with unilateral or bilateral hydrosalpinx and 41 patients with tubal damage attributable to previous sterilization or previous salpingectomy who served as controls. The pregnancy rate per transfer was 10% and the implantation rate was 4% in those patients with hydrosalpinx compared with a 23% pregnancy rate and an 11% implantation rate in the control group. A Danish study by Vejtorp et al. (31) also demonstrated a decreased pregnancy rate after IVF in women with hydrosalpinx. Transvaginal US was used before follicle stimulation to detect the presence or absence of hydrosalpinx. The pregnancy rate was 6% in the patients with hydrosalpinx who underwent 104 cycles. The pregnancy rate was 21% in women with tubal disease but without evidence of hydrosalpinx. Also noted in this study was a decreased pregnancy rate as the patient s age increased. This study emphasized that IVF should not be delayed in patients with evidence of hydrosalpinx so as to not further decrease the success of IVF in patients with hydrosalpinx. Fleming and Hull (32) conducted a retrospective study to determine whether the presence of hydrosalpinx affected the success of IVF/ET in women with inflammatory tubal disease. Three groups of women, which included 79 women with hydrosalpinx, 198 women with known inflammatory disease but no hydrosalpinx, and 22 women who had under- 376 Nackley and Muasher The significance of hydrosalpinx in in vitro fertilization Vol. 69, No. 3, March 1998

gone bilateral tubal ligation, were studied. There was no difference in the number of oocytes collected or fertilization rates between the three groups. The pregnancy rates per transfer were 23% in the hydrosalpinx group, 30% in the group with tubal disease but without hydrosalpinx, and 27% in the group of previously sterilized women. The implantation rates were 9% in the hydrosalpinx group, 16% in the group with tubal disease but without hydrosalpinx, and 16% in the previously sterilized group. This significant decrease in implantation rate and pregnancy rate per transfer in the hydrosalpinx group suggests an unfavorable uterine environment. It was suggested that this unfavorable environment could possibly be attributable to hydrosalpingeal fluid drainage into the endometrial cavity. Fleming and Hull (32) concluded that distal salpingostomy to drain the hydrosalpingeal fluid or even salpingectomy could improve IVF outcome. A recent study by Katz et al. (33) looked at the effects of hydrosalpinx on the outcome of IVF. This retrospective analysis involved 846 patients with tubal disease divided into two groups differentiated by the presence of hydrosalpinx diagnosed by US. The pregnancy rate per transfer in the hydrosalpinx group was 17% compared with 37% in the group without hydrosalpinx. A reduced implantation rate of 4% was found in the hydrosalpinx group versus an implantation rate of 12% in the nonhydrosalpinx group. Delivery rate per transfer was 9% versus 25%. This study involving 1,766 cycles is the largest to demonstrate a reduction in pregnancy rate and implantation rate attributable to the presence of hydrosalpinx. Freeman et al. (34) conducted a study designed to analyze the effect of hydrosalpinx on implantation rates and in vitro development of untransferred embryos. A comparison was made between patients with at least one hydrosalpinx to patients with tubal disease but no hydrosalpinx, endometriosis, male factor, or unexplained infertility. A significantly lower implantation rate per embryo transferred was found (15% compared with 26%, 34%, 29%, and 28%, respectively). The sibling embryos that remained in culture before cryopreservation were found to have fewer blastocysts developing when comparing the group with hydrosalpinx to the group with tubal disease but without hydrosalpinx. Freeman et al. (34) concluded that not only does hydrosalpinx negatively effect endometrial receptivity during implantation but it also exerts a negative influence over oocytes early in follicular recruitment. The presence of hydrosalpinx has also been shown to affect the implantation rates in unstimulated cycles. Akman et al. (35) demonstrated this by reviewing the outcome of IVF/ET using cryopreserved embryos in an unstimulated or natural cycle. Fourteen natural cycles in 10 patients with hydrosalpinx diagnosed by US and confirmed by previous hysterosalpingogram or laparoscopy were compared with 74 patients with tubal disease but no evidence of hydrosalpinx who underwent 98 natural cycles. Pregnancy rate for the group with hydrosalpinx was 7% with an implantation rate of 5%. The control group had a 24% pregnancy rate and an implantation rate of 11%. Strandell et al. (28) looked at pregnancy rates after frozen ET in the presence of hydrosalpinx. The pregnancy rate was 7% in the hydrosalpinx group and 18% in the group with tubal disease without hydrosalpinx. Hydrosalpinx also predisposes women to increased EPs after IVF/ET (35 37). The first human pregnancy after IVF was indeed a tubal pregnancy (38). Zouvres et al. (39) studied 891 IVF/ET cycles performed on patients with inoperable tubal disease or those who failed to conceive after reconstructive tubal surgery and found that 12% of pregnancies after IVF/ET were ectopic in the tubal factor group compared to 3% in the nontubal factor group. Zouvres et al. suggested consideration of prophylactic proximal tubal occlusion to prevent tubal pregnancy after IVF. This recommendation had also been suggested by Steptoe, Tucker and Herman and their colleagues (40 42). Not all studies have demonstrated a negative effect of hydrosalpinx on IVF/ET outcome. In a prospective study, Sharara et al. (43) observed 63 patients with hydrosalpinx and 60 patients without hydrosalpinx who underwent 192 IVF cycles. Those with hydrosalpinx had an implantation rate of 10%, a pregnancy rate of 27%, and an early pregnancy loss rate of 11%, whereas those without hydrosalpinx had an implantation rate of 13%, a pregnancy rate of 34%, and a pregnancy loss rate of 9%. Although a trend for lower implantation rates and pregnancy rates was noted, the differences were not statistically significant. No difference in early pregnancy loss was noted either. Sharara et al. (43) pointed out that their study had a 50% power to detect a difference in implantation and pregnancy rates and a 15% power to detect a difference in early pregnancy loss. Power analysis calculated the need for 370 patients to detect a difference. Sharara et al. also tried to identify those patients with positive titers of antibody to Chlamydia. In this study, treatment with antibiotics of those patients with hydrosalpinx and positive antibody titers before IVF/ET did not change their outcome. Table 2 demonstrates the effects of hydrosalpinx on pregnancy, miscarriage, implantation, and EP rates. EMBRYOTOXICITY AND HYDROSALPINX There are several factors that affect implantation rates after IVF/ET. An important factor that is not greatly understood is the intrauterine environment and the mechanism by which hydrosalpinx alters its receptive capabilities. It has been observed that the majority of pregnancy failures occur after ET. Most patients achieve oocyte FERTILITY & STERILITY 377

TABLE 2 Effects of hydrosalpinx on pregnancy, miscarriage, implantation, and ectopic rates. No. of pregnancies/no. of embryo transfer (%)* No. of miscarriages/total pregnancies (%) Implantation rate (%) Ectopic pregnancy rate (%) Author (reference) Hydrosalpinx Control Hydrosalpinx Control Hydrosalpinx Control Hydrosalpinx Control Sims et al. (27) 43/243 (18) 341/1,287 (26) 18/43 (42) 80/341 (23) 43/748 (6) 341/3,990 (9) 2/43 (5) 17/341 (5) Strandell et al. (28) 12/91 (13) 74/285 (26) 6/12 (50) 22/74 (30) Andersen et al. (29) 20/91 (22) 265/744 (36) 14/20 (70) 95/265 (36) 8/273 (3) 221/2,152 (10) 2/20 (10) 19/265 (7) Vandromme et al. (30)** 7/69 (10) 14/61 (23) 0/7 (0) 1/7 (14) 8/190 (4) 17/154 (11) 0 (0) 0 (0) Fleming and Hull (32) 18/77 (23) 57/190 (30) 3/18 (17) 4/57 (7) 19/218 (9) 84/537 (16) 2/18 (11) 4/57 (7) Katz et al. (33) 19/95 (17) 467/1,268 (37) 7/16 (44) 146/467 (44) 17/434 (4) 643/5,577 (12) 1/16 (6) 30/467 (6) Kassabji et al. (62) 43/234 (18) 70/223 (31) 20/43 (47) 14/70 (20) 59/769 (8) 83/710 (12) 2/43 (5) 0/70 (0) Sharara et al. (43) 28/103 (27) 30/89 (34) 11/103 (11) 8/89 (9) 43/437 (10) 50/396 (13) 2/103 (2) 0/89 (0) Note. Percentages have been rounded to the nearest whole number * Fresh embryo transfers. Implantation rate defined as number of gestational sacs divided by number of embryos transferred. P 0.05 for pregnancy and miscarriage rates. P 0.014 for pregnancy and miscarriage rates. P 0.01 for pregnancy rate, P 0.005 for miscarriage rate, and P 0.0005 for implantation rate. ** P 0.05 for pregnancy and miscarriage rates and P 0.01 for implantation rate. P 0.34 for pregnancy rate; P 0.43 for miscarriage rate; P 0.02 for implantation rate, P 0.89 for ectopic rate. P 0.001 for pregnancy, miscarriage and implantation rates. P 0.05 for pregnancy, miscarriage and implantation rates. P 0.39 for pregnancy rate; P 0.30 for implantation rate. recovery, fertilization, and embryo cleavage, whereas only a few embryos actually implant, which leads to a decreased pregnancy rate (44, 45). The possibility has been raised of a connection between the hydrosalpinx and the uterine cavity allowing a direct flow of hydrosalpingeal fluid into the uterus, thus exposing the endometrium and embryo to potentially toxic fluid. It is postulated that the fluid in damaged tubes contains microorganisms, debris, lymphocytes, and other toxic agents that flow into the uterus and exert a detrimental effect on the endometrium and developing embryo. There may also be substances, such as cytokines, prostaglandins and leukotrienes, interfering with normal endometrial function (28, 29). The exact mechanical, biochemical, and physiologic effects of hydrosalpinges are unknown, but a few insightful cases exist. Hill et al. (46) demonstrated in two case studies that hydrosalpinges may actually enlarge during ovarian stimulation. In a retrospective study, Schiller and Tsuchiyama (7) detected the presence of hydrosalpinx by US only after hormonal stimulation in a small subset of women undergoing ovulation induction. These women had no evidence of hydrosalpinx on their initial US. The development of unilateral or bilateral hydrosalpinx typically occurred 6 14 days after hormonal stimulation and these findings were confirmed by serial US. These patients had known tubal disease before ovulation induction and hydrosalpinx was confirmed by hysterosalpingogram or laparoscopy. Schiller and Tsuchiyama (7), as well as Hill et al. (46), believe that ovulation induction increases tubal secretions, making a hydrosalpinx more evident on US. Aboulghar et al. (47) observed that the presence of hydrosalpinges was associated with a decreased ovarian response to ovulation induction and made US monitoring of follicular growth and ovum pick up more difficult. Transvaginal aspiration of the hydrosalpinges was performed before IVF/ET and a better response to ovulation induction was noted. The cause of poor ovarian response was thought to be a mechanical effect of the hydrosalpinges on the ovarian blood supply. Russell et al. (48) reported a case in which transvaginal drainage of hydrosalpinges may be performed before IVF/ET that resulted in a successful intrauterine pregnancy. The hydrosalpinx had complicated previous IVF cycles. Mansour et al. (49) documented three cases showing evidence of accumulation of fluid in the endometrial cavity in patients with hydrosalpinx on both US and laparoscopy. Transvaginal aspiration of the fluid in the uterine cavity was attempted before ET, but unfortunately the fluid reaccumulated. It was suggested that closing the cornual ends, neosalpingostomy, or salpingectomy would prevent the hostile fluid from reaccumulating in the uterine cavity. An interesting study by Devoto et al. (50) investigated the histology of hydrosalpinges along with E 2 and P nuclear and cytosolic receptor concentrations. Histologic examination revealed loss of tubal folds resulting in flat epithelium in the damaged tubes. Significantly lower E 2 and P nuclear and 378 Nackley and Muasher The significance of hydrosalpinx in in vitro fertilization Vol. 69, No. 3, March 1998

cytosolic receptors were found in the hydrosalpinges. Steroids are thought to be the mediators that control tubal secretions. Alterations in these receptors could contribute to poor intrauterine environment for the transferred embryo. Schenk et al. (51) proposed that hydrosalpinx contents are directly toxic to embryos. The embryotoxic effects are evident both before and after implantation leading to decreased pregnancy rates and increased miscarriage rates. Nine samples of hydrosalpinx fluid were obtained by needle aspiration and tested for embryotoxicity. Eight of the nine samples did not meet the standards for acceptable culture media. Morphologic analysis of the embryos performed after 72 hours of culture in the hydrosalpingeal fluid resulted in only 20.3% of the embryos reaching the morula stage and only 15.6% achieving the blastocyst stage compared to 99.5% and 99%, respectively, in the group cultured in standard media. Fragmentation and degeneration of the developing embryos were seen in 67.9% of the hydrosalpinx group, whereas only 0.5% of the control group experienced fragmentation and degeneration. A study by Mukherjee et al. (52) examined the effect of hydrosalpingeal fluid on murine embryogenesis. Fluid from hydrosalpinges was collected laparoscopically and divided into three concentrations, 100%, 10%, and 1%. Single-cell mouse embryos were then cultured in the fluid and examined 96 hours later. All samples cultured in the 100% and 10% concentrations demonstrated significant embryotoxic effects by poor cavitation rates. Even the lowest dilution of 1% had evidence of embryotoxic effects. Chemical analysis also showed significantly higher ph values (8.45 8.65) along with decreased protein concentrations compared to serum. An abstract by Beyler et al. (53) demonstrated retardation of in vitro mouse embryo development when cultured with hydrosalpingeal fluid. After 96 hours in a 100% concentration of hydrosalpingeal fluid, 16% of the embryos remained in the 1- to 4-cell stage, whereas 20% progressed to the early blastocyst stage and 16% had progressed to the expanded blastocyst stage. Forty-eight percent, however, had undergone degeneration after 96 hours of culture. A second group of embryos were cultured in a 30% concentration of hydrosalpingeal fluid. Four percent remained in the 1- to 4-cell stage, whereas 10% went on to the early blastocyst stage and 43% progressed to the expanded blastocyst stage. A high percent (42%) underwent degeneration similar to those in the 100% concentration. Only a minimal percent of embryos cultured in the control medium degenerated (8%) and the majority of embryos progressed to the expanded blastocyst stage (72%). Chemical analysis was similar to that of serum with respect to sodium, potassium, chloride, and bicarbonate, but lower for calcium, phosphate, glucose, total protein, and osmolality. Table 3 summarizes the embryotoxic effects of hydrosalpingeal fluid. Hydrosalpinx can be the result of infection with Chlamydia trachomatis. Previous infection with C. trachomatis, as is evidenced by the detection of immunoglobulin G (IgG) antibodies, is more prevalent in patients with infertility attributable to tubal damage than in women with infertility from other causes (43, 54). Rowland et al. (54) found that past infection with C. trachomatis reduced the success rate of IVF by 50% (30% versus 65.6%). Licciardi et al. (55) found an association between previous exposure to C. trachomatis and spontaneous abortion after IVF/ET. In this study, 145 women undergoing IVF were tested for acute C. trachomatis infection by endocervical cultures and a previous infection by serum assay for IgG antibodies to C. trachomatis. None of the women had positive cervical cultures; however, 47.7% of the women with tubal disease had IgG antibodies to C. trachomatis, whereas only 17.9% of women with infertility attributable to other causes had IgG antibodies to C. trachomatis. In a group of 145 women undergoing IVF, the rate of spontaneous abortion after IVF/ET was 20%. Of those 145 women, 69% had IgG antibodies to C. trachomatis, compared with only 23.7% of women with successful pregnancies after IVF/ET. This study demonstrated an increased incidence of spontaneous abortion with IVF/ET attributable to previous C. trachomatis infection rather than active infection. Witkin et al. (56) studied women with previous C. trachomatis infection diagnosed by ELISA for Ig A antibodies and their IVF/ET outcomes. Increased levels of chlamydial heat shock proteins were noted. This heat shock protein is thought to be responsible for the induction of a local immune response that leads to an inflammatory reaction impairing implantation and facilitating immune rejection after ET. In their study of hydrosalpinx and IVF/ET, Sharara et al. (43) tested each patient for cervical infection with C. trachomatis and determined the serum levels of IgG antibodies to C. trachomatis. They attempted to evaluate the role of previous infection and hydrosalpinx in IVF outcome. Treatment with antibiotics before IVF/ET was recommended for patients with elevated titers of IgG antibodies to C. trachomatis. Of the 34 women who were seropositive for C. trachomatis and received treatment, 7 (21%) became pregnant after IVF/ET compared with 7 (12%) of the 58 seropositive women who did not receive treatment. No statistically significant difference was found, but the investigators noted that the study power was inadequate. Although the exact mechanism by which hydrosalpinx alters intrauterine receptivity remains unclear, a marker of uterine receptivity has been established. Integrins are adhesion molecules that participate in cell-cell interactions and are present on all human cells. Abnormal endometrial integrin expression has been demonstrated in women with defective uterine receptivity (57, 58). Lessey et al. (59) conducted an interesting study that FERTILITY & STERILITY 379

380 Nackley and Muasher The significance of hydrosalpinx in in vitro fertilization Vol. 69, No. 3, March 1998 TABLE 3 Embryotoxicity of hydrosalpingeal fluid. Author (reference) Concentration of fluid No. of hours in culture Initial embryo status No. of cavitated embryos/total no. of embryos (%) Mukherjee et al. (52) 100%* 96 1 cell 0/60 10%* 2/40 (5) 1% 24/38 (63) 0% control 24/38 (63) 1 4 cell embryos/total no. of embryos (%) Early blastocyst/total no. of embryos (%) Expanded blastocyst/total no. of embryos (%) Degenerated embryos/total no. of embryos (%) Beyler et al. (53) 100% 96 1 cell 25/157 (16) 31/157 (20) 25/157 (16) 76/157 (48) 30% 4/102 (4) 10/102 (10) 44/102 (43) 43/102 (42) 0% control 2/130 (2) 24/130 (18) 93/130 (72) 11/130 (8) Embryos in morula stage (%) Embryos in blastocyst stage (%) Embryos undergoing fragmentation/degeneration (%) Schenk et al. (51) 100% n 15 72 2 cell 20.3 15.6 67.9** 0% control n 30 99.4 99 0.5 Note. Mouse embryos were used in each study. * P 0.001 for the 100% and 10% concentrations compared to the control. P 0.05 for the 1% concentration compared to the control. P 0.001 for the 100% and 30% concentrations compared to the control. P 0.004 for the 100% concentration compared to the control. P 0.0001 for the 100% concentration compared to the control. ** P 0.0016 for the 100% concentration compared to the control.

examined endometrial integrin expression to evaluate the effects of hydrosalpinges on uterine receptivity. The expression of -integrin measured by immunohistochemical assays of endometrial biopsies was assessed. Women with hydrosalpinges expressed significantly lower levels than those without hydrosalpinges. It was also discovered that women who underwent surgical correction had a return to normal integrin levels in subsequent biopsies. REMOVAL OF HYDROSALPINX BEFORE IVF/ET Trimbos-Kemper et al. (60) conducted one of the earliest studies that addressed ablative surgery for severe tubal disease. Their study looked at spontaneous conception rates after paradoxical salpingo-oophorectomy was performed in infertile women with severe unilateral disease. Twentynine patients were diagnosed with unilateral tubal disease by laparoscopy. The majority had unilateral hydrosalpinx (19 of 29 patients). Five of them became pregnant spontaneously after laparoscopy, 15 declined further surgery, and 9 underwent paradoxical salpingo-oophorectomy 1 year after their diagnostic laparoscopy. A 78% pregnancy rate was found in the paradoxical salpingo-oophorectomy group versus 27% in the nonsurgical group. However, the distribution of hydrosalpinx between the two groups was not given. This case was fascinating in that the detrimental effects of hydrosalpinx and severely damaged tubes were eliminated by surgical treatment and found to improve pregnancy rates in spontaneous cycles. Garcia et al. (61) described a method of pelvic reconstruction for patients with long-standing infertility associated with severe pelvic adhesive disease. The group of patients involved in the study had such severe pelvic adhesive disease that US-guided follicular aspiration was not feasible. Lysis of adhesions, bilateral salpingectomy, and ovarian suspension were performed in 54 patients before IVF, resulting in an improved pregnancy rate (38.7%), which was comparable to the IVF population at large. The study by Vandromme et al. (30) sought to determine whether surgical treatment would benefit those patients with hydrosalpinx attempting IVF/ET. Three groups were compared in this retrospective study a group with bilateral hydrosalpinges, a group who had undergone surgical correction by salpingectomy or salpingoplasty, and a group which had undergone previous sterilization or salpingectomy for other indications serving as the control group. The ongoing pregnancy rate before surgery was 10.1%, whereas the postoperative group had an ongoing pregnancy rate of 31% and in the control group the rate was 21.3%. The results revealed that surgical correction by ablation of the diseased tubes restored the normal chances of success for patients with hydrosalpinges. Kassabji et al. (62) performed a retrospective study comparing 118 patients with hydrosalpinx to 157 patients with previous bilateral salpingectomies undergoing IVF/ET. A history of previous ectopic pregnancy was found in 30% of patients in the hydrosalpinx group and 40% in the bilateral salpingectomy group. The number of eggs aspirated and the number of embryos transferred were comparable in both groups. The pregnancy rate was 18% in the hydrosalpinx group and 31% in the salpingectomy group. Implantation, miscarriage, and EP rates were 7.6%,46.5%, and 4.6%, respectively, in the hydrosalpinx group and 11.6%, 20%, and 0% in the salpingectomy group. Kassabji et al. (62) concluded that the absence of diseased tubes is more beneficial to the patient than the presence of diseased and potentially infected tubes that retard the implantation ability of the endometrium. Levy et al. (63) conducted a retrospective study comparing the outcome of IVF after different surgical interventions to previous IVF success rates. Surgical procedures were performed laparoscopically and included salpingectomy, proximal tubal occlusion, and neosalpingostomy based on the surgeon s and patient s decision. Those patients with hydrosalpinx had an 8.5% clinical pregnancy rate and a 2.9% implantation rate before surgery. Those with tubal disease but no hydrosalpinx had a 39% clinical pregnancy rate and an implantation rate of 15%. Those patients with hydrosalpinx for whom IVF had previously failed went on to have surgery before their next IVF attempt. Their clinical pregnancy rate after surgery was 42.8% with an implantation rate of 17.4%. Patients who underwent surgery before their first IVF attempt had a clinical pregnancy rate of 40.3% and an implantation rate of 17.4%. The pregnancy rates were similar regardless of the type of surgery performed. Levy et al. (63) concluded that hydrosalpinx has a negative effect on the success of IVF and suggested that surgical correction should be performed before IVF attempts. Surgical correction by salpingectomy, proximal tubal occlusion, and neosalpingostomy produced equivalent beneficial effects on subsequent IVF outcomes. Shelton et al. (64) were the first to conduct a prospective study that demonstrated a positive impact on pregnancy rates in patients with repeated IVF failures by removing the hydrosalpinges. Fifteen patients with unilateral or bilateral hydrosalpinges with a history of repeated IVF failures underwent laparoscopic excision of the affected tubes. Because the patients undergoing surgical excision served as their own control, the ongoing pregnancy rate per transfer was 0% presalpingectomy. After salpingectomy the ongoing pregnancy per transfer rate was 25%. Improved pregnancy rates were noted for both the fresh and frozen ETs after surgery. In their study of integrins and endometrial receptivity, Lessey et al. (59) also compared pregnancy rates between patients with hydrosalpinx before and after surgical correction to patients with tubal disease but without hydrosalpinx. FERTILITY & STERILITY 381

Forty-two patients with hydrosalpinx undergoing 113 cycles had a pregnancy rate of 10%, whereas 127 patients without hydrosalpinx undergoing 327 cycles had a pregnancy rate of 20.9%. The pregnancy rate in the 15 patients who had undergone surgical correction of their hydrosalpinges and underwent 62 cycles was 43.2%. This was significantly increased compared to the hydrosalpinx group and had borderline significance compared to the nonhydrosalpinx group. This study was of great importance in that it linked decreased uterine receptivity reflected by lower integrin levels to the presence of a hydrosalpinx. They were also successful in demonstrating an improvement of integrin status and therefore, uterine receptivity after correction of the hydrosalpinx. Murray et al. (65) conducted a retrospective review of 83 patients with tubal disease who underwent 132 IVF cycles. The clinical pregnancy rate was 16% in the 25 patients with hydrosalpinx and 37% in the 107 patients without hydrosalpinx. Ten patients with hydrosalpinx proceeded to undergo salpingectomy, proximal tubal ligation, or neosalpingostomy. Of the 10 patients, 4 have completed an IVF cycle and 3 successfully conceived showing an improvement in the subsequent IVF pregnancy rate after surgical correction of hydrosalpinx. It is unclear whether salpingectomy has a detrimental effect on ovarian blood supply and neural linkage, thus affecting folliculogenesis and hormone production. Studies by Vandromme, Kassabji, and Shelton and their colleagues (30, 62, 63) showed no difference in ovarian response, oocyte retrieval, or fertilization rates after salpingectomy. Lessey et al. (59) also noted that hydrosalpinges did not affect the number of oocytes retrieved, fertilization, or cleavage rates. Verhulst et al. (66) performed a retrospective case-control study comparing women with bilateral salpingectomy to a group of women with normal tuboovarian status. There was no statistical difference in length of stimulation, preovulatory E 2 levels, and the number of oocytes retrieved between the two groups. However, a crucial point was made resection of the fallopian tube should be as close to the tube as possible to minimize damage to the ovarian blood supply. McComb and Delbelke (67) addressed the importance of maintaining the integrity of the anastomotic vessels between the ovary and tube. They evaluated the relationship between the ovary and oviduct using microsurgery to alter the structure of the fallopian tube. The number of ovulations was reduced by ablating the vasculature transmitted through the mesosalpinx. Preservation of the anastomotic ovarian blood supply at the time of salpingectomy was also emphasized by Herman et al. (36) to decrease the possible adverse effects of radical surgery on ovarian function. Salpingectomy is not without subsequent risk. The risk of interstitial pregnancy is not eliminated and the remote chance of uterine rupture at the site of salpingectomy exists (68, 69). In a retrospective study Dubuisson et al. (69) found that the incidence of interstitial pregnancy to be 4% in patients with previous bilateral salpingectomy after IVF. Pavic et al. (70) were the first to report an interstitial pregnancy after bilateral salpingectomy for hydrosalpinx and IVF. Cornual resection at the time of salpingectomy does not prevent interstitial pregnancies. Thus, it is always important to sonographically identify the location of the gestational sac after transfer. DEBATE The benefit of salpingectomy before IVF/ET in patients with hydrosalpinx has been debated by Putteman and Brosens (71). They believe that preventative salpingectomy should not be performed without demonstration of severe pathology, specifically chronic inflammation, by salpingoscopy. 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