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, Falu Hospital, S-791 82 Falun, Sweden
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Abstract |
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Key words: cumulative pregnancy rates/hydrosalpinx/IVF/randomized controlled trial/salpingectomy
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Introduction |
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One of the main explanations for the hydrosalpinx-related impairment suggests that the leakage of fluid into the uterine cavity creates an unfavourable endometrial environment for implantation and could also affect embryo development. According to this theory, surgical intervention with salpingectomy should remove any effect of the hydrosalpingeal fluid and restore pregnancy rates. Several retrospective studies have compared the outcome of IVF, with and without salpingectomy, in patients carrying hydrosalpinges (Kassabji et al., 1994; Vandromme et al., 1995
; Shelton et al., 1996
; Meyer et al., 1997
; Murray et al., 1998
; Ejdrup Bredkjaer et al., 1999
). All have demonstrated a positive effect of salpingectomy on pregnancy rates, although the retrospective designs do not provide evidence for the method's effectiveness. A small randomized pilot study indicated a positive effect of salpingectomy on implantation rates but without statistical significance (Déchaud et al., 1998
).
A multicentre randomized controlled trial with salpingectomy as the main intervention has been conducted within Scandinavia with the aim to test the hypothesis that removal of the hydrosalpinx prior to IVF treatment would improve pregnancy rates. The results from the first cycle (Strandell et al., 1999) clearly showed a benefit of salpingectomy in patients with hydrosalpinges that were large enough to be viewed sonographically (birth rates: 40.0 versus 17.5%, P = 0.040) and, in particular, if present bilaterally (55.0 versus 15.8%, P = 0.019). The aim of the present study was to examine whether salpingectomy was beneficial in terms of increased birth rates on a cumulative basis, taking into account all transfer cycles.
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Material and methods |
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Study design
The physician who referred the patient to IVF made the diagnosis of hydrosalpinx. Hysterosalpingography and/or laparoscopy were used as diagnostic methods. At each centre, patients under the age of 39 years with uni- or bilateral hydrosalpinges were randomized to laparoscopic salpingectomy or no intervention, in a ratio 3:2, prior to their first IVF treatment. Patients in the intervention group underwent a laparoscopic unilateral (n = 40) or bilateral (n = 63) salpingectomy, depending on whether one or two hydrosalpinges were present. Alternative procedures, like a proximal ligation and fenestration due to the presence of extensive adhesions (n = 6), or fertility-promoting procedures like salpingostomy (n = 1) or adhesiolysis (n = 1), were performed in eight cases. Patients in the non-intervention group started their IVF treatment directly according to routine practices. The stimulation procedures at the individual IVF centres were similar and included a long protocol. A maximum of two embryos were routinely transferred.
Two hundred and four patients were recruited of which 185 underwent at least one embryo transfer. The results of the first transfer cycles were analysed as a separate study (Strandell et al., 1999). At that time, one patient in the salpingectomy group had experienced two cycles of poor embryo development and no embryo transfer, but her third cycle succeeded and she was thus included in the cumulative analysis of transfer cycles, giving a sample size of 186 patients. Subsequently, all fresh and frozenthawed transfers were analysed on a cumulative per patient basis. After one or two failed cycles, patients in the control group were permitted to undergo salpingectomy.
The legislation and routine practice at the individual centres allowed for three stimulated cycles and subsequent transfers of frozenthawed embryos. The follow-up of all the 204 randomized patients has been completed.
Group allocation
One hundred and sixteen patients were randomized to salpingectomy and 88 patients to no intervention. Salpingectomy was not performed in five patients randomized to surgery before entering the IVF programme. Two of them underwent surgery after their first transfer cycle|one patient due to ectopic pregnancyand the three remaining patients never underwent the surgery at all. In the non-intervention group, one patient had a salpingectomy performed due to infection after her first oocyte retrieval but before transfer, which was postponed and conducted later as a transfer of frozenthawed embryos. The study protocol restricted the randomization allocation to the first cycle and allowed for a subsequent salpingectomy in the non-intervention group if failure occurred. Among the 77 patients undergoing transfer in the randomization group of non-intervention, 24 patients had in fact undergone a salpingectomy after one or two failed cycles. Of these 24 cases, four were due to ectopic pregnancies, while the remaining surgeries were performed upon the patient's expressed request. The salpingectomies performed were unilateral in nine and bilateral in 15 of these 24 patients. None of the patients have undergone additional cycles after a full-term pregnancy. Figure 1 summarizes the patient flow.
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Subgroup analysis
Patients with bilateral and/or ultrasound-visible hydrosalpinges were included in subgroups defined at the start of the study. The ultrasound examination was performed before the start of ovarian stimulation. The ultrasound data were not available for all patients due to local routines, such as distance monitoring. Data were compared with surgery reports and histopathological examination. The tube was assumed to be visible on ultrasound in cases where ultrasound data were missing and where it was documented that the tube was dilated with a diameter measuring 20 mm (n = 17).
Complementary groups to the defined subgroups were analysed regarding pregnancy outcome. The complementary groups included patients with a unilateral hydrosalpinx, patients with hydrosalpinges that were non-visible on ultrasound, and patients with a non-visible unilateral hydrosalpinx.
Statistical methods
The data were subjected both to an intention-to-treat analysis and to an analysis of actual treatment. The intention-to-treat analysis was performed, taking into consideration only the randomization allocation, regardless of subsequent surgical intervention. 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.
As described above, in a large proportion of cycles, the randomization group was not equivalent to the actual treatment group. In order to account for all transfer cycles, regardless of randomization allocation, a statistical method was used which would consider actual treatment without exclusions. The statistical analysis of the primary outcome (birth) was performed with the Cox regression model, using the time-dependent co-variates of treatment group, age, number of good quality embryos transferred and number of transfer cycles before surgery. The cycle number was thus used as a discrete time variable. The Cox regression model was not suitable for analysing the secondary outcome (clinical pregnancy) as this is not a terminal event, since a pregnancy can occur more than once per individual. Instead, clinical pregnancy was analysed by a multivariate logistic regression model for longitudinal data, using the method of generalized estimation equations (Diggle et al., 1994). This method gives robust estimates adjusted for the dependence within each woman. The independent variables included that of treatment group (salpingectomy or no surgical intervention), number of transfer cycles in each treatment group, age and mean number of good quality embryos. For comparison of the continuous variables between groups, mean individual values were calculated to which the Wilcoxon two-sample test was applied. The secondary endpoint, implantation, was compared in the treatment groups of salpingectomy and non-intervention. In the non-intervention group, cycles performed after non-randomized surgery were excluded to avoid inclusion of the same patient in both groups. Two-tailed statistical tests were conducted at the 5% level of significance. The BonferroniHolm method was used to correct for multiple comparisons (Holm, 1979
).
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Results |
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Demographic data
Patient characteristics were similar with respect to age and obstetric history in the two randomization groups (Strandell et al., 1999). The cycle characteristics for the two treatment groups are presented in Table I
. No significant differences were detected.
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Approximately one-third (25/78) of the patients randomized to no surgical intervention underwent a salpingectomy after one or two failed cycles. Their cycle characteristics and types of hydrosalpinges as well as pregnancy outcome are compared in Table V with those of patients who did not undergo the surgery at all.
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Discussion |
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A previous report of retrospective design has suggested that patients with ultrasound-visible hydrosalpinges carry the worst prognosis compared with all other tubal factor infertility (de Wit et al., 1998). Also, studies in which ultrasound has been used for the diagnosis of hydrosalpinx tend to express larger differences in pregnancy rates between hydrosalpinx patients and controls (Andersen et al., 1994; Katz et al., 1996
; Van Voorhis et al., 1998
). From the results of the present study, it is obvious that patients with hydrosalpinges large enough to be visible on ultrasound benefit the most from a salpingectomy. None of the groups complementary to the subgroups demonstrated any effect of salpingectomy on birth rates. It was concluded that the positive effect of salpingectomy in the total study population and in patients with bilateral hydrosalpinges was due to the presence of patients with ultrasound-visible hydrosalpinges within these groups.
Furthermore, the theories of how hydrosalpinges exert a negative effect on the implantation rate deal mainly with the hydrosalpingeal fluid, supporting the identification of patients with ultrasound-visible hydrosalpinges as being a poor prognosis group. The suggested mechanisms have focused on the embryotoxicity of the fluid (Mukherjee et al., 1996; Beyler et al., 1997
; Murray et al., 1997
; Rawe et al., 1997
; Sachdev et al., 1997
; Granot et al., 1998
; Koong et al., 1998
; Strandell et al., 1998
; Roberts et al., 1999
; Strandell 2000
), or the mechanical leakage of the fluid into the uterine cavity, causing endometrial alterations, hostile to embryo implantation and development (Meyer et al., 1997
; Cohen et al., 1999
), or simply a mechanical wash-out of embryos (Andersen et al., 1996
; Sharara 1999
).
There has been debate over the risk of unnecessary removal of Fallopian tubes (Puttemans et al., 2000). There are patients referred for IVF who have not had their tubes properly evaluated, and a distally occluded tube may be found to be suitable for functional surgery. In cases of uncertainty, a diagnostic distal salpingostomy for evaluation of the mucosa, prior to any salpingectomy, is of value. However, in the present study histopathological evaluation of the removed tubes confirmed that the occurrence of a healthy mucosa is very rare (Strandell and Lindhard, 2000
), and only one woman had a therapeutic salpingostomy performed. As long as a salpingostomy does not re-occlude, it is likely to have a positive effect on IVF outcome, besides the chance of a spontaneous conception and the risk of an ectopic pregnancy, although there is no prospective study to support this speculation. Other treatment options, such as transvaginal aspiration of the hydrosalpingeal fluid have been examined in retrospective studies but with contradictory results (Sowter et al., 1997
; Van Voorhis et al., 1998
). Hitherto, salpingectomy is the only treatment of hydrosalpinges that has been evaluated in a prospective randomized trial. It is also the only suggested treatment without any need for repeated intervention.
There has also been concern about whether the ovarian function could be at risk of being disturbed by a surgical procedure like salpingectomy. Previous studies on ovarian performance after unilateral salpingectomy due to ectopic pregnancy have not demonstrated any overall effect on the ovarian response to gonadotrophins (Lass et al., 1998; Dar et al., 2000
), although the study results were contradictory when separate sides were compared. A separate analysis within the present study, of patients undergoing prophylactic salpingectomy of which the majority was a bilateral procedure, showed that there was no significant reduction in ovarian performance (Strandell et al., 2001
).
The intention-to-treat analysis displayed equally high birth rates in both randomization groups. Obviously, with one-third of the patients in the non-intervention group having finally undergone the salpingectomy at a later occasion, the cumulative intention-to-treat analysis no longer reflected the surgical intervention. However, it was reassuring to find that the patients reached a full-term pregnancy to the same extent, whether they had undergone a salpingectomy prior to their first IVF or after one or two failed cycles, albeit more cycles were required in the latter case and at a higher expense.
The present study has proven the hypothesis that removal of a hydrosalpinx before undergoing IVF treatment improves birth rates is efficacious, and supports the theory that hydrosalpingeal fluid has a causative role in impaired pregnancy outcome. Based on the present results, the following clinical decision can therefore be made: patients with hydrosalpinges, uni- or bilateral and large enough to be seen as fluid-filled by ultrasound before initiating ovarian stimulation, can be recommended for a laparoscopic salpingectomy in order to improve their chance of achieving a birth after IVF treatment.
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Acknowledgements |
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Notes |
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4 To whom correspondence should be addressed. E-mail: annika.strandell{at}medfak.gu.se
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References |
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Submitted on February 6, 2001; accepted on August 9, 2001.