Adverse effects of hydrosalpinx on pregnancy rates after in vitro fertilization embryo transfer

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1 FERTILITY AND STERILITY VOL. 70, NO. 3, SEPTEMBER 1998 Copyright 1998 American Society for Reproductive Medicine Published by Elsevier Science Inc. Printed on acid-free paper in U.S.A. Adverse effects of hydrosalpinx on pregnancy rates after in vitro fertilization embryo transfer Hulusi B. Zeyneloglu, M.D., Aydin Arici, M.D., and David L. Olive, M.D. Division of Reproductive Endocrinology, Department of Obstetrics and Gynecology, Yale University School of Medicine, New Haven, Connecticut Objective: To determine the effect of hydrosalpinx on the establishment of pregnancy after IVF-ET. Design: Metaanalysis. Setting: University medical center. Patient(s) and Intervention(s): All published reports (n 13) and abstracts (n 10) in English that examined the relation between hydrosalpinx and IVF-ET were included in the analysis. The metaanalysis was performed by first calculating the odds ratios for each trial and then combining them to obtain a pooled estimate of the odds ratio and a 95% confidence interval. Main Outcome Measure(s): Clinical pregnancy. Result(s): A total of 5,569 cycles was reviewed in the group without hydrosalpinx, and a total of 1,144 was reviewed in the group with hydrosalpinx. The clinical pregnancy rate was approximately 50% lower in patients who had hydrosalpinx. Similarly, the implantation rate was decreased by 50%. These effects were observed also in thawed ET cycles. The abortion rate was more than twofold higher in patients who had hydrosalpinx. Conclusion(s): This metaanalysis suggests that hydrosalpinx is associated with a reduced chance of implantation and an increased risk of pregnancy loss. (Fertil Steril 1998;70: by American Society for Reproductive Medicine.) Key Words: Hydrosalpinx, IVF-ET, pregnancy rate, implantation, pregnancy loss Received December 5, 1997; revised and accepted May 7, Reprint requests: David L. Olive, M.D., Department of Obstetrics and Gynecology, Yale University School of Medicine, 333 Cedar Street, New Haven, Connecticut (FAX: ) /98/$19.00 PII S (98) IVF-ET has been used to treat couples with a variety of infertility diagnoses. However, the classic indication is tubal factor infertility. The rationale for this intervention is straightforward: In the presence of abnormally functioning fallopian tubes, an effective approach to treatment would be to bypass the contribution of these structures to the reproductive process. Such circumvention should lead to high pregnancy rates (PRs) with IVF-ET, as most couples with tubal factor infertility are otherwise fertile. The above argument fails to consider that, on occasion, tubal disease may actively inhibit reproduction rather than passively reduce fecundity. There are several possible causes of such an active effect: Adhesion tissue products might prove toxic to gametes or embryos, abnormal tubal epithelium may secrete detrimental hormones or growth factors, or altered uterotubal flow might affect the implantation cascade. An extreme form of tubal disease is tubal hydrosalpinges. Fluid collection from such structures is known to increase with controlled ovarian stimulation (1), and this fluid empties into the uterine lumen (2). Could hydrosalpinx prove detrimental to the establishment of pregnancy after IVF-ET? A recent study suggested that human hydrosalpinx fluid was detrimental to the growth and development of mouse embryos in vitro (3). Although the inhibitory component of the fluid is as yet unidentified, it is clear that if such an effect is also seen with human embryos, then hydrosalpinx may be disadvantageous at the time of ET. This study examines the clinical literature investigating this issue. MATERIALS AND METHODS We attempted to locate all published reports and abstracts in English that examined the relation between hydrosalpinx and assisted reproduction. Our search included MEDLINE, 492

2 FERTILITY & STERILITY 493 TABLE 1 Summary of studies on the relation between hydrosalpinx and IVF-ET. Author(s) Year of study Documentation Study group Control group Sims et al. (14)* 1993 (ASRM) HSG, LS, LT Hydrosalpinx Strandell et al. (5) 1994 HSG, LS, LT Hydrosalpinx Andersen et al. (6) 1994 USG Hydrosalpinx Lessey* 1994 (ASRM)? Hydrosalpinx Group with salpingectomy Specifications Included in metaanalysis There were 3 groups in the original report; group 2 is excluded; frozen cycles were analyzed separately There were 4 groups; only groups cited on the columns to the left are considered hydrosalpinges Kassabji et al. (7) 1994 HSG, LS Hydrosalpinx Murray* 1995 (ASRM) HSG, LS, LT Hydrosalpinx Levy et al. (15)* 1996 (ASRM) LS Hydrosalpinx hydrosalpinges hydrosalpinges Vandromme et al. (8) 1995 Hydrosalpinx Sharara et al. (9) 1996 HSG, LS, LT Hydrosalpinx Fleming and Hull (10) 1996 HSG, LS Hydrosalpinx Shelton et al. (11) 1996 HSG, LS Hydrosalpinx Akman et al. (4) 1996 HSG, LS Hydrosalpinx Katz et al. (12) 1996 HSG, LS Hydrosalpinx HSG, LS, Blazar et al. (13) 1997 LT, USG Hydrosalpinx 15 patients with previous hydrosalpinges who had undergone salpingectomy Patients with Integrin v3 score was found to be low in the endometrium of the patients with hydrosalpinges salpingectomy Patients from hydrosalpinx group after correction Patients from hydrosalpinx group There were 3 treatment groups: after surgical salpingectomy, proximal tubal correction ligation, neosalpingostomy Patients from hydrosalpinx group There were 3 groups, but only 2 after correction were considered There were 4 groups; only groups without antibiotics were considered There were 3 groups, but only 2 were considered Patients who failed previous IVF cycles and underwent salpingectomies Prospective These studies analyze the implantation of frozen embryos hydrosalpinges * Abstract, American Society for Reproductive Medicine. Note: ASRM American Society for Reproductive Medicine; HSG hysterosalpingography; LS laparoscopy; LT laparotomy; USG ultrasonography.

3 TABLE 2 Summary of studies on the relation between hydrosalpinx and IVF-ET that were included in the present metaanalysis. Size Pregnancy Ongoing pregnancies/deliveries Miscarriages Author(s) Hydrosalpinx Control Hydrosalpinx Control Hydrosalpinx Control Hydrosalpinx Control Sims et al. (14)* 234 1, Strandell et al. (5) Strandell et al. (5) (thaw cycle) Andersen et al. (6) Lessey* Levy et al. (15)* Murray* Sharara et al. (9) Fleming and Hull (10) Akman et al. (4) Katz et al. (12) 95 1, Blazar et al. (13) * Abstract. reference lists from original articles, and proceedings from international and other major meetings in reproductive medicine. This search produced 13 published studies and 10 abstracts (Table 1) (4 15). All studies had a cohort design. If an abstract was published subsequently in a journal as a manuscript, then the abstract was excluded from the analysis. The studies were analyzed, and those included met the following criteria: [1] hydrosalpinges documented with hysterosalpingography (HSG), laparoscopy, laparotomy, or ultrasonography; and [2] a control group consisting of patients with tubal factor infertility but without hydrosalpinx. Subgroups or complete studies were excluded if controls included patients with surgical correction of hydrosalpinges, if control patients had surgical sterilization, or if controls received antibiotics. In the metaanalysis, pregnancy was defined as being a clinically demonstrated event; biochemical pregnancies that did not progress to clinical pregnancy were not included as a positive outcome. The studies included in this analysis are listed in Table 2. Two studies reported the results from frozen cycles (4, 5). Strandell et al. (5) reported results from both frozen and fresh cycles; we analyzed these as separate reports to assess whether freezing had any impact on the effect of hydrosalpinx. The metaanalysis was performed by first calculating the odds ratios (ORs) for each trial and then combining them using the methods of Peto (modified Mantel-Haenszel) (16), referred to as a fixed-effects model, to obtain a pooled estimate of the OR and a 95% confidence interval (95% CI). Homogeneity was tested with the Breslow-Day test (17) and was rejected at P If significant heterogeneity was present, we calculated a common OR using a randomeffects model (18). By definition, if the 95% CI range included 1.0, there was no statistical difference between the groups. RESULTS Clinical PRs The clinical PR in patients with hydrosalpinx was significantly lower in all groups. The total numbers of pregnancies and cycles were 1,544 and 5,569 in the group without hydrosalpinx and 187 and 1,144 in the group with hydrosalpinx, respectively. The lowest OR was (95% CI, ) (15) and the highest was (95% CI, ) (13). The CIs ranged from to The studies were heterogeneous ( , df 12, P 0.058), and thus we used the method of random ORs (Fig. 1). The common OR of pregnancy for hydrosalpinx versus no hydrosalpinx was (95% CI, ), which indicated that hydrosalpinx decreased the chances of pregnancy to half that of patients with tubal factor but no hydrosalpinx. Of all cycles, 64.13% were reviewed in published studies; of all pregnancies, 67.46% were reviewed in published studies. There were 9 reports in 8 articles. The total numbers of pregnancies and cycles were 1,043 and 3,574 in the group without hydrosalpinx and 125 and 699 in the group with hydrosalpinx, respectively (Fig. 1A). The common OR for published studies was (95% CI, ). Although the common OR did not differ from the previous analysis, homogeneity among the studies was seen ( , df 8, P 0.44). Metaanalysis of the four abstracts showed that there was 494 Zeyneloglu et al. Hydrosalpinx and IVF Vol. 70, No. 3, September 1998

4 FIGURE 1 Metaanalysis of PRs. (A), Metaanalysis of all studies showing OR for PR per cycle. (B), Metaanalysis of studies showing OR for the PR per ET cycle. heterogeneity between the studies. Although the random OR method was applied, the heterogeneity test was significant (Breslow-Day score ; P ). The heterogeneity was mainly due to the results of Sims et al. (14). The common OR was (95% CI, ). We analyzed the PRs per ET cycle separately (Fig. 1B). The common OR for the PR per ET was (95% CI, ), and the Breslow-Day score was (df 10, P 0.39). In the published studies, the common OR for the PR per ET was (95% CI, ), and the Breslow-Day score was 5.46 (df 5, P 0.36). When only fresh cycles were considered, the common OR for the PR per ET was (95% CI, ). However, the common OR for the same outcome in the abstracts was (95% CI, ), but the heterogeneity test was significant (P 0.001). Pregnancy Rates for Thaw Cycles Acute ovarian stimulation may enlarge hydrosalpinges, which theoretically may be detrimental because of the increased fluid content. Therefore, we also analyzed the thaw cycles for the frozen embryos separately. The common OR FERTILITY & STERILITY 495

5 FIGURE 2 Metaanalysis of studies showing OR for implantation rates per ET cycle. for the PR per ET of patients with hydrosalpinx versus patients without hydrosalpinx was (95% CI, ; Breslow-Day score 0.406, df 1, P 0.52). Implantation Rates When implantation rates were analyzed, the results showed heterogeneity, probably because the number of transferred em- FIGURE 3 Metaanalysis of studies showing OR for ongoing pregnancies in fresh cycles. 496 Zeyneloglu et al. Hydrosalpinx and IVF Vol. 70, No. 3, September 1998

6 FIGURE 4 Metaanalysis of studies showing OR for abortion rates. bryos per cycle varied greatly among the studies (Breslow-Day score , df 6, P 0.013). Only published studies reported implantation rates, with a common OR of (95% CI, ) (Fig. 2). Thus, despite the heterogene- FIGURE 5 Metaanalysis of studies showing OR for ectopic pregnancy rates. FERTILITY & STERILITY 497

7 FIGURE 6 Metaanalysis of studies showing OR for the PR per ET cycle against the sample size of the study. ity, implantation rates decreased by half in the hydrosalpinx group. Ongoing Pregnancies Because the rate of ongoing pregnancies in the thaw cycles was limited, only fresh cycles were considered for the analysis (Fig. 3). For ongoing pregnancies in the hydrosalpinx group, the OR was (95% CI, ; Breslow-Day score , df 7, P 0.11). Thus, the likelihood of an ongoing pregnancy was decreased by half in women with hydrosalpinx. Abortion Rates Although all published studies reported abortion rates, abortion rates were found in only one abstract (Fig. 4). The chance of abortion in patients with hydrosalpinx was increased significantly (common OR 2.333; 95% CI, ; Breslow-Day score , P 0.29). Ectopic Pregnancy The chance of ectopic pregnancy tended to be higher in patients with hydrosalpinges; however, the CIs were wide (common OR 1.295; 95% CI, , Breslow-Day score 1.142, df 6, P 0.98) (Fig. 5). DISCUSSION On the basis of the limited data available, this metaanalysis shows that hydrosalpinx is associated with a reduced chance of implantation and an increased risk of pregnancy loss. The PR for the patients with hydrosalpinx was only half that of patients with tubal factor but without hydrosalpinx. The frequency of hydrosalpinges among IVF-ET patients with tubal infertility appears to be in the range of 10% 13% by ultrasonography. However, when diagnosis is based on HSG or operative findings, the incidence is 25% 30%, indicating that many cases are missed by ultrasonography during routine clinical work-up. Atri et al. (19) reported that endovaginal ultrasonography before HSG identified only 34% of patients with hydrosalpinx diagnosed by HSG. There are several hypotheses regarding the adverse effect of hydrosalpinges on implantation, pregnancy, and abortion rates. In 1960, Palmer (20) showed that pregnancy outcome was poor in the presence of chronic progressive inflammation. David and Czernobilsky (21) showed that the hydrosalpinx wall was fibrotic and the epithelial lining was impaired. The fluid had low levels of protein and bicarbonate with fluctuating ph levels between 7.2 and 7.7, suggesting passive transudation rather than active secretion. Mukherjee et al. (3) reported that hydrosalpinx fluid was toxic to murine embryo development even in log-fold dilutions; furthermore, correcting the high ph of the fluid did not change the results. Although the distal end of a hydrosalpinx is blocked, the proximal end is usually in free communication with the uterine cavity, which may allow a direct flow of microorganisms, toxic debris, and lymphocytes into the uterus. Cytokines, prostaglandins, and other agents also may be transferred directly to the endometrium. Anecdotal reports suggest that such a mechanism may be important clinically. 498 Zeyneloglu et al. Hydrosalpinx and IVF Vol. 70, No. 3, September 1998

8 Mansour et al. (2) reported the drainage of brownish fluid from the cervix of IVF patients with hydrosalpinges, especially in the second half of the cycle; these patients could not conceive after IVF-ET. Russel et al. (22) reported a patient with hydrosalpinx who failed to conceive in the first IVF-ET attempt but who conceived in the second cycle. Before the second cycle, ultrasound-guided transvaginal aspiration of the hydrosalpinges was performed. Oehninger et al. (23) showed that the best results in IVF-ET were obtained in patients with pure mechanical factor (bilateral tubal ligation). They noticed a trend toward poorer results in patients with more severe tubal or tuboovarian disease compared with patients with milder forms. In the same study, the investigators showed that bilateral salpingectomy or any other tubal surgery did not produce any difference in steroid production, follicle development, oocyte maturation, or PR. Boutteville et al. (24) showed that in patients with one ovary, fewer mature oocytes may be retrieved, yet the chance of conception was similar to that of patients with both ovaries preserved. Although this metaanalysis suggests a strong effect of hydrosalpinx on the PR in IVF cycles, it is far from definite. None of the studies included are prospective in design, and all run the risk of bias from confounding variables. However, publication bias does not seem to be an issue; when plotting OR versus sample size, an appropriate funneling effect was seen (Fig. 6). Thus, although flaws are apparent among the published studies, there was an adequate level of consistency in the results for most of the clinical questions raised. In this metaanalysis, we did not evaluate the effect of salpingectomy on the PRs. To date, there are no prospective, randomized, controlled studies investigating this effect, and investigators who have looked at this issue have used biased or poorly controlled study designs. A multicenter trial developed to address this issue would be both timely and responsible. References 1. Hill GA, Herbert CM, Fleischer AC, Webster BW, Maxson WS, Wentz AC. Enlargement of hydrosalpinges during ovarian stimulation protocols for in-vitro fertilization and embryo replacement. Fertil Steril 1986;45: Mansour RT, Aboulghar MA, Serour GI, Riad R. Fluid accumulation of the uterine cavity before embryo transfer: a possible hindrance for implantation. J In Vitro Fert Embryo Transf 1991;8: Mukherjee T, Copperman AB, McCaffrey C, Cook CA, Bustillo M, Obasaju MF. Hydrosalpinx fluid has embryotoxic effects on murine embryogenesis: a case for prophylactic salpingectomy. Fertil Steril 1996;66: Akman MA, Garcia JE, Damewood MD, Watts LD, Katz E. Hydrosalpinx affects the implantation of previously cryopreserved embryos. Hum Reprod 1996;11: Strandell A, Waldenstrom U, Nillson L, Hamberger L. Hydrosalpinx reduces in-vitro fertilization/embryo transfer pregnancy rates. Hum Reprod 1994;9: Andersen AN, Yue Z, Meng FJ, Petersen K. Low implantation rate after in-vitro fertilization in patients with hydrosalpinges diagnosed by ultrasonography. Hum Reprod 1994;9: Kassabji M, Sims JA, Butler L, Muasher SJ. Reduced pregnancy outcome in patients with unilateral or bilateral hydrosalpinx after in vitro fertilization. Eur J Obstet Gynecol Reprod Biol 1994;56: Vandromme J, Chasse E, Lejeune B, Van Rysselberge M, Delvigne A, Leroy F. Hydrosalpinges in in-vitro fertilization: an unfavourable prognostic feature. Hum Reprod 1995;10: Sharara FI, Scott RT Jr, Marut EL, Queenan JT Jr. In-vitro fertilization outcome in women with hydrosalpinx. Hum Reprod 1996;11: Fleming C, Hull MGR. Impaired implantation after in vitro fertilisation treatment associated with hydrosalpinx. Br J Obstet Gynaecol 1996; 103: Shelton KE, Butler L, Toner JP, Oehninger S, Muasher SJ. Salpingectomy improves the pregnancy rate in in-vitro fertilization patients with hydrosalpinx. Hum Reprod 1996;11: Katz E, Akman MA, Damewood MD, Garcia JE. Deleterious effect of the presence of hydrosalpinx on implantation and pregnancy rates with in vitro fertilization. Fertil Steril 1996;66: Blazar AS, Hogan JW, Seifer DB, Frishman GN, Wheeler CA, Haning RV. The impact of hydrosalpinx on successful pregnancy in tubal factor infertility treated by in vitro fertilization. Fertil Steril 1997;67: Sims JA, Jones D, Butler L, Muasher SJ. Effect of hydrosalpinx on outcome in in-vitro fertilization (IVF). Abstract no. P-032. American Fertility Society Meeting, Montreal, Levy MJ, Murray D, Sagoskin A. The adverse effect of hydrosalpinges on IVF success rates are reversed equally by salpingectomy, proximal tubal occlusion, and neosalpingostomy [Abstract no. O-128]. Fertil Steril 1996;66(3 suppl. 1): Yusuf S, Lewis J, Collins R, Sleight P. Beta blockade during and after myocardial infarction: an overview of the randomized trials. Prog Cardiovasc Dis 1985;27: Breslow NE, Day NE. Statistical methods in cancer research. Vol. 1. The analysis of case-control studies. IARC scientific publication no Lyon, France: International Agency for Research on Cancer, DerSimonian R, Laird N. Meta-analysis in clinical trials. Control Clin Trials 1986;7: Atri M, Tran CN, Bret PM, Aldis AE, Kintzen GM. Accuracy of endovaginal sonography for the detection of fallopian tube blockage. J Ultrasound Med 1994;13: Palmer R. Discussion on modern methods of salpingostomy. Proc K Soc Med 1960;53: David A, Garcia CR, Czernobilsky B. Human hydrosalpinx: histologic study and chemical composition of fluid. Am J Obstet Gynecol 1969; 105: Russell JB, Rodriguez Z, Komins JI. The use of transvaginal ultrasound to aspirate bilateral hydrosalpinges prior to in vitro fertilization: a case report. J In Vitro Fert Embryo Transf 1991;8: Oehninger S, Scott R, Muasher SJ, Acosta AA, Jones HW Jr, Rosenwaks Z. Effects of the severity of tubo-ovarian disease and previous tubal surgery on the results of in vitro fertilization and embryo transfer. Fertil Steril 1989;51: Boutteville C, Muasher SJ, Acosta AA, Jones HW Jr, Rosenwaks Z. Results of in vitro fertilization attempts in patients with one or two ovaries. Fertil Steril 1987;47: FERTILITY & STERILITY 499