Bourn Hall Clinic, Bourn, Cambridge CB3 7TR, UK
The presence of hydrosalpinges is a relatively common condition in in-vitro fertilization (IVF) patients suffering from tubal disease. The prevalence of it can range from 1013% when diagnosed by vaginal ultrasound scan (Andersen et al., 1994; Katz et al., 1996
) and up to 30% when the diagnosis is based on hysterosalpingography (HSG), or direct vision via laparoscopy or in surgery (Strandell et al., 1994
; Blazar et al., 1997
; Murray et al., 1997
). This difference is probably related to the diagnostic limitations of vaginal ultrasound in detecting small hydrosalpinges (Atri et al., 1994
; de Wit et al., 1998
). IVF treatment has become the main treatment for tubal infertile women with hydrosalpinges, but the effect of hydrosalpinges on IVF outcome, the mechanism(s) of this effect and, above all, the preferred method of treatment, are very controversial (Bloechle, 1999
; Sharara, 1999
). Not surprisingly, therefore, numerous studies, with conflicting results, have been published in recent years on these topics.
The effect of untreated hydrosalpinges on IVF outcome
Several authors investigated IVF outcome in patients with untreated hydrosalpinges, and most of them found reduced pregnancy and/or implantation rates in these patients compared with control groups (Andersen et al., 1994; Kassabji et al., 1994
; Strandell et al., 1994
; Vandromme et al., 1995
; Fleming and Hull, 1996
; Katz et al., 1996
; Blazar et al., 1997
). A similar picture was found following the transfer of cryopreservedthawed embryos (Strandell et al., 1994
; Akman et al., 1996
). Only one group showed a (non-significant) lower pregnancy rate in the hydrosalpinges group (Sharara et al., 1996
). A meta-analysis was carried out on all published reports (n = 13) and abstracts (n = 10) up to 1997 (Zeyneloglu et al., 1998
), to examine the association between hydrosalpinges and IVF outcome. The authors concluded that clinical pregnancy and implantation rates were 50% lower in women who had hydrosalpinges, while the miscarriage rate was two-fold higher. They summarized the study by saying that: `although this meta-analysis suggests a strong effect of hydrosalpinges on the pregnancy rate in IVF cycles, it is far from definite. None of the studies included are prospective in design'. Indeed, since this publication, new studies have been emerged with conflicting results. Another retrospective study (Ng et al., 1997
), reported similar implantation, pregnancy and clinical miscarriage rates in 43 women who had hydrosalpinges compared with 101 tubal patients without hydrosalpinges; however, the ectopic rates were higher in the former (n = 3 versus 0, P = 0.03). However, other studies (Sowter et al., 1997
; Wainer et al., 1997
; Murray et al., 1997
; Freeman et al., 1998
; de-Wit et al., 1998
) have confirmed reduced pregnancy and implantation rates in women with hydrosalpinges. The decreased pregnancy rate may be correlated with the size of the hydrosalpinges because such association was not observed in women whose hydrosalpinges were not visible on ultrasound scan (de Wit et al., 1998
).
Possible mechanisms of the effect of hydrosalpinges on IVF outcome
In spite of intensive research, there is no clear explanation for the detrimental effect of hydrosalpinges on pregnancy rate, and a few possible mechanisms have been suggested.
Mechanical factors
The reflux of the hydrosalpinges fluid (HF) into the uterine cavity produces a `flushing' effect that inhibits embryo from implantation (Mansour et al., 1991; Andersen et al., 1994
; 1996; Sawin et al., 1998
). Sharara and McClamrock noticed that the hydrosalpinges enlarged with ovarian stimulation, causing fluid reflux into the uterine cavity that was only noted after human chorionic gonadotrophin (HCG) administration (Sharara and McClamrock, 1997
).
Reduced endometrial receptivity
The release of cytokines, prostaglandins and other inflammatory components to the endometrium resulting in reduced endometrial receptivity. Lower concentrations of vß3 integrin were found in endometrial biopsies of women with hydrosalpinges (Andersen et al., 1994
; Meyer et al., 1997
).
Embryotoxic effect of hydrosalpinges fluid
Several authors (Mukherjee et al., 1996; Rawe et al., 1997
; Beyler et al., 1997
; Nackley and Mausher, 1998) have suggested that the HF contains embryotoxic and lipophilic factors which are detrimental to the normal development of embryos. Schadeve et al. cultured mouse embryos at 0 (controls), 0.3, 0.6 and 0.9% (HF) concentrations and demonstrated significantly lower blastulation rates at each value, compared with the controls (Schadeve et al., 1997
). Another report (Murray et al., 1998
) showed that mouse embryos cultured in 100% human (HF) were significantly inhibited developmentally compared to control groups, but when lactate (10 mM) was added to the HF, a similar proportion of embryos reached the blastocyst stage. They speculated that no potent embryotoxic agent is present in the HF but that the inhibitory effect of HF on embryonic development is due to the absence of essential factors which can be corrected by adding energy sources. Interestingly, all the above studies investigated mouse embryos and not human embryos. Recently, two sets of authors (Granot et al., 1998
; Strandell et al., 1998
) have challenged the `embryotoxic theory' by claiming that HF does not adversely affect the normal development of human embryos. Moreover, Sawin et al. (1997) found that, not only is there no detrimental effect of HF, but that HF improved human trophoblast viability in vitro and enhanced the production of tropho-uteronectin and ß-HCG by these cells. This improvement was dose-dependent to the concentration of HF. It may be, therefore, that HF adversely effect mouse embryos (which are more sensitive) but not human embryos (Sawin et al., 1998
).
What is the best treatment for hydrosalpinges?
The body of evidence described above, is quite convincing with regard to hydrosalpinges having a detrimental effect of on implantation and on-going pregnancy rates in IVF treatment, regardless of the exact mechanism of this effect. This conclusion led researchers to investigate methods which could give women who wish to conceive using IVF, a similar chance of success as women with tubal infertility without hydrosalpinges. But what is the preferred method in these circumstances? The answer is simply not known and the debate goes on. Recently, an excellent review (Aboulghar et al., 1998), opened the discussion with the statement that: `The management of hydrosalpinges is a difficult clinical problem'. Here, I wish to present a personal view based on the current available data and to highlight the issue from a slightly different angle.
Currently, three treatment modalities for hydrosalpinges for women planning IVF are described in the literature: drug therapy, mechanical drainage of the hydrosalpinges, or a surgical approach using either salpingectomy or salpingoplasty (Table I).
|
A high proportion of immunoglobulin (Ig)G for Chlamydia trachomatis has been found in serum samples of women with hydrosalpinges (74.6%) in proportions similar to those of tubal factor infertile women without hydrosalpinges (68.3%) (Sharara et al., 1996). All patients with elevated titres of IgG antibodies to Chlamydia were treated with doxycycline and after the antibiotic course, there was no difference in pregnancy and implantation rates between women with and without hydrosalpinges. So far, it is the only published study for drug therapy for hydrosalpinges in IVF cycles and further prospective controlled study are urgently required.
Drainage of the hydrosalpinges
Aspiration of the HF before beginning IVF stimulation produced a better ovarian response and a higher number of embryos available for transfer in 32 women who had undertaken this procedure (Aboulghar et al., 1990). However, the procedure did not improve the pregnancy rate. Two other anecdotal reports (Russel et al., 1991
; Sharara et al., 1996
) on the success of this procedure have been published. The former described aspiration of HF a month before IVF with successful pregnancy for a single woman, while the second was part of larger study, describing aspiration of HF at the time of oocyte retrieval in seven women undergoing 11 cycles in which five pregnancies were achieved, but unfortunately three resulted in miscarriage. Recently, two groups of researchers investigating the potential benefit of hydrosalpinges drainage on IVF outcome have conducted retrospective studies and reported conflicting results. An improved pregnancy rate was found in 18 patients who had aspiration immediately following oocyte retrieval (31%) (Van Voorhis et al., 1998
) compared with a pregnancy rate of only 5% in those who have not undergone this procedure. In a larger series of 56 women whose HF was drained, no improvement in pregnancy rate was found following the drainage (Sowter et al., 1997
). These results, albeit in a small number of studies, together with rapid refilling of the tubes as quickly as 2 days after the procedure (Bloechle et al., 1997
), lead me to conclude that HF aspiration is not the ideal treatment.
Salpingectomy before IVF
Several authors have suggested to performing salpingectomy before IVF treatment to overcome the negative effects of hydrosalpinges on pregnancy, implantation and miscarriage rates (Verhulst et al., 1994; Vandromme et al., 1995
; Shelton et al., 1996
; Freeman et al., 1998
; Murray et al., 1998
). However, all of these studies were retrospective, based on a small number of patients and gave conflicting results (Table I
). Zeyneloglu et al. summarized their recent meta-analysis, which did not evaluate the effect of salpingectomy on the pregnancy rates by declaring that: `To date, there are no prospective, randomized, controlled studies investigating this effect' (Zeyneloglu et al., 1998
). The single prospective controlled study published at the same time, which also included a small number of patients with hydrosalpinges (Dechaud et al., 1998
) did not demonstrate a significant benefit from prophylactic salpingectomy for these patients. Moreover, salpingectomy is not a procedure without the recognized complications of operative laparoscopy and/or laparotomy in addition to the rare complications of interstitial (Raziel et al., 1989
) or abdominal pregnancy (Fisch et al., 1996
) following salpingectomy.
Recently, a retrospective Danish study of the largest series to date of women with hydrosalpinges was published (Ejdrup Bredkjaer et al., 1999). They concluded that bilateral salpingectomy due to hydrosalpinges restores a normal delivery as well as implantation rate after IVF treatment compared with controls. In addition, they demonstrated a similar ovarian response, at least represented by average number of oocytes retrieved (9.3 compared with 9.1) in 139 women following bilateral salpingectomy and 139 tubal damaged control groups. However, their control group included patients who had previous ectopic pregnancy treated by salpingectomy or conservative surgery. They did not compare the ovarian response of patients in their study group to patients without any surgery performed on their Fallopian tubes. One study (Oehninger et al., 1989
) found that neither history of pelvic adhesions nor previous tubal surgery had a significant influence on the IVF results, but a later study (Csemiczky et al., 1996
) demonstrated that women with severe tubal damage (grade IV) have already reduced ovarian reserve reflected in lower response to ovarian stimulation.
We have shown recently (Lass et al., 1998) that, in women who had had unilateral salpingectomy, there were fewer follicles and, consequently, fewer oocytes were retrieved from the side of operation in comparison with side with intact adnexa, without differences in pregnancy or implantation rates. The mechanism in which salpingectomy might cause reduced ovarian response is not clear but unilateral or bilateral removal of the Fallopian tubes may have a detrimental effect on the ovarian arterial supply. The medial tubal artery, which is most important for supply of blood to the tube, has its origin at the same point as the median ovarian artery. Salpingectomy, not properly performed close to the tube, may disrupt the normal blood flow to the ovary. This may have a negative impact on steroid production and further follicular development. Previously fewer ovulations on the side of microsurgical fimbriectomy (Beyth and Winston, 1981
) and of surgical division of the anasthomotic blood vessels between the ovary and the fimbria (McComb and Delbeke, 1984
) have been demonstrated in rabbits.
We did not use Doppler flow measurements in our study (Lass et al., 1998), and to the best of my knowledge, such a study has never been published, therefore further works are required to consolidate this suspicion. Salpingectomy for women with hydrosalpinges may cause even further deterioration in the ovarian reserve. While thoroughly assessing the condition of the tube(s) which could be suitable for re-constructive surgery (Puttermans and Brosens, 1996), special attention should be paid to the ovaries themselves. For women who have a damaged or missing ovary (not an uncommon situation in women with severe pelvic disease), or women already suspected of having reduced ovarian reserve (i.e in their late 30s, early 40s, raised basal concentrations of follicle stimulating hormones (FSH), decreased basal inhibin-ß concentrations), the detrimental effect of unilateral or bilateral salpingectomy may be greater than the potential benefit of this procedure. In these cases, `clamping' the proximal part of the hydrosalpinges rather than salpingectomy would be the preferred management.
Notes
This debate was previously published on Webtrack 60, April 8, 1999
References
Aboulghar, M.A., Mansour, R.T., Serour, G.I. et al. (1990) Transvaginal ultrasonic needle guided aspiration of pelvic inflammatory cystic masses before ovulation induction for in vitro fertilization. Fertil. Steril., 53, 311314.[ISI][Medline]
Aboulghar. M.A., Mansour R.T. and Serour, G.I. (1998) Controversies in the modern management of hydrosalpinx. Hum. Reprod. Update, 4, 882890.
Akman, M.A., Garcia, J.E., Damewood, M.D. et al. (1996) Hydrosalpinx affects the implantation of previously cryopreserved embryos. Hum. Reprod., 11, 10131014.[Abstract]
Andersen, A.N., Lindlard, A., Loft, A. et al. (1996) The infertile patient with hydrosalpingesIVF with or without salpingectomy? Hum. Reprod., 11, 20812084.[ISI][Medline]
Andersen, A.N., Yue, Z., Meng, F.J. and Petersen, K. (1994) Low implantation rate after in-vitro fertilization in patients with hydrosalpinges diagnosed by ultrasonography. Hum. Reprod., 9, 19351938.[Abstract]
Atri, M., Tran, C.N., Bret, P.M. et al. (1994) Accuracy of endovaginalsonography for the detection of fallopian tube blockage. J. Ultrasound Med., 13, 429434.[Abstract]
Beyler, A.S., James, K.P., Frits, M.A. and Meyer, W.R. (1997) Hydrosalpingeal fluid inhibits in-vitro embryonic development in a murine model. Hum. Reprod., 12, 27242728.[Abstract]
Beyth, Y. and Winston, R.M.L. (1981) Ovum capture and fertility following microsurgical fimbriectomy in the rabbit. Fertil. Steril., 35, 464466.[ISI][Medline]
Blazar, A.S., Hogan, J.W., Seifer, D.B. et al. (1997) The impact of hydrosalpinx on successful pregnancy in tubal factor infertility treated by in vitro fertilization. Fertil. Steril., 67, 517520.[ISI][Medline]
Bloechle, M., Schreiner, Th. and Lisse, K. (1997) Recurrence of hydrosalpinges after transvaginal aspiration of tubal fluid in an IVF cycle with development of serometra. Hum. Reprod., 12, 703705.[Abstract]
Bloechle, M. (1999) What effect does hydrosalpinx have on assisted reproduction? What is a hydrosalpinx? A plea for the use of a proper terminology in scientific discussion. Hum. Reprod., 14, 102.
Csemiczky, G., Landgren, B.M., Fried, G. et al. (1996) High tubal damage grade is associated with low pregnancy rate in women undergoing in-vitro fertilization treatment. Hum. Reprod., 11, 24382440.[Abstract]
de Wit, W., Gowrising, C.J., Kuik, D.J. et al. (1998) Only hydrosalpinges visible on ultrasound are associated with reduced implantation and pregnancy rates after in-vitro fertilization. Hum. Reprod., 13, 16961701.[Abstract]
Dechaud, H., Daures, J.P., Arnal, F. et al. (1998) Does previous salpingectomy improve implantation and pregnancy rates in patients with severe tubal factor infertility who are undergoing in vitro fertilization? A pilot prospective randomized study. Fertil. Steril., 69, 10201025.[ISI][Medline]
Ejdrup Bredkjaer, H., Ziebe, S., Hamid, B. et al. (1999) Delivery rate after in-vitro fertilization following bilateral salpingectomy due to hydrosalpinges: a case control study. Hum. Reprod., 14, 101105.
Fisch, B., Peled, Y., Kaplan, B. et al. (1996) Abdominal pregnancy following in vitro fertilization in a patient with previous bilateral salpingectomy. Obstet. Gynecol., 88, 642643.
Fleming, H. and Hull, M.G.R. (1996) Impaired implantation after in vitro fertilization treatment associated with hydrosalpinx. Br. J. Obstet. Gynecol., 103, 268272.[ISI][Medline]
Freeman, M.R., Whitworth, C.M. and George, A.H. (1998) Permanent impairment of embryo development by hydrosalpinges. Hum. Reprod., 13, 983986.[Abstract]
Granot, I., Dekel, N., Segal, I. et al. (1998) Is hydrosalpinx fluid cytotoxic? Hum. Reprod., 13, 16201624.[Abstract]
Kassabji, M., Sims, J.A., Butler, L. and Muasher, S.J. (1994) Reduced pregnancy outcome in patients with unilateral or bilateral hydrosalpinx after in vitro fertilization. Eur. J. Obstet. Gynecol. Reprod. Biol., 56, 129132.[ISI][Medline]
Katz, E., Akman, M.A., Damewood, M.D. and Garcia, J.E. (1996) Deleterious effect of the presence of hydrosalpinx on implantation and pregnancy rates with in vitro fertilization. Fertil. Steril., 66, 122125.[ISI][Medline]
Lass, A., Ellenbogen, A., Crouche, R.C. et al. (1998) The effect of salpingectomy on ovarian response to superovulation in an in-vitro fertilization embryo transfer programme. Fertil. Steril., 70, 10351038.[ISI][Medline]
Mansour, R.T., Aboulghar, M.A., Serour, G.I. and Riad, R. (1991) Fluid accumulation of the uterine cavity before embryo transfer: a possible hindrance for implantation. J. In Vitro Fertil. Embryo Transfer, 8, 11571159.
McComb, P., Delbeke, L. (1984) Decreasing the number of ovulations in the rabbit with surgical division of the blood vessels between the fallopian tube and ovary. J. Reprod. Med., 29, 827829.[ISI][Medline]
Meyer, W.R., Castelbaum, A.J., Somkuti, S. et al. (1997) Hydrosalpinges adversely affect markers of endometrial receptivity. Hum. Reprod., 12, 13931398.[Abstract]
Mukherjee, T., Copperman, A.B., McCaffrey, C. et al. (1996) Hydrosalpinx fluid has embryotoxic effects on murine embryogenesis: a case for prophylactic salpingectomy. Fertil. Steril., 66, 851853.[ISI][Medline]
Murray, C.A., Clarke, H.J., Tulandi, T. and Tan, S.L. (1997) Inhibitory effect of human hydrosalpingeal fluid on mouth preimplantation embryonic development is significantly reduced by the addition of lactate. Hum. Reprod., 11, 25042507.
Murray, D.L., Sagoskin, A.W., Widra, E.A. and Levy, M.L. (1998) The adverse effect of hydrosalpinges on in vitro fertilization pregnancy rates and the benefit of surgical correction. Fertil. Steril., 69, 4145.[ISI][Medline]
Nackley, A.C. and Muasher, S.J. (1998) The significance of hydrosalpinx in in vitro fertilization. Fertil. Steril., 69, 373383.[ISI][Medline]
Ng, E.H., Yeung, W.S. and Ho, P.C. (1997) The presence of hydrosalpinx may not adversely affect the implantation and pregnancy rates in in vitro fertilization treatment. J. Assist. Reprod. Genet., 14, 508512.[ISI][Medline]
Oehninger, S., Scoot, R., Muasher, S.J. et al. (1989) Effects of the severity of tuboovarian disease and previous tubal surgery on the results of in vitro fertilization and embryo transfer. Fertil. Steril., 51, 126130.[ISI][Medline]
Puttemans, P.J. and Brosens, I.A. (1996) Salpingectomy improves in-vitro fertilization outcome in patients with a hydrosalpinx: blind victimization of the Fallopian tube? Hum. Reprod., 11, 20792081.[ISI][Medline]
Rawe, V.J., Liu, J., Shaffer, S. et al. (1997) Effect of human hydrosalpinx fluid on murine embryo development and implantation. Fertil. Steril., 68, 668670.[ISI][Medline]
Raziel, A., El, R.R., Wardimon, J. et al. (1989) Ultrasonographic diagnosis of post salpingectomy interstitial pregnancy. Case report and review of literature. Acta Obstet. Gynecol. Scand., 68, 8586.[ISI][Medline]
Russel, J.B., Rodriquez, Z. and Komins, J.I. (1991) The use of transvaginal ultrasound to aspirate bilateral hydrosalpinges prior to in vitro fertilization: a case report. J. In vitro Fertil. Embryo Transfer, 8, 213215.[ISI][Medline]
Sawin, S.W., Loret de Mola, J.R., Monzon-Bordonaba, F. and Wang, C.L. (1998) effect of hydrosalpinx on IVF outcome-mechanism? Fertil. Steril., 70, 787.[ISI][Medline]
Sawin, S.W., Loret de Mola, J.R., Monzon-Bordonaba, F. et al. (1997) Hydrosalpinx fluid enhances human trophoblast viability and function in vitro: implications for embryonic implantation in assisted reproduction. Fertil. Steril., 68, 6571.[ISI][Medline]
Schadeve, R., Kemmann, E., Bohrer, M.K. and el-Danasouri, I. (1997) detrimental effect of hydrosalpinx fluid on the development and blastulation of mouse embryos in vitro. Fertil. Steril., 68, 531533.[ISI][Medline]
Sharara, F.I. (1999) What effect does hydrosalpinx have on assisted reproduction? The role of hydrosalpinx in IVF: simply mechanical?. Hum. Reprod., 14, 101102.
Sharara, F.I. and McClamrock, H.D. (1997) Endometrial fluid collection in women with hydrosalpinx after human chorionic gonadotrophin administration: a report of two cases and implications for management. Hum. Reprod., 12, 28162819.[Abstract]
Sharara, F.I., Scott, R.T., Jr., Marut, E.L. et al. (1996) In-vitro fertilization outcome in women with hydrosalpinx. Hum. Reprod., 11, 526530.[Abstract]
Shelton, K.E., Butler, L., Toner, J.P. et al. (1996) Salpingectomy improves the pregnancy rate in in-vitro fertilization patients with hydrosalpinx. Hum. Reprod., 11, 523525.[Abstract]
Sowter, M.C., Akande, V.A., Williams, J.A.C. and Hull, M.G.R. (1997) Is the outcome of in-vitro fertilization and embryo transfer treatment improved by spontaneous or surgical drainage of hydrosalpinx? Hum. Reprod., 12, 21472150.[Abstract]
Strandell, A., Sjogren, A., Bentin-Ley, U. et al. (1998) Hydrosalpinx fluid does not adversly affect the normal development of human embryos and implantation in vitro. Hum. Reprod., 13, 29212925.
Strandell, A., Waldenstrøm, U., Nilsson, L. and Hamberger, L. (1994) Hydrosalpinx reduces in-vitro fertilization/embryo transfer pregnancy rates. Hum. Reprod., 9, 861863.[Abstract]
Van Voorhis, B.J., Sparks, A.E., Syrop, C.H. and Stovall, D.W. (1998) Ultrasound-guided aspiration of hydrosalpinges is associated with improved pregnancy and implantation rates after in-vitro fertilization cycles. Hum. Reprod., 13, 736739.[Abstract]
Vandromme, J., Chasse, E., Lejeune, B. et al. (1995) Hydrosalpinges in in vitro fertilization: an unfavourable prognostic feature. Hum. Reprod., 10, 576579.[Abstract]
Verhulst, G., Vandersteen, N., Van Steirteghem, A.C. and Devroey, P. (1994) Bilateral salpingectomy does not compromise ovarian stimulation in an in-vitro fertilization/embryo transfer programme. Hum. Reprod., 9, 624628.[Abstract]
Wainer, R., Camus, E., Camier, B. et al. (1997) Does hydrosalpinx reduce the pregnancy rate after in vitro fertilization? Fertil. Steril., 68, 10221026.[ISI][Medline]
Zeyneloglu, H.B., Arici, A. and Olive, D.L. (1998) Adverse effects of hydrosalpinx on pregnancy erates after in vitro fertilzationembryo transfer. Fertil. Steril., 70, 492499.[ISI][Medline]