Written by 29 June, 2015 12:37 am Category Academic Articles Archives, Archives Articles, Invited Articles.

mandakini_parihar

Dr Mandakini Parihar

Navi Mumbai
Past Chairperson, Family Welfare Committee, FOGSI
Past President, NMOGS
Email : mandakiniparihar@gmail.com

Introduction

When the first IVF baby, Louise Brown, was born in 1978, in- vitro Fertilization (IVF) was still an experimental technique. She was born in a natural cycle IVF of a woman who had bilateral tubal block making IVF the only option for having a child. Prior to this, there was no hope for patients with tubal factor infertility of ever achieving their own child. The results with tubal reconstructive surgery were unsatisfactory and had a high incidence of ectopic pregnancies. The last 3 decades has seen astounding progress in the field of ART.  Today, thanks to advances in modern medicine, infertility treatment has become almost a routine procedure. With the advent of better quality ovulation induction drugs and increasing availability and accessibility of Assisted Reproductive Technologies (ART), there have been more than one and a half million babies born with the help of ART. The happiness this has brought to families all over the world is incalculable. Today thanks to ART, tubal disease and tubal factor infertility is easily overcome. The aim of this review is to highlight the importance of identifying hydrosalpinges and its association with reduced fertility outcome using assisted reproductive technologies. The ultimate aim in ART is to improve the take home baby rate and dealing with hydrosalpinx prior to ART is important. The literature review is by the MEDLINE (1966 to November 2008), the Cochrane Library databases, and journal search, for the different options available for the same, and highlights the current modes of treatment.

Hydrosalpinx and ART Outcome

The accepted theory today is that the hydrosalpinx fluid plays a causative role in the reduced pregnancy rate with ART. It is well known that the success of ART for patients with tubal disease with hydrosalpinx is reduced by half compared with patients without hydrosalpinx. During the past decade, the influence of the presence of hydrosalpinx on IVF success rates has been an issue of debate and research. Many retrospective studies have shown an impaired outcome of IVF in the presence of hydrosalpinx and the meta-analyses has demonstrated that the probability of achieving a pregnancy in the presence of hydrosalpinx is reduced by half and even if pregnancy is achieved the incidence of spontaneous abortion is doubled. 1, 2, 3 Hence any surgical intervention blocking the communication between the tube and the uterus would remove the leakage of the hydrosalpinx fluid and restore pregnancy rates. Ideal would be removal of a hydrosalpinx by laparoscopic salpingectomy to improve pregnancy rates. 4, 5, 6 However in some cases this is not feasible due to dense pelvic adhesions making access difficult. In such cases it is recommended that even de-linking the tube from the uterus would help in improving the ART outcome.7

The results of prospective randomized studies on salpingectomy in patients with hydrosalpinges are now forthcoming and greatly assist the debate on whether or not IVF will benefit from salpingectomy.  In the study by Strandell et al 5 the diagnosis of hydrosalpinx was made by a previous hysterosalpingography (HSG) or diagnostic laparoscopy, at which time reconstructive surgery had been rejected. The patients were divided into groups, IVF after Salpingectomy and IVF cycle without removing the hydrosalpinges. The authors reported on the outcome of the first IVF cycle and concluded that salpingectomy can be recommended for patients with hydrosalpinges, especially those enlarged enough to be visible on ultrasound and in particular for those affected bilaterally.5 These studies have resulted in the Cochrane library recommendation of Salpingectomy for hydrosalpinges.8.9 While there is clinical evidence supporting the causative role of the fluid itself, there is a lack of knowledge as to how the fluid exerts its negative effects. It is generally believed that the fluid holds a key position in impairing implantation potential.

Sonographically visible Hydrosalpinx – is it a new clinical entity?

The hydrosalpinx that is visible on transvaginal sonography is proposed as a new clinical entity by de Wit et al in 1998 10, although the diagnostic and pathophysiological features of this subgroup are poorly defined. However, transvaginal ultrasound prior to HSG /laparoscopy identifies 34% of the patients with a hydrosalpinx. This means that many of hydrosalpinges present may be missed if one relies on ultrasound alone. 11 It also said, those patients with ultrasonographically visible hydrosalpinx had a poorer outcome if not removed. These also tended to enlarge more during ovarian stimulation. The mechanism of enlargement of hydrosalpinges during ovarian stimulation is unknown.12 In experimental conditions, distal occlusion results in a very slow distension of the mechanically induced hydrosalpinx, taking >12 weeks, while the combination of a distal and proximal block results in a significant distension within 2 weeks. It can be speculated that uterine junctional zone contractions play a fundamental role in the movements of both uterine and tubal fluids. 13,14 The altered fluid movements caused by junctional zone contractions during ovarian stimulation in the presence of a thin-walled hydrosalpinx could be responsible for an adverse effect, e.g. by acting as a mechanical barrier to embryo implantation 12,14,15,16

Is there a role of salpingoscopy in selecting cases for tubal surgery?

The question to address is how the patients that are most suitable for functional surgery can be selected?

The studies of Dechaud et al, 17, Strandell et al18 indicated that the removal of thick-walled hydrosalpinges as well as the ones which are sonographically visible. Also, always remember that the sonographically visible hydrosalpinx is likely to be a thin-walled hydrosalpinx. Thick-walled hydrosalpinges with a mean diameter of 1–2 cm, a wall thickness of 2–10 mm and a frequently obliterated lumen are not likely to distend during ovarian stimulation and are, or become, visible at ultrasound. 19, 20

Vasquez et al, 21. 22 in a prospective study concluded that the mucosal adhesions are the most important factor in determining fertility outcome. Their study with thin-walled hydrosalpinges showed that in the presence of normal or flattened mucosa but no mucosal adhesions there was a 58% pregnancy rate and a low risk of tubal pregnancy. However, thin-walled hydrosalpinges with mucosal adhesions had a high rate of tubal pregnancy, and thick-walled hydrosalpinges with fibrosis of the wall are incompatible with a normal pregnancy. 20,21,22

However, tubal endoscopy has not yet gained widespread clinical acceptance23. Several studies on hydrosalpinges have shown that when salpingoscopy can exclude the presence of mucosal adhesions it thereby identifies the subgroup with a >50% intra-uterine and a <5% tubal pregnancy rate following reconstructive surgery 24,25,26,27,28,29. Functional surgery is, therefore, indicated in patients with thin-walled hydrosalpinges with minimal or no mucosal adhesions. It is, however, unclear whether these patients represent the same subgroup as the patients with sonographically visible hydrosalpinx.

Hydrosalpinx Fluid

Many retrospective studies have shown that hydrosalpinx is associated with poor IVF outcome. 3,4,15,30,31,32 Recent data suggest that patients with hydrosalpinx constitute a heterogeneous population with potentially different outcomes. 20,32,33 It would be valuable to identify a subset of patients who would benefit most from elective salpingectomy. The area of major concern is whether or not there is an impact on ovarian function. Many studies have reported that there is no effect on ovarian repsonse3,4,20,34, some mention equivocal response 32,33,35,36 and some show that there is definite decrease in ovarian response due to affection of the blood supply during salpingectomy37 The role of hydrosalpinx aspiration at oocyte retrieval still awaits evaluation in a well designed prospective trial. 38,39,40

Constituents of Hydrosalpinx fluid15

Epidermal growth factor (EGF)
Tumor necrosis factor- (TNF-)
Cytokines
Integrin β
Growth factors

Why is there reduced fertility with hydrosalpinx?

The answer to this will be evident only when we understand the possible mechanisms causing embryo-toxicity. As yet there are no clearly defined reasons. However there have been a variety of cause-effect postulations by different authors. The hydrosalpinx fluid is suggested to act on two different target systems: directly on the transferred embryos or on the endometrium and its receptivity for implantation, or both. There are many theories postulated but none actually proven. We mention them all in brief here as it is not possible to discuss them all at length. 3,4,6,7,9,13,14,15,31,32,33

In spite of so much research and so many theories, there is no single explanation over period of decades. The evidence clearly points to an adverse effect in the presence of hydrosalpinx and these are due to:

  1. Mechanical effects
  2. Embryo and gametotoxicity
  3. Alterations in endometrial receptivity markers resulting in poor implantation
  4. Direct effect on endometrium, leading to intrauterine fluid formation.

Questions regarding the mechanism of toxicity of hydrosalpinx fluid that are still unanswered

  1. Are there any Embryotoxic properties of hydrosalpinx fluid –the doubt raised is – Is there a common toxin or are there individual variations?
  2. Is hydrosalpinx fluid toxic – there are no pathogenic micro-organisms but there are elevated concentrations of endotoxin in the fluids.
  3. Oxidative stress ? Oxidative stress has been defined as an elevation in the steady-state concentration of various reactive oxygen species on a cellular level and has been suggested to be of importance in hydrosalpinx cases. 41This hypothesis needs further evaluation.
  4. Do transferred embryos starve in the presence of hydrosalpinx fluid? Glucose rather than pyruvate is the energy substrate needed during the development of blastocyst. Studies on embryo development in hydrosalpinx fluid suggest a lack of nutrients, which explains the impaired development to blastocysts. Is this the possible explanation for the reduced implantation rates? 31,32,42,43,44
  5. Does it affect the endometrial receptivity?
    There is evidence to suggest that the link to implantation is the cross-talk between the embryo and endometrium. The dialogue between the embryo and endometrium is mediated by the secretion and expression of certain cytokines and other substances during the implantation window. This balance may be disturbed in the presence of hydrosalpinx fluid. 1,31,45,46,47
  6. Are embryos simply washed out?
    The leakage of hydrosalpingeal fluid through the uterine cavity resulting in disposal of embryos has been suggested as a mechanism by several authors 13,14,15,30,31,48
  7. Does hydrosalpinx fluid cause increased endometrial peristalsis?
    Ijland and co-workers investigated the relationship between endometrial wave-like activity and fecundability in spontaneous cycles Conception cycles showed the slowest wave production. There may also be a role of reflux of the fluid from the tube due to pressure gradient. 16,20,30,32

Conclusions

Hydrosalpinx is a common cause of female infertility. Lower implantation and pregnancy rates have been reported in women with hydrosalpinges. How hydrosalpinx exerts its negative effect on the implantation process is not clearly understood. It is intriguing that there is an effective treatment (salpingectomy) for its management but we don’t know how and why it works. It is not only of academic interest to know, it is also of clinical value.  In women who are identified to have hydrosalpinges during controlled ovarian stimulation during IVF, aspiration of hydrosalpinges during oocyte collection may be effective in improving pregnancy rates. Laparoscopic surgery has a place in the diagnosis and management of hydrosalpinx. Further randomized trials are required to assess other surgical treatment options for hydrosalpinx, such as laparoscopic salpingostomy, laparoscopic or hysteroscopic tubal occlusion, and drainage of hydrosalpinx before or during oocyte retrieval.49,50

References

  1. Strandell, A. (2000) The influence of hydrosalpinx on in-vitro fertilisation and embryo transfer—a review. Hum. Reprod. Update, 6, 387–395
  2. Puttemans P , Campo R, Gordts R, Brosens I. (2000) Hydrosalpinx and ART. Human Reproduction, Vol. 15, No. 7, 1427-1430, July 2000
  3. Camus, E., Poncelet, C., Goffinet, F. et al. (1999) Pregnancy rates after in-vitro fertilization in cases of tubal infertility with and without hydrosalpinx: a meta-analysis of published comparative studies. Hum. Reprod., 14, 1243–1249.
  4. Dar, P., Sachs, G.S., Strassburger, D. et al. (2000) Ovarian function before and after salpingectomy in artificial reproductive technology patients. Hum. Reprod., 15, 142–144
  5. Strandell, A., Lindhard, A., Waldenström, U. et al. (1999) Hydrosalpinx and IVF outcome: a prospective, randomized multicentre trial in Scandinavia on salpingectomy prior to IVF. Hum. Reprod., 14, 2762–2769.
  6. Strandell, A., Sjogren, A., Bentin-Ley, U. et al. (1998) Hydrosalpinx fluid does not adversely affect the normal development of human embryos and implantation in vitro. Hum. Reprod., 13, 2921–2925.
  7. Chin-Der Chen, Jehn-Hsiahn Yang, Ko-Chen Lin, Kuang-Han Chao, Hong-Nerng Ho and Yu-Shih Yang. (2002). The significance of cytokines, chemical composition, and murine embryo development in hydrosalpinx fluid for predicting the IVF outcome in women with hydrosalpinx. Human Reproduction, Vol. 17, No. 1, 128-133, January 2002
  8. Johnson NP,  Mak W, Sowter MC.  Laparoscopic salpingectomy for women with hydrosalpinges enhances the success of IVF: a Cochrane review. Hum Reprod. 2002 Mar;17(3):543-8
  9. Cochrane Database Syst Rev. 2004;(3):CD002125. Surgical treatment for tubal disease in women due to undergo in vitro fertilization.[Cochrane Database Syst Rev. 2004]
  10. 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, 1696–1701
  11. Lass, A. (1999) What effect does a hydrosalpinx have on assisted reproduction? What is the preferred treatment for hydrosalpinges? The ovary’s perspective. Hum. Reprod., 14, 1674–1677
  12. Strandell, A., Lindhard, A., Waldenstrom, U. and Thorburn, J. (2001) Hydrosalpinx and IVF outcome: cumulative results in a randomized controlled trial. Hum. Reprod., 16, 2403–2410
  13. Levi, A.J., Segars, J.H., Miller, B.T. and Leondires, M.P. (2001) Endometrial cavity fluid is associated with poor ovarian response and increased cancellation rates in ART cycles. Hum. Reprod., 16, 2610–2615
  14. Eytan, O., Azem, F., Gull, I., Wolman, I., Elad, D. and Jaffa, A.J. (2001) The mechanism of hydrosalpinx in embryo implantation. Hum. Reprod., 16, 2662–2667.
  15. Chen, C.D., Yang, J.H., Lin, K.C., Chao, K.H., Ho, H.N. and Yang, Y.S. (2002) The significance of cytokines, chemical composition, and murine embryo development in hydrosalpinx fluid for predicting the in-vitro fertilization outcome in women with hydrosalpinx. Hum. Reprod., 17, 128–133
  16. IJland, M.M., Hoogland, H.J., Dunselman, G.A.J. et al. (1999) Endometrial wave direction switch and the outcome of in vitro fertilization. Fertil. Steril., 71, 476–481.
  17. Dechaud, H., Daurès, J.P., Arnal, F. et al. (1998a) Does previous salpingectomy improve implantation and pregnancy rates in patients with severe tubal factor infertility who are undergoing in vitro fertilization? A prospective randomized pilot study. Fertil. Steril., 69, 1020–1025
  18. 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, 2079–2081
  19. Strandell, A., Waldenström, U., Nilsson, L. and Hamberger, L. (1994) Hydrosalpinx reduces in-vitro fertilization/embryo transfer pregnancy rates. Hum. Reprod., 9, 861–863
  20. Sharara, F.I. (1999) What effect does hydrosalpinx have on assisted reproduction? The role of hydrosalpinx in IVF: simply mechanical? Hum. Reprod., 14, 577–578
  21. Vasquez, G., Boeckx, W. and Brosens, I. (1995a) Prospective study of tubal mucosal lesions and fertility in hydrosalpinges. Hum. Reprod., 10, 1075–1078.
  22. Vasquez, G., Boeckx, W. and Brosens, I. (1995b) No correlation between peritubal and mucosal adhesions in hydrosalpinges. Fertil. Steril., 64, 1032–1033.
  23. Puttemans, P.J., De Bruyne, F. and Heylen, S.M. (1998) A decade of salpingoscopy. Eur. J. Obstet. Gynecol. Reprod. Biol., 81, 197–206.
  24. Dechaud, H., Daurès, J.P. and Hedon, B. (1998b) Prospective evaluation of falloposcopy. Hum. Reprod., 13, 1815–1818.
  25. Marana, R., Muzii, L., Rizzi, M. et al. (1995) Prognostic role of laparoscopic salpingoscopy of the only remaining tube after contralateral ectopic pregnancy. Fertil. Steril., 63, 303–306.
  26. Marana, R., Catalano, G.F., Muzii, L. et al. (1999) The prognostic role of salpingoscopy in laparoscopic tubal surgery. Hum. Reprod., 14, 2991–2995
  27. Watrelot, A., Dreyfus, J.M. and Andine, J.P. (1999) Evaluation of the performance of fertiloscopy in 160 consecutive infertile patients with no obvious pathology. Hum. Reprod., 14, 707–711
  28. Surrey, E.S. (1999) Microendoscopy of the human fallopian tube. J. Am. Assoc. Gynecol. Laparosc., 6, 383–389
  29. De Bruyne, F., Puttemans, P., Boeckx, W. and Brosens, I. (1989) The clinical value of salpingoscopy in tubal infertility. Fertil. Steril., 51, 339–340
  30. Andersen, A.N., Lindhard, A., Loft, A. et al. (1996) The infertile patient with hydrosalpinges – IVF with or without salpingectomy? Hum. Reprod., 11, 2081–2084
  31. Zeyneloglu, H.B., Arici, A. and Olive, D.L. (1998) Adverse effects of hydrosalpinx on pregnancy rates after in vitro fertilization–embryo transfer. Fertil. Steril., 70, 492–499
  32. A Strandell and A Lindhard. Why does hydrosalpinx reduce fertility? The importance of hydrosalpinx fluid. Human Reproduction, Vol. 17, No. 5, 1141-1145, May 2002
  33. Puttemans P, Campo R, Gordts S and Brosens I. Hydrosalpinx and ART – surgery or ART? Human Reproduction, Vol. 15, No. 7, 1427-1430, July 2000
  34. Bontis JN, Laparoscopic management of hydrosalpinx. Ann N Y Acad Sci. 2006 Dec;1092:199-210.
  35. Granot, I., Dekel, N., Segal, I. et al. (1998) Is hydrosalpinx fluid cytotoxic? Hum. Reprod., 13, 1620–1624
  36. Barmat, L.I., Nasti, K., Yang, X. et al. (1999) Are cytokines and growth factors responsible for the detrimental effects of hydrosalpingeal fluid on pregnancy rates after in vitro fertilization-embryo transfer? Fertil. Steril., 72, 1110–1112
  37. Dechaud, H. and Hedon, B. (2000). What effect does hydrosalpinx have on assisted reproduction? The role of salpingectomy remains controversial. Hum. Reprod., 15, 234–235
  38. Hammadieh N, Coomarasamy A. Ultrasound-guided hydrosalpinx aspiration during oocyte collection improves pregnancy outcome in IVF: a randomized controlled trial. Hum Reprod. 2008 May;23(5):1113-7. Epub 2008
  39. Sharara FI. Ultrasound-guided hydrosalpinx aspiration during oocyte collection improves outcome in IVF. Hum Reprod. 2008 Dec 19. [Epub ahead of print]
  40. 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, 736–739
  41. Bedaiwy, M.A., Goldberg, J.M., Singh, M., Sharma, R., Wang, X., Nelson, D. and Falcone, T. (2002) Relationship between oxidative stress and embryotoxicity of hydrosalpingeal fluid. Hum. Reprod., 17, 601–604.
  42. de Vantéry Arrighi, C., Lucas, H., El-Mowafi, D., Campana, A. and Chardonnens, D. (2001) Effects of human hydrosalpinx fluid on in-vitro murine fertilization. Hum. Reprod, 16, 676–682
  43. Tay, J.I., Rutherford, A.J., Killick, S.R., Maguiness, S.D., Partridge, R.J. and Leese, H.J. (1997) Human tubal fluid: production, nutrient composition and response to adrenergic agents. Hum. Reprod., 12, 2451–2456.
  44. Dickens, C.J., Maguiness, S.D., Comer, M.T., Palmer, A., Rutherford, A.J. and Leese, H.J. (1995) Human tubal fluid: formation and composition during vascular perfusion of the Fallopian tube. Hum. Reprod., 10, 505–508
  45. Simón, C., Gimeno, M.J., Mercader, A., O’Connor, J.E., Remohi, J., Polan, M.L. and Pellicer, A. (1997) Embryonic regulation of integrins beta 3, alpha 4, and alpha 1 in human endometrial epithelial cells in vitro. J. Clin. Endocrinol. Metab., 82, 2607–2616
  46. Sawin, S.W, Loret de Mola, J.R., Monzon-Bordonaba, F., Wang, C.L. and Feinberg, R.F. (1997) Hydrosalpinx fluid enhances human trophoblast viability and function in vitro: implications for embryonic implantation in assisted reproduction. Fertil. Steril., 68, 65–71
  47. Meyer, W.R., Castelbaum, A.J., Somkuti, S., Sagoskin, A.W., Doyle, M., Harris, J.E. and Lessey, B.A. (1997) Hydrosalpinges adversely affect markers of endometrial receptivity. Hum. Reprod., 12, 1393–1398
  48. Mansour, R.T., Aboulghar, M.A., Serrour, G.I. and Riad, R. (1991) Fluid accumulation of the uterine cavity before embryo transfer: a possible hindrance for implantation. J. In vitro Fert. Embryo Transf.
  49. Kontoravdis A, Makrakis E, Pantos K, Botsis D, Deligeoroglou E, Creatsas G. Proximal tubal occlusion and salpingectomy result in similar improvement in IVF outcome in patients with hydrosalpinx. Fertil Steril.2006 Dec 86 (6):1642-9
  50. Ozmen B, Diedrich K, Al-Hasani S. Hydrosalpinx and IVF: assessment of treatments implemented prior to IVF. Reprod Biomed Online. 2007, Feb; 14(2):235-41