Cost effectiveness analysis of salpingectomy prior to IVF, based on a randomized controlled trial

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1 Human Reproduction Vol.20, No.12 pp , 2005 Advance Access publication August 11, doi: /humrep/dei244 Cost effectiveness analysis of salpingectomy prior to IVF, based on a randomized controlled trial Annika Strandell 1,4, Anette Lindhard 2 and Ingemar Eckerlund 3 1 Reproductive Medicine, Department of Obstetrics and Gynecology, Sahlgrenska University Hospital, Göteborg, Sweden, 2 Fertility Unit, Department of Gynecology and Obstetrics, Roskilde Hospital, Copenhagen University, Roskilde, Denmark and 3 Swedish Council on Technology Assessment in Health Care, Stockholm, Sweden 4 To whom correspondence should be addressed. annika.strandell@medfak.gu.se BACKGROUND: In patients with ultrasound-visible hydrosalpinges, salpingectomy prior to IVF increases the chance of a live birth. This study compared the cost-effectiveness of this strategy (intervention) with that of optional salpingectomy after a failed cycle (control). METHODS: Data from a Scandinavian randomized controlled trial were used to calculate the individual number of treatments and their outcomes. Only patients with ultrasound-visible hydrosalpinges were considered in the main analysis, and a maximum of three fresh cycles were included. The costs for surgical procedures, IVF treatment, medication, complications, management of pregnancy and delivery as well as of early pregnancy losses were calculated from standardized hospital charges. RESULTS: Among the 51 patients in the intervention group, the live birth rate was 60.8% compared with 40.9% in 44 controls. The average cost per patient was and , respectively. Thus, the average cost per live birth was in the intervention group and in the control group. The incremental cost-effectiveness ratio for adopting the intervention strategy was estimated at CONCLUSIONS: The incremental cost to achieve the higher birth rate of the intervention strategy seems reasonable. Key words: cost-effectiveness/hydrosalpinx/incremental cost-effectiveness ratio/in vitro fertilization/salpingectomy Introduction The role of hydrosalpinx in relation to IVF and embryo transfer has been debated since the first publication in 1994 (Strandell et al., 1994). Consistency in results demonstrating a negative influence on pregnancy rates has been demonstrated in metaanalyses of retrospective studies (Zeyneloglu et al., 1998; Camus et al., 1999). Various theories to explain the underlying mechanism has been suggested. Embryotoxic properties of the hydrosalpingeal fluid, presence of reactive oxygen species, endotoxins, impaired endometrial receptivity and mechanical washout of embryos are all plausible theories but none of them can explain the entire effect (Andersen et al., 1996; Mukherjee et al., 1996; Meyer et al 1997; Strandell et al., 1998; Barmat et al., 1999; Bedaiwy et al., 2002; Strandell et al., 2004). The suggested treatments have focused on the disposal of the hydrosalpingeal fluid. Various surgical methods, such as salpingectomy, salpingostomy, proximal tubal ligation and transvaginal aspiration of fluid, have been studied (Stadtmauer et al., 2000; Surrey and Schoolcraft 2001; Sowter et al., 1997; Van Voorhis et al., 1998) as well as the use of antibiotics alone (Hurst et al., 2001). However, salpingectomy is the only method that has been evaluated in prospective randomized controlled trials (Déchaud et al., 1998; Goldstein et al., 1998; Strandell et al., 1999), while all the other methods are presented in different retrospective designs. The largest randomized trial including the first IVF cycle demonstrated a significant benefit in terms of a doubled birth rate after salpingectomy compared with no intervention prior to IVF, in patients with hydrosalpinx that were fluid-filled to the extent that they could be detected at transvaginal sonography (Strandell et al., 1999). A second analysis included all subsequent IVF cycles, before which patients without prior salpingectomy had the option to undergo the procedure after a failed first or second cycle (Strandell et al., 2001). Also, the cumulative results demonstrated a doubled hazard ratio after salpingectomy. From a crude rate perspective, including spontaneous pregnancies and allowing for salpingectomy in the no-intervention group, the cumulative birth rates in the intention-to-treat analysis were equal and reached 55%. There is clear evidence for the benefit of salpingectomy, but there are other aspects, such as a psychological dilemma about whether to remove the tubes, and also economic considerations, which have not been described previously. The present study compares the cost-effectiveness of two strategies among hydrosalpinx patients: performing salpingectomy prior to the first IVF cycle, and optional salpingectomy after failed cycles. The analysis is based on the cumulative result of the Scandinavian multicentre study (Strandell et al., 2001). Materials and methods Study population The Scandinavian multicentre study on salpingectomy prior to IVF was conducted in five centres in Sweden, one in Denmark, two in 3284 The Author Published by Oxford University Press on behalf of the European Society of Human Reproduction and Embryology. All rights reserved. For Permissions, please journals.permissions@oupjournals.org

2 The cost effectiveness of salpingectomy prior to IVF Norway and one in Iceland. The countries are similar regarding health-care organization, funding and policies of fertility treatments. A total of 204 patients with hydrosalpinges, primarily diagnosed by either hysterosalpingography or laparoscopy, were randomized in a ratio 3:2 at each centre, to undergo a laparoscopic salpingectomy or to have no intervention before their first cycle. The power calculation, randomization procedure, IVF performance and group allocation are described in detail in the original publication (Strandell et al., 1999). A later publication includes all subsequent cycles, routinely not more than three transfer cycles per couple and allowing for salpingectomy in the control group (Strandell et al., 2001). These original publications have shown that the benefit of salpingectomy is particularly evident in patients with large hydrosalpinges that are visible on ultrasound, a subgroup recognized before the start of the study. It was concluded that patients with ultrasound-visible hydrosalpinges had twice as high a chance of achieving a live birth if they had a salpingectomy prior to IVF, and this is the group which is recommended salpingectomy. Thus, in the present report, the focus is on this group. In the present analysis, group allocation is according to the ontreatment-based analysis, in which the intervention strategy is defined as salpingectomy preceding the first embryo transfer and the control strategy allowing salpingectomy after one transfer. Thus, six patients from each group are excluded since they never started IVF treatment and six patients are reallocated (Figure 1). Three patients randomized to salpingectomy never underwent surgery and two patients randomized to salpingectomy underwent a complete IVF cycle before the 116 patients randomised to laparoscopic salpingectomy 6 did not start IVF = patients underwent laparoscopy 105 patients started IVF 106 patients included in the cost analysis 204 patients randomised in a ratio 3:2 2 patients had one IVF-cycle prior to surgery 1 patient underwent surgery prior to a freeze transfer surgery was performed. One patient randomized to no intervention had her first and only embryo transfer after a salpingectomy, which was performed after freezing of all embryos. Two patients randomized to salpingectomy conceived spontaneously after completed IVF treatment but their pregnancies are not included in the present analysis. The various surgical interventions and their potential complications in the intervention group have been described previously (Strandell et al., 1999). Data from the control group show that 28 of the 86 patients had a salpingectomy performed after a failed first or second cycle. A maximum of three complete treatment cycles (including ovarian stimulation, one fresh and additional frozen embryo transfers) per patient were included. For each patient, the outcomes of treatment have been recorded as number of complete cycles of standard IVF and ICSI, cycles ending after oocyte retrieval, started cycles cancelled before oocyte retrieval, frozen/thawed transfer cycles, and complications during any procedure. The outcomes of clinical pregnancies were recorded as spontaneous abortions (gestational week 6 12 or >12 weeks), managed conservatively or surgically by curettage, ectopic pregnancies treated by laparoscopic salpingectomy, termination of pregnancy after >12 gestational weeks, stillbirths and live births. Routes of delivery were recorded as vaginal delivery with/without complications and Caesarean section with/without complications. The number of children per birth (singleton or twin) was also registered. A twin live birth was counted as only one birth. Several pregnancies, but only one birth per patient could be included in the analysis. 88 patients randomised to no intervention before IVF 6 did not start IVF = 82 3 patients did not undergo surgery 87 patients started IVF 86 patients included in the cost analysis 13 cycles cancelled before oocyte retrieval 16 cycles cancelled before oocyte retrieval 20 cycles cancelled before transfer 8 cycles cancelled before transfer 57 live births (10 duplex) 1 intrauterine death 15 spontaneous abortions 3 ectopic pregnancies 1 termination of pregnancy 196 fresh transfer cycles 43 freeze transfer cycles 170 fresh transfer cycles 32 freeze transfer cycles 41 live births (12 duplex) 1 intrauterine death 9 spontaneous abortions 5 ectopic pregnancies Figure 1. Flow chart of patients in the Scandinavian multicentre study on salpingectomy prior to IVF, describing the allocation of patients and the overall results for inclusion in the cost-effectiveness analysis. 3285

3 A.Strandell, A.Lindhard and I.Eckerlund Calculation of costs The costs of treatments and interventions were calculated from standardized hospital charges at the main Swedish centre, Sahlgrenska University Hospital. These charges, which are partly based on diagnosis-related groups, are routinely used for invoicing between departments within the hospital and for referred patients. Only direct medical costs, i.e. treatment costs and costs that are related to the outcome, such as costs for spontaneous abortion or delivery, were included. Direct non-medical costs, such as cost for transportation to and from the hospital, and indirect costs for production loss due to sick leave related to treatment, were not included (Eisenberg, 1989; Drummond et al., 1997). The costs for laparoscopic salpingectomy were based on the charges for using the anaesthetic and the surgical facilities and the charges for the post-operative gynaecological ward. Patients were generally discharged from the hospital on the first post-operative day. Hence, the hospital charge for 1 day was used to calculate the cost associated with post-operative care. Post-operative complications requiring additional hospitalization were recorded and costs for additional days in hospital were calculated. No follow-up visits were scheduled. The medication costs were calculated as the average cost of drugs given to the patients undergoing IVF, including pituitary down-regulation with a GnRH analogue and gonadotrophins. The cost of GnRH analogues was based on the average cost of the total dose of three different preparations used in the study (buserelin acetate administered nasally or subcutaneously, or nasal nafarelin acetate). The majority of cycles used recombinant or highly purified FSH and the costs for gonadotrophins are based on the cycles using recombinant FSH. Costs for luteal support are based on the use of vaginal progesterone, which was the most common preparation used. The different types of medication were evenly distributed between groups. All medication costs are based on the retail prices of the Swedish pharmacy chain Apoteket, The vast majority of frozen/thawed cycles (88%) were performed in natural cycles and no drug costs for stimulation were thus included. The charge for IVF treatment set by the hospital was levelled according to the completeness of each treatment cycle, considering cancellations before and after oocyte retrieval. All follow-up visits were included. Complications such as ovarian hyperstimulation syndrome (OHSS) and infections requiring hospitalization were registered as days in hospital and the corresponding costs were calculated. Complications such as adnexal torsion due to enlarged hyperstimulated ovaries were considered related to the IVF treatment and the corresponding costs for surgery were thus referred to IVF-related complications. Pregnancy-related costs included routine antenatal controls, spontaneous abortions, ectopic pregnancies, termination of pregnancy and delivery. The calculation of delivery-related costs was based on number of children, route of delivery and complications such as intrauterine death and antenatal care due to risk of premature delivery. For instrumental deliveries by vacuum extraction or forceps, as well as for twin deliveries, the hospital charge for delivery-with-complication was used. Neonatal care was accounted for by using the hospital charges, which were set according to birth weight classes. The effectiveness of the two strategies (salpingectomy prior to IVF versus option to undergo salpingectomy in case of failed cycle) was expressed in terms of live birth rate per patient. The average cost per patient, was calculated from individual data, with the 95% confidence interval (CI) for the difference between groups, and the cost-effectiveness ratios were calculated as the average cost (excluding neonatal costs) per patient divided by the live birth rate. The incremental cost-effectiveness ratio (ICER), the extra 3286 cost per unit of outcome obtained, i.e. the extra cost to achieve one more live birth, was calculated as: ICER = (C 1 C C )/(E 1 E C ), where C is cost, E is effectiveness and the subscripts I and C denote intervention group and control group, respectively. We used bootstrapping to calculate 95% confidence intervals for the ICER and for the differences in cost-effectiveness ratios between groups. The bootstrap method is used to obtain a robust non-parametric estimate of the confidence interval. A bootstrap sample, of the same sample size as the original study, is generated with replacement from the obtained empirical distribution, i.e. the original study sample. The cost-effectiveness ratio is computed by using the bootstrap sample in place of the original sample. These procedures are repeated 1000 times and the 2.5th and 97.5th percentiles of the calculated cost-effectiveness ratio in the 1000 bootstrap samples form the 95% confidence interval of the cost-effectiveness ratio (Chernick, 1999). All costs were expressed in terms of the price level of 2004 and converted from Swedish kronor (SEK) into euros ( ) at the exchange rate of 1 = 9.0 SEK. Significance analyses were performed using the two-sample t-test for continuous variables and Fisher s exact test for proportions. An α-level of 0.05 was considered significant. Results All demographic data have been presented previously (Strandell et al., 1999). The intervention group comprises 106 patients and the control group 86 patients. The entire patient flow is described in Figure 1. The mean duration of surgery was 109 min (SD 32, range ). One complication, a pelvic haematoma, was noted in the intervention group. Not all patients completed a full set of three fresh cycles; 30 patients (28.3%) in the intervention strategy and 24 (27.9%) among controls. In the intervention group, the mean number of started cycles was 2.14 (SD 1.03) and the mean number of fresh and frozen thawed embryo transfers was 2.25 (SD 1.22). The corresponding numbers among controls were 2.20 (SD 0.99) started cycles and 2.35 (SD 1.26) embryo transfers, which did not differ significantly from the intervention group. The mean number of embryos transferred was equal (2.0) in the two groups and embryo quality did not differ; neither did the day of transfer. Table I describes the total number of surgical interventions and treatment cycles. Details of all included cycles, with outcome and timing of salpingectomy are shown in Figure 2. Complications of IVF occurred in 12 patients (11%) in the intervention strategy; 10 patients developed OHSS (requiring a total of 20 days in hospital) and two patients with infections (fever and abdominal pain) required hospitalization for a total of 5 days. Among controls, 11 patients (13%) suffered from complications; seven patients developed OHSS (17 days in hospital), three patients were treated for pelvic infections (10 days in hospital) and one patient underwent laparotomy due to adnexal torsion. In all, 95 patients were diagnosed with ultrasound-visible hydrosalpinges before the start of treatment. Among the 51 patients in the intervention group, 23.5% did not complete a full set of three stimulated cycles. The mean number of started cycles was 2.02 (SD 0.99) and mean number of transfers was 2.27 (SD 1.25). Among the 44 controls, 31.8% did not fulfil

4 The cost effectiveness of salpingectomy prior to IVF Table I. Treatment-related costs Cost ( ) Patients diagnosed with ultrasoundvisible hydrosalpinges (n) Total study population (n) (n = 51) (n = 44) (n = 106) (n = 86) Laparoscopic salpingectomy (100%) 17 (39%) 106 (100%) 28 (33%) Complications of surgery IVF Cycle cancelled during stimulation Cycle cancelled after oocyte retrieval Fresh transfer cycle Fresh transfer cycle ICSI Frozen/thawed transfer IVF medication Complete cycle Cycle cancelled after oocyte retrieval Cycle cancelled during stimulation Complications of IVF OHSS or infections (cost per day) (10%) 4 (9%) 12 (11%) 10 (12%) Adnexal torsion requiring laparotomy three stimulated cycles. The mean number of started cycles was 2.16 (SD 1.01) and the mean number of transfers was 2.25 (SD 1.24). Seventeen patients (39%) underwent salpingectomy after a failed cycle, of which 16 were after the first cycle. Six patients completed a full set of three stimulated cycles without undergoing salpingectomy. The live birth rates were 60.8% in the intervention group and 40.9% among controls, the difference being 19.9% (95% CI 0.4, 40.1). The basic data for calculation of costs associated with treatment, pregnancy and neonatal care are described in detail in Tables I IV. The average treatment costs per patient, including surgery and IVF, were in the intervention strategy and 9996 among controls, i.e. a difference of 961 (95% CI 863, 2 787). The average cost per patient, including treatment and Cycle patients included in the cost analysis started first cycle pregnancy-related costs, in the intervention group was compared with among controls, a difference of 1852 (95% CI 57, 3646). The cost-effectiveness, expressed as cost per live birth, excluding neonatal costs, was in the intervention group and among controls, a difference of (95% CI , 2 991). The ICER, was calculated as: ( )/( ) = 1852/0.199 = 9306 (95% CI 8653, ). That is, the intervention strategy (among patients with ultrasound visible hydrosalpinges) results in an extra live birth at a cost of A summary of all costs is displayed in Table V. A cost-effectiveness analysis, including also patients with hydrosalpinges that were not visible on ultrasound, was also conducted, and the summary results are shown in Table VI. 86 patients included in the cost analysis started first cycle 6 patients 10 patients 29 live births (7 duplex) 6 spontaneous abortions 1 ectopic pregnancy 12 patients had 87 patients had fresh transfer 15 had additional freeze transfer 1 had only freeze transfer 3 patients had 73 patients had fresh transfer 19 had additional freeze transfer 14 live births (7 duplex) 1 intrauterine death + 1 live birth w.27 5 spontaneous abortions 3 ectopic pregnancies Figure 2. Flow chart of all included cycles, describing the outcome of all cycles and time for salpingectomy. 3287

5 A.Strandell, A.Lindhard and I.Eckerlund Cycle 2 77 patients whose first cycle 71 patients whose first cycle 5 patients did not start a second cycle 19 patients underwent surgery prior to second cycle 8 patients did not start a second cycle 12 live births (3 duplex) 1 termination of pregnancy (trisomy 18) 6 spontaneous abortions 1 ectopic pregnancy Cycle 3 20 patients did not start a third cycle 72 patients started second IVF-cycle 6 patients 4 patients had 62 patients had fresh transfer 21 had additional freeze transfer 60 patients whose previous cycles 40 patients started third IVF-cycle 1 patient 3 patients had 63 patients started second IVF-cycle 5 patients 2 patient had 56 patients had fresh transfer 4 had additional freeze transfer 51 patients whose previous cycles 6 patients underwent surgery prior to third cycle 37 patients started third IVF-cycle 1 patient 3 patients had 12 live births (3 duplex) 2 spontaneous abortions 2 ectopic pregnancies 14 patients did not start a third cycle 14 live births (0 duplex) 3 spontaneous abortions 1 ectopic pregnancy 36 patients had fresh transfer 3 had additional freeze transfer 33 patients had fresh transfer 8 had additional freeze transfer 9 live births (2 duplex) 2 spontaneous abortions Figure 2. continued 3288

6 The cost effectiveness of salpingectomy prior to IVF Cycle 4 25 patients whose previous cycles 28 patients whose previous cycles 15 patients did not start a fourth cycle (12 had completed treatment 3 stopped in advance) 1 patient underwent surgery prior to fourth cycle 19 patients did not start a fourth cycle (17 had completed treatment 2 stopped in advance) 10 patients started fourth IVF-cycle 9 patients started fourth IVF-cycle 1 live single birth Cycle 5 7 patients had completed treatment 0 patients 1 patients had 9 patients had fresh transfer 3 had additional freeze transfer 9 patients whose previous cycles 2 patients started fifth IVF-cycle 0 patients 0 patient 0 patient had 9 patients had fresh transfer 1 had additional freeze transfer 5 live births (0 duplex) 4 patients whose previous cycles All 4 had completed treatment 0 patients had 1 live single birth 2 patients had fresh transfer 0 had freeze transfer Figure 2. continued The ICER was (95% CI , ). Thus, despite the doubled sample size, the 95% CI is even wider than for the targeted group of ultrasound-visible hydrosalpinges, due to the small difference in effect size. Discussion As a result of the Scandinavian multicentre study on salpingectomy, the guidelines in many countries have been revised to recommend salpingectomy prior to IVF in patients with large 3289

7 A.Strandell, A.Lindhard and I.Eckerlund Table II. Pregnancy-related costs Cost ( ) Patients diagnosed with ultrasound-visible hydrosalpinges (n) Total study population (n) (n = 51) (n = 44) (n = 106) (n = 86) Antenatal care Clinical pregnancies Spontaneous abortions v Spontaneous abortions >v Ectopic pregnancies Termination of pregnancy >v Stillbirth c 1 b 1 a 1 b Live birth c a One duplex pregnancy resulting in intrauterine death of one fetus (gestational week 30) and birth of one child (gestational week 34). b One triplex pregnancy resulting in intrauterine death of two fetuses and one live birth, gestational week 27. c Costs of stillbirths and live births are included in delivery-related costs (Table III). Table III. Delivery-related costs Cost ( ) Patients diagnosed with ultrasound-visible hydrosalpinges (n) (n = 51) (n = 44) Total study population (n) (n = 106) Antenatal care due to risk of premature delivery in gestational week Mode of delivery Vaginal uncomplicated Vaginal complicated Caesarean section (CS) CS complicated Table IV. Neonatal costs according to birth-weight classes Birth weight (g) Cost ( ) Patients diagnosed with ultrasound visible hydrosalpinges (n = 51) No. of children (n = 44) No. of children Total study population (n = 106) No. of children < > Total (n = 86) (n = 86) No. of children hydrosalpinges that are visible on ultrasound. Some patients are, however, reluctant to undergo this procedure, mainly due to psychological aspects of having to undergo surgery or losing the Fallopian tubes. The present analysis demonstrated that the cost per live birth is higher in the strategy in which surgery is performed after failed IVF, while the cost per treatment is somewhat lower. The disadvantage of this strategy is that each IVF cycle is tiresome and one extra cycle may be too heavy a burden, mainly psychologically but also physically (Hammarberg et al., 2001). In the present study, 28% did not complete a full set of three stimulated cycles and there was no significant difference between the two strategies. Another reason for not completing the offered treatment cycles was that spontaneous pregnancies occurred in patients who had undergone a unilateral salpingectomy. A few case series have pointed out a positive effect of salpingectomy on the chance of spontaneous pregnancy (Choe and Check, 1999; Aboulghar et al., 2002). The ICER of 9306 in the main analysis, concerning patients with ultrasound-visible hydrosalpinges, seems quite reasonable. Even the upper limit of the 95% CI seems to be a reasonable cost for saving another child. The wide confidence interval is due to the rather small sample in this group. From 3290

8 The cost effectiveness of salpingectomy prior to IVF Table V. Direct medical costs ( ) in patients with ultrasound visible hydrosalpinges Difference 95% CI for the difference Mean SD Range Mean SD Range No. of patients Treatment costs , , , 2787 Pregnancy-related costs , , , 454 Delivery related costs/per patient giving birth , , , 917 Total cost/patient (excl.neonatal care) , , , 3646 Cost of neonatal care/patient giving birth , , , 3305 Total cost/patient (incl. neonatal care) , , , 5516 No. of live births Cost (excl. neonatal)/live birth rate , 2991 Total cost (incl. neonatal)/live birth rate Table VI. Direct medical costs ( ) in the entire study population the perspective of the payers, of course, it is relevant to take into account that the average cost per patient is higher if salpingectomy is performed before the first cycle, even if the cost per live birth is lower. From the patients perspective, the reimbursement system for IVF and surgery may influence the choice of treatment strategy. It should be pointed out that the original study designated salpingectomy prior to the first cycle and the management of subsequent cycles varied between centres, implying that the discussion of salpingectomy after failed cycles was not always initiated. This design results in a heterogeneous control group, considering that salpingectomy could be performed after the first or second failed cycle, or not at all. Among controls, 39% had a salpingectomy performed and only six patients (14%) completed a full set of three stimulated cycles without having undergone a salpingectomy and not achieving a live birth, suggesting that the vast majority of patients were offered surgery. While the study was conducted and no result regarding the benefit of salpingectomy was yet available, patients were obviously offered, and accepted, salpingectomy. At present, several years after the positive result was published, the dissemination and implementation of salpingectomy as a recommendation vary between clinics and physicians. A survey of IVF clinics in the UK demonstrated that 12% of units did not recommend treatment of hydrosalpinx prior to IVF treatment, while 36, 33 and 19% recommended treatment weakly, strongly and very strongly respectively (Hammadieh et al., 2004). Considering this scenario, it is likely that the control group in the present study is a strong reflection of clinical practice. Difference 95% CI for the difference Mean SD Range Mean SD Range No. of patients Treatment costs , , , 2035 Pregnancy related costs , , , 195 Delivery related costs/per patient giving birth , , , 303 Total cost/patient (excl.neonatal care) , , , 2129 Cost of neonatal care/ patient giving birth , , , 1210 Total cost/patient (incl. neonatal care) , , , 2517 No. of live births Cost (excl. neonatal)/live birth rate , 5396 Total cost (incl. neonatal)/live birth rate The cost of salpingectomy depends very much on the length of hospitalization. In the present analysis, the cost of one overnight stay was included, since these surgeries were performed later in the afternoon, in the hospital we used as a model. The salpingectomy procedure could certainly be performed in a day-surgery setting, which would further reduce the cost of salpingectomy. On the other hand, if indirect costs due to sick leave after surgery (general recommendation of 1 week) had been included, the cost of the salpingectomy strategy would have increased, since all patients in the active intervention group underwent surgery, compared with only 39% of controls. The cost of production loss is difficult to calculate since the actual number of days on sick leave was not recorded. On average, however, this means an extra cost of approximately 665 per patient (5 days 133) in the intervention group and 260 per patient ( days 133) among controls. This difference of 405 implies an ICER of among those with ultrasound-visible hydrosalpinges. Other indirect costs are supposed to be evenly distributed between the two strategies. The rather high complication rate will increase the costs of IVF treatment, but only marginally. More important is that complications like OHSS and infections were evenly distributed between the groups and will not affect the difference in costs. Inclusion of neonatal costs in the analysis would skew the results in favour of the intervention strategy, because of the fairly low numbers of births and the skewed distribution of multiple births. The higher twin rate among controls (22 versus 3291

9 A.Strandell, A.Lindhard and I.Eckerlund 16%) was not statistically significant, and there is no rationale for patients in the control group to have a higher twin rate than patients having salpingectomy prior to their first IVF. In a larger sample, the need for neonatal care would probably have been more evenly distributed. Thus, it is reasonable to exclude the costs of neonatal care when calculating the cost-effectiveness ratios. Currently, single embryo transfers are more common and performed as a routine procedure in many Scandinavian centres and the problem of low birth weight in twin births has already decreased in these countries. In conclusion, the incremental cost to achieve the higher birth rate by adhering to the intervention strategy, i.e. salpingectomy prior to the first IVF cycle, seems quite reasonable in patients with ultrasound-visible hydrosalpinges. Acknowledgements We thank Nils-Gunnar Pehrsson for performing the bootstrapping procedures to construct confidence intervals for ratios. References Aboulghar MA, Mansour RT and Serour GI (2002) Spontaneous intrauterine pregnancy following salpingectomy for a unilateral hydrosalpinx. Hum Reprod 17, Andersen AN, Lindhard A, Loft A, Ziebe S and Andersen CY (1996) The infertile patient with hydrosalpinges-ivf with or without salpingectomy. Hum Reprod 11, Barmat LI, Nasti K, Yang X, Spandorfer S, Kowalik A and El-Roeiy A (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, Bedaiwy MA, Goldberg JM, Singh M, Sharma R, Wang X, Nelson D and Falcone T (2002) Relationship between oxidative stress and embryotoxicity of hydrosalpingeal fluid. 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Hum Reprod 13, Zeyneloglu HB, Arici A and Olive DL (1998) Adverse effects of hydrosalpinx on pregnancy rates after in vitro fertilization-embryo transfer. Fertil Steril 70, Submitted on March 2, 2005; resubmitted on May 28, 2005; accepted on June 6,