Investigation of the infertile couple

Should diagnostic laparoscopy be performed in the infertility work up programme in patients undergoing intrauterine insemination?

Sandra J. Tanahatoe, Peter G.A. Hompes and Cornelis B. Lambalk1

Department of Obstetrics, Gynaecology and Reproductive Medicine, ‘Vrije universiteit’ Medical Centre PO Box 7057, 1007 MB Amsterdam, The Netherlands 1 To whom correspondence should be addressed. e-mail: cb.lambalk@vumc.nl


    Abstract
 Top
 Abstract
 Introduction
 Laparascopic findings and...
 Adhesions
 Endometriosis
 Laparoscopy and IUI
 Conclusion
 References
 
Diagnostic laparoscopy is normally the standard procedure performed as the final test in the infertility work up before progressing to infertility treatment. Recently, there has been a growing tendency to bypass diagnostic laparoscopy after a normal hysterosalpingogram and instead to start direct infertility treatment [intrauterine insemination (IUI) or IVF] for indications such as unexplained infertility, male subfertility and cervical hostility. In our clinic, laparoscopy revealed abnormalities that resulted in changed treatment decisions in 25% of the patients who would normally have been scheduled for IUI if laparoscopy had not been performed. The changed treatments mainly concerned surgery for minimal/mild endometriosis and periadnexal adhesions, both performed during the diagnostic laparoscopy. Because the effect of such interventions on the success rate of IUI has never been described, it still remains unclear whether laparoscopy is usefully performed in these cases. Therefore, further prospective studies should be performed to assess whether delaying, or bypassing entirely, diagnostic laparoscopy is more cost effective and if laparoscopic interventions for intra-abdominal abnormalities are effective in terms of higher pregnancy rates after treatment with IUI.

Key words: diagnostic laparoscopy/endometriosis/hysterosalpingogram/infertility work up/intrauterine insemination


    Introduction
 Top
 Abstract
 Introduction
 Laparascopic findings and...
 Adhesions
 Endometriosis
 Laparoscopy and IUI
 Conclusion
 References
 
It is generally accepted that diagnostic laparoscopy is the gold standard in diagnosing tubal pathology and other intra-abdominal causes of infertility. Diagnostic laparoscopy, therefore, is frequently a standard procedure performed as the final test in the infertility work up in many clinics before the couple progresses to infertility treatment. This diagnostic scenario concerns couples eligible for intrauterine insemination (IUI), i.e. unexplained infertility, male subfertility and cervical hostility. Laparoscopy is not usually performed in patients who are already planned for IVF or ICSI since assessment of the tubes and other intra-abdominal pathology is of less concern except for the presence of hydrosalpinges which can be diagnosed by ultrasonography (Strandell et al., 1999Go).

In infertile couples laparoscopy reveals abnormal findings in 21–68 % of the cases after normal hysterosalpingogram (HSG) ( Wood, 1983Go; Henig et al., 1991Go; Opsahl et al., 1993Go; Cundiff et al., 1995Go; Belisle et al., 1996Go; al Badawi et al., 1999Go; Corson et al., 2000Go). This high prevalence of abnormal findings gives the impression that diagnostic laparoscopy might be of considerable value. However, the additional value of laparoscopy over a normal HSG does not only depend on the prevalence of disclosed pathology, but also on the contribution of diagnostic laparoscopy with regard to the decision of which treatment should be applied. Depending on the severity of the laparoscopic findings, the initial treatment decision, IUI, can be changed into direct laparoscopic correction of the abnormality followed by IUI, fertility-improving surgery by laparotomy or referral to IVF.

Recently, there has been a growing tendency for bypassing diagnostic laparoscopy in couples suspected of having unexplained infertility including a normal HSG as suggested in recent debates in this journal by Balasch and by Fatum et al. (Balasch, 2000Go; Fatum et al., 2002Go). Fatum et al. stated that couples with unexplained infertility should be treated by 3–6 cycles of combined gonadotrophins and IUI without preceding diagnostic laparoscopy, and if unsuccessful they should be switched directly to IVF. In their opinion, this approach would probably prove to be the most cost effective and efficient treatment protocol. If this was the case, then such treatment protocols should not only be applied in couples suspected of having unexplained infertility, but also in couples with other infertility factors requiring IUI such as mild male subfertility and cervical hostility.


    Laparascopic findings and consequences to treatment
 Top
 Abstract
 Introduction
 Laparascopic findings and...
 Adhesions
 Endometriosis
 Laparoscopy and IUI
 Conclusion
 References
 
To assess whether diagnostic laparoscopy is of value prior to IUI with respect to laparoscopic findings and subsequent treatment decisions, we retrospectively reviewed the surgery reports of 495 couples with medical grounds for IUI treatment, who underwent diagnostic laparoscopy as part of the infertility work up in the period 1995–1999 (Tanahatoe et al., 2003Go). The further standard infertility work up includes a basal body temperature chart, at least two semen samples, a post coital test, a late luteal endometrial biopsy and a serial HSG. The study included couples with unexplained infertility (no abnormality found during standard infertility work up), male subfertility (total motile sperm count of <20 x 106 progressively motile sperm and at least 1 x 106 progressively motile sperm after processing) and cervical hostility (repeated absence of progressively motile sperm or presence of non progressively motile sperm in a well-timed postcoital test) but with normal HSG results. In our hospital, all patients with medical grounds for IUI treatment undergo standard diagnostic laparoscopy at the end of the infertility work up. Overall, in 124 (25%) cases laparoscopy discovered abnormalities resulting in a changed treatment decision. There was no difference in the number of laparoscopy-changing treatment decisions between the various indication groups. The changed treatment decisions consisted of (i) direct laparoscopic surgery of minimal/mild endometriosis and periadnexal adhesions (103 cases, 20.8%), (ii) open surgery of double sided adhesions, moderate/severe endometriosis and double sided phimosis (13 cases, 2.6%), and (iii) referral to IVF due to severe periadnexal adhesions, hydrosalpinx and bilateral tubal occlusions (8 cases, 1.6%). These data suggest that diagnostic laparoscopy may be of considerable value even after a normal HSG, provided that the change of treatment is effective. However, whether this change of treatment is effective needs to be assessed.

Most findings concerned tubal adhesions and minimal or mild endometriosis. In these cases, laparoscopy was not only diagnostic but also therapeutic, because of laparoscopic removal of tubal adhesions and coagulation or laser evaporation of endometriosis. Therefore, the clinical value of ‘diagnostic’ laparoscopy in infertility work up is probably primarily determined by the effect of these laparoscopic interventions to pregnancy rates.


    Adhesions
 Top
 Abstract
 Introduction
 Laparascopic findings and...
 Adhesions
 Endometriosis
 Laparoscopy and IUI
 Conclusion
 References
 
In case of adhesions, there are no studies comparing fecundity rate after laparoscopic adhesiolysis with no treatment. Only one non-randomized study compared open adhesiolysis versus no treatment. In this study, 69 infertile women having periadnexal adhesions were treated by laparotomy and salpingo-ovariolysis and 78 were not treated. The cumulative pregnancy rate at 12 and 24 months follow-up was 32 and 45% in the treated group and 11 and 16% in the non-treatment group. Both differences in cumulative pregnancy rates between those groups were highly significant (Tulandi et al., 1990Go). This suggests that adhesiolysis might be associated with higher spontaneous pregnancy rates. However, whether laparoscopic adhesiolysis also enhances pregnancy rates after IUI has never been studied. Assuming that the pathophysiological mechanism of peritubal adhesions is based on impaired ovum pick up due to decreased tubal motility, it is likely that laparoscopic adhesiolysis might increase spontaneous pregnancy rates as well as pregnancy rates after IUI.

In our clinic, chlamydia antibody testing (CAT) is not used as a diagnostic test for the assessment of tubal pathology. Therefore we could not identify its additional value with respect to the identification of patients with relevant tubal pathology after normal HSG. The use of CAT is based on the assumption that a Chlamydia trachomatis infection in the past is the cause of tubal pathology. If CAT identifies a large enough proportion of patients with tubal pathology who would benefit from laparoscopy, then the selection process is enhanced and routine laparoscopy could be unnecessary. However, CAT fails to provide information about the extent of tubal pathology which is of significance to further treatment decisions. Furthermore, CAT is unable to detect other causes of tubal pathology nor the presence of endometriosis. Since in our clinic endometriosis is more frequently found at laparoscopy than tubal pathology, 96 (19%) cases of endometriosis and 28 (6%) cases of tubal pathology, the use of CAT would be of limited additional value after normal HSG.


    Endometriosis
 Top
 Abstract
 Introduction
 Laparascopic findings and...
 Adhesions
 Endometriosis
 Laparoscopy and IUI
 Conclusion
 References
 
Concerning treatment of endometriosis, there are two randomized controlled trials comparing laparoscopic ablation of minimal and mild endometriosis with no treatment (Marcoux et al., 1997Go; Parazzini, 1999Go). The study of Marcoux et al., in which 341 infertile patients with minimal and mild endometriosis were randomized to laparoscopic ablation or expectant management, showed that laparoscopic ablation of minimal and mild endometriosis doubled the cumulative fecundity rate after a follow up period of 36 weeks, 30.7% in the treatment group versus 17.7% in the no treatment group (Marcoux et al., 1997Go). A second Italian Study could neither reject nor confirm this observation. The 100 infertile patients with minimal and mild endometriosis were randomized to laparoscopic surgery or expectant management, but demonstrated no difference in fecundity rate of 24 versus 29% between the treatment and no treatment group respectively after a follow up period of 1 year (Parazzini, 1999Go). This could have been due to a lack of power as a result of the study’s small sample size. A recent review combined the results of these two randomized controlled trials into a meta-analysis (Olive and Pritts, 2002Go). This analysis showed that surgical treatment is favourable instead of expectant management (odds ratio for pregnancy 1.7; 95% confidence interval 1.1–2.5).

The reported prevalence of endometriosis found at laparoscopy in infertile women is 25–35%, whereas the prevalence in the general population is probably 3–10% (Strathy et al., 1982Go; Candiani et al., 1991Go; Olive and Schwartz, 1993Go; Guzick et al., 1994Go; Gruppo Italiano per lo Studio dell’Endometriosi, 1994Go). This high prevalence of endometriosis in infertile women has led to the assumption that there might be a causal relationship between infertility and the presence of endometriosis. In severe stages of endometriosis, the negative influence on fertility can be understood by the impaired tubal motility and ovum pick up function, but in less severe stages the pathophysiology cannot fully be explained by this mechanism and some hypothesize that immunological factors may play a role in endometriosis-associated infertility (Harada et al., 2001Go). Although the mechanism of infertility associated with minimal and mild endometriosis remains unclear, treatment with controlled ovarian stimulation and IUI enhances monthly pregnancy rates compared with that of expectant management in infertile patients with minimal to mild endometriosis (Deaton et al., 1990Go; Tummon et al., 1997Go). Future studies should determine if prior surgical treatment in these cases will increase pregnancy rates after IUI or whether directly proceeding to IUI would be equally or more beneficial.

It is likely that the laparoscopic surgical treatment will significantly enhance pregnancy rates of IUI, since surgical treatment increases natural pregnancy rates. Furthermore, pre-treatment with GnRH agonist of minimal and mild endometriosis before IUI enhances pregnancy rates as shown by a randomized study of Kim et al. (Kim et al., 1996Go). This study showed that long term pre-treatment with GnRH agonist prior to controlled ovarian stimulation and IUI resulted in a higher pregnancy rate per cycle in infertile patients with endometriosis compared with controlled ovarian stimulation without pre-treatment.


    Laparoscopy and IUI
 Top
 Abstract
 Introduction
 Laparascopic findings and...
 Adhesions
 Endometriosis
 Laparoscopy and IUI
 Conclusion
 References
 
In our view, the statements by Balasch and Fatum et al. that direct treatment with IUI as opposed to finalizing the infertility work up by diagnostic laparoscopy, is a more effective and efficient treatment protocol is not evidence based. However, we do not deny the possibility that leaving out the diagnostic laparoscopy prior to IUI can be more effective compared with performing diagnostic laparoscopy as a standard procedure. As already mentioned earlier, there is evidence that laparoscopic surgery of the most frequently found abnormalities leads to higher fecundity rates. Therefore, it seems quite logical that the same effect will also be seen in pregnancy rates after IUI; however, this has never been described. In theory, assuming that the change of treatment resulting from laparoscopic findings is effective to the outcome of IUI treatment, then 25% of the patients would have been incorrectly treated with IUI, if diagnostic laparoscopy had not been performed. If so, then leaving out the laparoscopy may lead to lower pregnancy rates or to a longer time to achieve pregnancy. Furthermore, if direct treatment with IVF after unsuccessful IUI is applied without assessing the presence of tubal pathology and other intra-abdominal causes of infertility, then this strategy could also lead to more patients ending up in IVF treatment, which is also an expensive procedure. It is also a matter of debate whether laparoscopic treatment should be followed by planned treatment with IUI or by expectant management for a certain period of time implying that the surgical intervention would enhance the chance of a spontaneous conception. So far there are no studies available that indicate the additional value of putting in or leaving out the diagnostic laparoscopy in the work up of couples with IUI indications. Consequently, it is also not known whether there is an influence of timing of laparoscopy (before IUI treatment or after a certain number of unsuccessful IUI cycles) with regard to laparoscopic yield and the reduction in number of laparoscopies.

In the previous debates, Balasch and Fatum et al. advocate proceeding directly to three to six cycles of IUI and if unsuccessful immediately switched to IVF instead of finalizing the infertility work up by diagnostic laparoscopy (Balasch, 2000Go; Fatum et al., 2002Go). In our opinion randomized studies assessing the cost effectiveness and timing of diagnostic laparoscopy prior to IUI should be performed before drawing these conclusions. Further studies should assess whether diagnostic laparoscopy is effective prior to IUI in terms of pregnancy rates and additional costs, and whether delayed performance of diagnostic laparoscopy after a few unsuccessful cycles of IUI instead of prior to IUI treatment is more effective.


    Conclusion
 Top
 Abstract
 Introduction
 Laparascopic findings and...
 Adhesions
 Endometriosis
 Laparoscopy and IUI
 Conclusion
 References
 
In conclusion, the role of diagnostic laparoscopy in patients undergoing IUI after normal HSG should be reconsidered. Therefore, further prospective studies should be performed to assess whether delaying or bypassing entirely diagnostic laparoscopy is more cost effective and if laparoscopic interventions of intra-abdominal abnormalities are effective in terms of higher pregnancy rates after treatment with IUI.


    References
 Top
 Abstract
 Introduction
 Laparascopic findings and...
 Adhesions
 Endometriosis
 Laparoscopy and IUI
 Conclusion
 References
 
al Badawi, I.A., Fluker, M.R. and Bebbington, M.W. (1999) Diagnostic laparoscopy in infertile women with normal hysterosalpingograms. J. Reprod. Med., 44, 953–957.[ISI][Medline]

Balasch, J. (2000) Investigation of the infertile couple: investigation of the infertile couple in the era of assisted reproductive technology: a time for reappraisal. Hum. Reprod., 15, 2251–2257.[Abstract/Free Full Text]

Belisle, S., Collins, J.A., Burrows, E.A. and Willan, A.R. (1996) The value of laparoscopy among infertile women with tubal patency. J. Soc. Obstet. Gynecol. Can., 18, 326–336.

Candiani, G.B., Vercellini, P., Fedele, L., Colombo, A. and Candiani, M. (1991) Mild endometriosis and infertility: a critical review of epidemiologic data, diagnostic pitfalls, and classification limits. Obstet. Gynecol. Surv., 46, 374–382.

Corson, S.L., Cheng, A. and Gutmann, J.N. (2000) Laparoscopy in the "normal" infertile patient: a question revisited. J. Am. Assoc. Gynecol. Laparosc., 7, 317–324.[ISI][Medline]

Cundiff, G., Carr, B.R. and Marshburn, P.B. (1995) Infertile couples with a normal hysterosalpingogram. Reproductive outcome and its relationship to clinical and laparoscopic findings. J. Reprod. Med., 40, 19–24.[ISI][Medline]

Deaton, J.L., Gibson, M., Blackmer, K.M., Nakajima, S.T., Badger, G.J. and Brumsted, J.R. (1990) A randomized, controlled trial of clomiphene citrate and intrauterine insemination in couples with unexplained infertility or surgically corrected endometriosis. Fertil. Steril., 54, 1083–1088.[ISI][Medline]

Fatum, M., Laufer, N. and Simon, A. (2002) Investigation of the infertile couple: should diagnostic laparoscopy be performed after normal hysterosalpingography in treating infertility suspected to be of unknown origin? Hum. Reprod., 17, 1–3.[Abstract/Free Full Text]

Gruppo Italiano per lo Studio dell’Endometriosi (1994) Prevalence and anatomical distribution of endometriosis in women with selected gynaecological conditions: results from a multicentric Italian study. Hum. Reprod., 9, 1158–1162.

Guzick, D.S., Grefenstette, I., Baffone, K., Berga, S.L., Krasnow, J.S., Stovall, D.W. and Naus, G.J. (1994) Infertility evaluation in fertile women: a model for assessing the efficacy of infertility testing. Hum. Reprod., 9, 2306–2310.[Abstract]

Harada, T., Iwabe, T. and Terakawa, N. (2001) Role of cytokines in endometriosis. Fertil. Steril., 76, 1–10.[CrossRef][ISI][Medline]

Henig,I., Prough, S.G., Cheatwood, M. and DeLong, E. (1991) Hysterosalpingography, laparoscopy and hysteroscopy in infertility. A comparative study. J. Reprod. Med., 36, 573–575.[ISI][Medline]

Kim, C.H., Cho, Y.K. and Mok, J.E. (1996) Simplified ultra-long protocol of gonadotrophin-releasing hormone agonist for ovulation induction with intrauterine insemination in patients with endometriosis. Hum. Reprod., 11, 398–402.[Abstract]

Marcoux, S., Maheux, R. and Berube, S. (1997) Laparoscopic surgery in infertile women with minimal or mild endometriosis. Canadian Collaborative Group on Endometriosis. N. Engl. J. Med., 337, 217–222.[Abstract/Free Full Text]

Olive, D.L. and Pritts, E.A. (2002) The treatment of endometriosis: a review of the evidence. Ann. N. Y. Acad. Sci., 955, 360–372.[Abstract/Free Full Text]

Olive, D.L. and Schwartz, L.B. (1993) Endometriosis. N. Engl. J. Med., 328, 1759–1769.[Free Full Text]

Opsahl, M.S., Miller, B. and Klein, T.A. (1993) The predictive value of hysterosalpingography for tubal and peritoneal infertility factors. Fertil. Steril., 60, 444–448.[ISI][Medline]

Parazzini, F. (1999) Ablation of lesions or no treatment in minimal-mild endometriosis in infertile women: a randomized trial. Hum. Reprod., 14, 1332–1334.[Abstract/Free Full Text]

Strandell, A., Lindhard, A., Waldenstrom, U., Thorburn, J., Janson, P.O. and Hamberger, L. (1999) Hydrosalpinx and IVF outcome: a prospective, randomized multicentre trial in Scandinavia on salpingectomy prior to IVF. Hum. Reprod., 14, 2762–2769.[Abstract/Free Full Text]

Strathy, J.H., Molgaard, C.A., Coulam, C.B. and Melton, L.J. 3rd. (1982) Endometriosis and infertility: a laparoscopic study of endometriosis among fertile and infertile women. Fertil. Steril., 38, 667–672.[ISI][Medline]

Tanahatoe, S.J., Hompes, P.G.A. and Lambalk, C.B. (2003) Accuarcy of diagnostic laparoscopy in the infertility work up before intrauterine insemination. Fertil. Steril., in press.

Tulandi, T., Collins, J.A., Burrows, E., Jarrell, J.F., McInnes, R.A., Wrixon, W. and Simpson, C.W. (1990) Treatment-dependent and treatment-independent pregnancy among women with periadnexal adhesions. Am. J. Obstet. Gynecol., 162, 354–357.[ISI][Medline]

Tummon, I.S., Asher, L.J., Martin, J.S. and Tulandi, T. (1997) Randomized controlled trial of superovulation and insemination for infertility associated with minimal or mild endometriosis. Fertil. Steril., 68, 8–12.[CrossRef][ISI][Medline]

Wood, G.P. (1983) Laparoscopic examination of the normal infertile woman. Obstet. Gynecol., 62, 642–643.[Abstract]