1 Department of Obstetrics and Gynaecology, Sahlgrenska University Hospital, S-413 45 Göteborg, Sweden, 2 The Fertility Clinic, Copenhagen University Hospital, Rigshospitalet, Blegdamsvej 9, DK-2100 Copenhagen, Denmark and 3 IVF Center Falun, Department of Obstetrics and Gynaecology, Falu Hospital, S-791 82 Falun, Sweden
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Abstract |
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Key words: hydrosalpinx/in-vitro fertilization/randomized controlled trial/pregnancy rates/salpingectomy
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Introduction |
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Different theories trying to explain the mechanism behind the association between the presence of hydrosalpinges and poor pregnancy outcome have been presented. The main explanations have implied that the leakage of fluid into the uterine cavity renders the endometrium a hostile environment to implantation and could also affect embryo development. Consequently, surgical removal of the diseased tubes would improve pregnancy rates. Without any prospective study testing the effects of surgical intervention and based on only retrospective data, clinical practice changed over time and several IVF programmes have offered their hydrosalpinx patients a salpingectomy prior to IVF treatment. However, a retrospective design does not offer a causal inference and a major intervention like salpingectomy should be investigated in a prospective randomized trial before it is generally applied.
The present prospective study was initiated after publishing our first retrospective data (Strandell et al., 1994), demonstrating a 50% reduction in clinical pregnancy rate in the presence of hydrosalpinges compared with other tubal infertility (13 versus 26%). It was postulated that any intervention causing a disruption of fluid leakage would improve IVF results.
The present study was designed within Scandinavia as a multicentre randomized controlled trial with salpingectomy as the main intervention. The aim was to test the hypothesis that removal of hydrosalpinx before undergoing IVF treatment would improve pregnancy rates.
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Materials and methods |
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Study criteria
In the study, hydrosalpinx was defined as a distally occluded tube which was pathologically dilated or became pathologically dilated when patency was tested by hysterosalpingography (HSG) or laparoscopy.
Patient inclusion criteria were presence of uni- or bilateral hydrosalpinges, suitability for IVF treatment, laparoscopic accessibility and age <39 years at the time of randomization. Exclusion criteria were previous IVF treatments and presence of uterine fibroids needing surgical removal before IVF. A concomitant male factor that required intracytoplasmic sperm injection (ICSI) was accepted if the centre was running an established ICSI programme with pregnancy rates equivalent to those of their conventional IVF programme.
Study design
Patient recruitment started in 1994. After informed consent was obtained from the patients fulfilling the criteria of the study, randomization was carried out at each centre by using sealed opaque envelopes in blocks of 1030 depending on the estimated recruitment ability.
The diagnosis of hydrosalpinx was made by the physician who referred the patient to IVF, and the time awaiting treatment varied between 1 month and 2 years.
Patients in the intervention group underwent a laparoscopic uni- or bilateral salpingectomy, depending on whether one or two hydrosalpinges were present. In cases causing technical difficulties intra-operatively, due to the presence of extensive adhesions, a proximal ligation and a distal fenestration were recommended. A period of minimum 2 months between surgery and oocyte aspiration was advised. The rationale for the time span was to give the endometrium a wash-out period after the potential negative influence of hydrosalpingeal fluid of at least one ordinary menstrual cycle before starting down-regulation with gonadotrophin releasing hormone analogue (GnRHa). Patients in the non-intervention group started their IVF treatment according to routine practice at the individual IVF centres. The number of tubes with hydrosalpinx formation per patient was noted. Ultrasound data on the visibility of hydrosalpinx before and during stimulation were recorded.
IVF performance
The IVF treatment was carried out according to the routines of each centre, although the policies were very similar including a long protocol down-regulation with a GnRHa administered nasally or s.c., stimulation with either human menopausal gonadotrophin (HMG), highly purified or recombinant follicle stimulating hormone (FSH) and transvaginal ultrasound-guided oocyte retrieval. A maximum of two embryos were routinely transferred, but occasionally three embryos were transferred. In order to identify transfers with impaired quality embryos, a two-grade embryo score was used for assessment of embryo quality, where grade 1 included good quality embryos with <20% fragmentation of the blastomeres. Doses, administration and duration of all medications were noted, as well as the number of retrieved, fertilized and cleaved oocytes, sperm quality, fertilization method and any cancellation of cycles.
Group allocation
If a cycle was disrupted during stimulation or after oocyte retrieval, the first subsequent cycle ending in a transfer was included in the analysis. If a patient did not undergo a transfer on a cumulative basis, her first disrupted cycle reaching to the phase of oocyte aspiration was included. If she did not reach oocyte aspiration, her disrupted stimulation cycle was included. Patients who were randomized but never started a cycle were included and analysed on an intention-to-treat basis. Patients who were randomized to surgery, but subsequently were reluctant to undergo the procedure, were included and analysed both according to an intention-to-treat and according to the actual treatment group. If the patient under the same circumstances again changed her mind after the first cycle and underwent salpingectomy, the subsequent transfer cycle in which the randomization group and the actual treatment group were the same, was used for first-cycle analysis.
If, at the time of laparoscopy, the diagnosis of hydrosalpinx was found to be incorrect, the allocation to the intervention group was still kept, regardless of the surgical procedure performed. Patients were not excluded if they had an accidental aspiration of hydrosalpingeal fluid at the time of oocyte retrieval (n = 1).
Pregnancy definitions
Any positive pregnancy test was recorded, but unless the pregnancy was verified by ultrasound as a gestational sac, it was considered to be biochemical and not included. Only clinical pregnancy rates were used for further analysis. Implantation rate was calculated as the number of gestational sacs visible on ultrasound divided by the number of embryos transferred. An ectopic implantation was considered as one implanted embryo. The outcome of each pregnancy was noted: spontaneous abortion, childbirth (or ongoing pregnancy >20 weeks) or ectopic pregnancy. Primary endpoint was clinical pregnancy rate calculated per patient, based on her first transfer cycle. Secondary endpoints were implantation and delivery rates.
Statistical methods
The comparative analyses included only one cycle per patient and were completed both on an intention-to-treat basis and on treatment basis. For comparison between groups MannWhitney U-test was used. Fisher's exact test was used for comparison of dichotomous variables between groups. MantelHaenszel's 2-test was used for test of linear association in ordered contingency tables (Mantel and Haenszel, 1959
). Spearman's rank correlation coefficient was used to analyse correlation between data. Two-tailed statistical tests were conducted at the 5% level of significance.
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Results |
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The time interval between surgery and transfer varied between 50 and 577 days (mean 178).
Reproductive outcome
Implantation and pregnancy rates are presented in Table III (analyses based on intention-to-treat) and Table IV
(analyses based on actual treatment given). A statistically significant difference was found between the delivery rates in the on-treatment based analysis, including all patients. Among patients starting IVF, the delivery rates were 28.7% versus 16.7 (P = 0.059), demonstrating a 72% improvement by salpingectomy.
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Within the non-intervention group, clinical pregnancy rate was 21.4% if the hydrosalpinx was visible on ultrasound before ovarian stimulation was initiated, but reached 34.4% if it was non-visible (not significant, P = 0.29).
Subgroups of patients with the predictive variables were analysed and results of transfer cycles are presented in Table V. Within the subgroup of patients with bilateral hydrosalpinges at inclusion, implantation rate was found to be significantly higher in the group who underwent surgical intervention (P = 0.038) and pregnancy and delivery rates were doubled (not significant, P = 0.0570.07). Patients with ultrasound-visible hydrosalpinges expressed a similar effect of salpingectomy with an 2.4-fold increase of the delivery rate (P = 0.038) whereas the combined subgroup of patients with bilateral ultrasound visible hydrosalpinges increased its delivery rate 3.5-fold (P = 0.019).
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Discussion |
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The mechanism that causes the implantation failure is not yet fully understood. The main theories have focused on the embryotoxicity of the fluid or the mechanical leakage of the fluid into the uterine cavity, causing endometrial alterations hostile to embryo implantation and development or simply a mechanical washout of embryos. Although several mouse studies have demonstrated an impaired blastocyst development in the presence of hydrosalpinx fluid (Mukherjee et al., 1996; Beyler et al., 1997
; Rawe et al., 1997
; Sachdev et al., 1997
), studies on human embryos have not shown any embryonic toxicity (Granot et al., 1998
; Strandell et al., 1998
). Studies on mouse (Murray et al., 1997
; Koong et al., 1998
) and human embryos (Strandell et al., 1998
) reflecting impairment of embryo development detectable only in 100% hydrosalpinx fluid have concluded that there is no potent embryotoxic factor present, but merely a deficiency of essential nutrients causing the impaired development. This theory is further supported by Murray et al. who demonstrated that the impaired blastocyst developmental rate in 100% hydrosalpinx fluid was counteracted by the addition of energy sources (Murray et al., 1998
).
The theory of the negatively affected endometrium is supported by Cohen et al. where hydrosalpinx was studied in patients in an oocyte donor programme and significantly lower embryo implantation rates were found in hydrosalpinx patients than in normal controls (Cohen et al., 1999). The endometrial receptivity has been studied (Meyer et al., 1996), where integrin expression was examined in endometrial biopsies. Integrins are adhesion molecules that have been identified as markers of uterine receptivity, and women with hydrosalpinges expressed significantly lower amounts of integrins than those without hydrosalpinges. After surgical correction, a return to normal integrin values was demonstrated. Still, there is a lack of knowledge as to what substance or agent or physiological event actually causes the endometrial changes. A strict mechanical explanation has been discussed (Sharara, 1999
), suggesting that embryonal apposition to the endometrial surface will be compromised when a fluid interface exists.
Different treatment options with the purpose of disrupting the connection of hydrosalpinx fluid into the uterus have been suggested. Transvaginal aspiration at the time of oocyte retrieval has been described in two retrospective trials (Sowter et al., 1997; Van Voorhis et al., 1998
), of which only the latter showed a positive effect. Both studies were of small size, and therefore we believe no definitive conclusions can be drawn.
Several retrospective studies have compared the outcome of IVF in patients after salpingectomy with patients carrying hydrosalpinges (Kassabji et al., 1994; Vandromme et al., 1995
; Shelton et al., 1996
; Meyer et al., 1997
) and they all demonstrate a positive effect on pregnancy rates after salpingectomy, although the retrospective design carries an inherent risk of methodological and statistical error. Other laparoscopic procedures, including proximal ligation, neosalpingostomy and salpingectomy, have also been studied retrospectively (Murray et al., 1998
). Although the surgical procedures taken together seem to be beneficial, the numbers are too small to draw any conclusions concerning the separate procedures. In a casecontrol study analysing the effect of bilateral salpingectomy in hydrosalpinx patients as a single procedure, a positive impact on pregnancy rates was shown (Ejdrup Bredkjaer et al., 1999
).
The only hitherto prospective randomized trial, besides the current study, examining the effect of any surgical intervention is a pilot study which indicated a positive effect of salpingectomy on implantation rates but without any statistical significance (Déchaud et al., 1998). Due to the small size of the study, the power to detect any true difference between the groups was only 11% and the authors ask for future studies that could form the base for a future meta-analysis.
Another alternative to answer the question whether salpingectomy is of clinical benefit, is to conduct a multicentre trial as in the present study. However, a difficulty is that the results of IVF have improved over time and the original sample size calculation based on retrospective data from the early 1990s, gave a smaller sample size than a calculation based on present results. Consequently, the sample size requirements tend to increase over time which results in a progressively smaller likelihood of reaching statistical significance. The present study is the largest of its kind to date. A 72% (relative risk = 1.72) improvement of delivery rates in patients starting IVF after salpingectomy clearly indicates a benefit from surgical intervention. Patients with bilateral hydrosalpinges showed a significant increase in implantation rate after salpingectomy and delivery rates were more than doubled (relative risk = 2.27). The calculated confidence intervals clearly show that the results are in the positive direction only. These results agree well with a previous retrospective study, which demonstrated significantly lower implantation and pregnancy rates in patients with bilateral hydrosalpinges as compared with unilateral (Wainer et al., 1997).
In the debate about hydrosalpinx most authors have advocated prophylactic salpingectomy, with one exception (Puttemans and Brosens, 1996) stating that salpingoscopy is mandatory to avoid unnecessary removal of Fallopian tubes, which would leave the patient irreversibly compromised. In the present study, the diagnosis of hydrosalpinx had been made by a previous HSG or diagnostic laparoscopy, at which tubal surgery had already been rejected. Obviously, the judgement of suitability for tubal surgery differs between centres, and, as a referral centre, we found tubes that were more suitable for reconstruction than removal.
Another aspect concerning salpingectomy is the risk of ovarian function being disturbed. Retrospective studies using patients with previous salpingectomy do not show any differences in ovulation stimulation variables (Kassabji et al., 1994; Vandromme et al., 1995
; Shelton et al., 1996
; Murray et al., 1998
; Ejdrup Bredkjaer et al., 1999
) and the data in this prospective study are in agreement. In a casecontrol study of ovarian function after salpingectomy, no differences in stimulation variables or number of retrieved oocytes could be detected (Verhulst et al., 1994
). However, the first study to examine the adnexal sides separately demonstrated a significant reduction in number of developed follicles and number of retrieved oocytes from the ovary ipsilateral to which a unilateral salpingectomy was previously performed, although there were no differences in total numbers when considering both sides (Lass et al., 1998
).
It was proposed in a retrospective study (Freeman et al., 1998) that hydrosalpinges may have a permanent negative influence on ovarian function, follicular development and oocyte quality since implantation of transferred embryos and normal blastulation of untransferred embryos remained low and in-vitro growth arrest and degeneration remained high despite surgical treatment of hydrosalpinges. The results of this study are partly supportive, since the laparoscopy group to a significantly larger extent had bilateral hydrosalpinges at inclusion and in their results tended to express a higher degree of poor embryo quality than in the non-intervention group in which unilateral hydrosalpinges were more frequent. However, the difference is not of any statistical significance and no signs of impaired follicular development were present in the laparoscopy group to support the observations of Freeman et al.
Besides bilaterality, the visibility of hydrosalpinx on ultrasound was analysed, as a potential predictor of fluid accumulation. Studies using ultrasound to diagnose hydrosalpinx have tended to show larger differences in pregnancy rates between hydrosalpinx patients and controls (Andersen et al., 1994; Katz et al., 1996
; Van Voorhis et al., 1998
). Another retrospective study clearly demonstrated that patients with ultrasound-visible hydrosalpinges carried a far worse prognosis compared with both non-visible hydrosalpinges and other tubal factor infertility (de Wit et al., 1998
). The data presented here are in agreement with the results from the studies based on ultrasound. Moreover, an improved outcome after salpingectomy in this patient category has been confirmed. A history of hydrorrhoea combined with a sonographically visible hydrosalpinx may impair the prognosis even more (Andersen et al., 1996
).
It has to be emphasized that the present study is based only on a first cycle. With that in mind, a general recommendation of preventive salpingectomy for all patients diagnosed with hydrosalpinges cannot be given. It would be valuable to identify a subset of patients who would benefit most from surgery, as suggested (Aboulghar et al., 1998). The present study was able to show that a surgical intervention increased implantation rates in patients with bilateral hydrosalpinges. A clear benefit of salpingectomy in patients with ultrasound-visible hydrosalpinges was also demonstrated. Based on the results of the present study, it is concluded that a preventive salpingectomy can be recommended for patients with hydrosalpinges enlarged enough to be visible on ultrasound and in particular for those affected bilaterally. The patients in the present study will in the near future have completed all their cycles and the cumulative data will hopefully provide more precise guidelines regarding preventive salpingectomy.
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Acknowledgments |
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Notes |
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* The study group for the multicentre trial and responsible investigator at each site were as follows. Sweden: Annika Strandell, Dept Ob/Gyn, Sahlgrenska University Hospital, Göteborg; Urban Waldenström, IVF Center Falun, Dept Ob/Gyn, Falun; Niklas Simberg, Dept Ob/Gyn, Uppsala University Hospital, Uppsala; Leif Hägglund, International Fertility Center, Malmö; György Csemiczky, Dept Ob/Gyn, Karolinska Hospital, Stockholm. Denmark: Anette Lindhard, The Fertility Clinic, Rigshospitalet, University Hospital, Copenhagen. Norway: Vidar von Düring, Dept Ob/Gyn, Trondheim; Kari Flo, Dept Ob/Gyn, University of Tromsø. Iceland: Gudmundur Arason, Dept Ob/Gyn, National University Hospital, Reykjavik.
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References |
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Submitted on April 6, 1999; accepted on August 3, 1999.