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Abstract

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. METHODS
  5. RESULTS
  6. DISCUSSION
  7. References

Objective The traditional treatment of ectopic pregnancy is salpingectomy, while conservative surgery aims to save the function of the uterine tube. This study compares the effectiveness and the economic costs of salpingectomy and conservative tubal surgery in women with a tubal pregnancy.

Methods Salpingectomy and conservative tubal surgery were compared economically, based on a combined retrospective and prospective cohort study and a review of the literature. A model was developed in which conservative surgery and salpingectomy with in vitro fertilisation and embryo-transfer (IVF-ET) were compared with salpingectomy alone.

Participants One hundred and fifteen consecutive women treated laparoscopically for tubal pregnancy.

Main outcome measures Complete removal of the tubal pregnancy; subsequent intrauterine pregnancy rate; economic analysis.

Results Tubal pregnancy was always treated successfully by both methods, sometimes with additional treatment for persistent trophoblast. In the short term costs per patient were £1554 (95% confidence interval [CI] £1501–£1656) for salpingectomy and £1787 (95% CI £1683–£1930) for conservative surgery. The mean difference between costs of salpingectomy and costs of conservative surgery was £233 (95% CI £80–£371). Concerning subsequent intrauterine pregnancy, conservative surgery is slightly more effective than salpingectomy but is more expensive. Costs per subsequent intrauterine pregnancy are £4063. If IVF-ET is performed in all women who are not pregnant within three years after salpingectomy, costs per subsequent intrauterine pregnancy are £15,629.

Conclusions Salpingectomy is the treatment of choice in women not desiring future pregnancy. Salpingectomy seems less effective than conservative surgery when future pregnancy is desired, but is less costly. Conservative surgery seems more cost effective than salpingectomy with additional IVF-ET.


INTRODUCTION

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. METHODS
  5. RESULTS
  6. DISCUSSION
  7. References

Conservative surgery for ectopic pregnancy is gradually replacing salpingectomy as the treatment of choice in women with unruptured tubal pregnancy who wish to preserve their reproductive capacity. In evaluating the effectiveness of treatment of tubal pregnancy two outcome measures should be taken into account: the complete elimination of trophoblast, and the subsequent fertility of the woman. Salpingectomy virtually guarantees complete elimination of trophoblast but, since the uterine tube is removed, future fertility may be affected. Conservative surgery aims to save tubal integrity in order to maintain reproductive capacity, at the expense of an increased risk of persistent trophoblast and possibly of a repeat ectopic pregnancy.

Additional costs of conservative surgery are only justified if they result in a higher rate of spontaneous intrauterine pregnancy, thereby saving the cost of the diagnosis and treatment of subsequent infertility1. Therefore the choice between salpingectomy and conservative surgery for tubal pregnancy should be based on both the clinical effectiveness and the costs of the treatments.

From a clinical perspective, the choice between salpingectomy and conservative surgery is not based on sound evidence. No randomised clinical trials are available in which persistent trophoblast or fertility rates after salpingectomy and conservative surgery have been compared. A review of the available uncontrolled studies snows the average rate ot persistent tropnoblast to be 4.1% after conservative open surgery and 8.1% after conservative laparoscopic surgery2. Cohort studies comparing fertility rates show an equal probability of intrauterine pregnancy after conservative surgery and salpingectomy (pregnancy rate ratio 1.0, 95% confidence interval [CI] 0.91–1.2), and an increased risk of ectopic pregnancy after conservative surgery (ectopic pregnancy rate ratio 1.4 (95% CI 1.1–1.9)3,4. These studies have several methodological weaknesses. The follow up period after salpingectomy and conservative surgery often varies, and some studies fail to indicate the desire for pregnancy among the women. How subsequent pregnancies were achieved remains unclear, whether naturally or as a result of in vitro fertilisation with embryo transfer (IVF-ET), which may reflect a failure of the primary goal to preserve fertility. In addition, none of the studies gives any account of subsequent tubal surgery after the initial ectopic pregnancy. A recently published cohort study in which most of these problems were addressed found the adjusted pregnancy rate ratio of intrauterine pregnancy after conservative surgery to be 1.2 (95% CI 0.7–2.2)5.

We performed an economic evaluation to compare the clinical effectiveness and economic costs of laparoscopic salpingectomy and conservative laparoscopic treatment of tubal pregnancy. Since the available evidence on fertility after both treatments is weak, threshold analysis was performed, to determine the minimum required increase in spontaneous pregnancy rate to make conservative surgery more cost-effective than IVF-ET after salpingectomy. The central issue is the balance between the costs of preserving the uterine tube and the costs of subsequent diagnosis and treatment of any infertility or repeat ectopic pregnancy.

METHODS

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. METHODS
  5. RESULTS
  6. DISCUSSION
  7. References

The economic evaluation of a treatment examines the consequences of the treatment in terms of clinical effectiveness and economic costs6. If two treatments appear to be equally effective clinically, the economic evaluation is essentially a search for the least expensive alternative. This is done in a cost-minimisation analysis. If, however, a difference in clinical effectiveness is present, both costs and clinical effectiveness should be weighted in a cost effectiveness analysis. Cost-effectiveness is expressed as a ratio of net health care costs to net health benefits of a particular strategy, compared with a reference7.

Participants

All women who underwent laparoscopic surgery for tubal pregnancy in the Academic Medical Centre between 1 September 1992 and 1 November 1995 and in the Onze Lieve Vrouwe Gasthuis between 1 September 1993 and 1 November 1995 in Amsterdam, The Netherlands, were included in the study. From 1 September 1993 onwards, the women were included prospectively. Data from women treated before this date were obtained retrospectively from the medical files.

Patients with heterotopic pregnancies were excluded from the analysis. In both cohorts, the diagnosis of tubal pregnancy was made by transvaginal ultrasound and serum human chorionic gonadotrophin (hCG) monitoring, confirmed by diagnostic laparoscopy8.

The women were treated either by salpingectomy or conservative surgery. The choice of treatment depended on the clinical situation and the desire for pregnancy. In order to compare the group clinical symptoms (abdominal pain and vaginal bleeding), hCG level on the day of laparoscopy, gestational age (calculated from the first day of the last menstrual period), presence of peritubal adhesions, and presence of tubal rupture were recorded. Differences were statistically assessed using the χ2 test, Student's t test, or the Mann-Whitney U test.

Clinical effectiveness

We defined short term clinical effectiveness as the elimination of trophoblast, either immediately or after further treatment. Persistent trophoblast was defined as rising or static serum hCG concentrations during the post-operative course. This was treated by systemic methotrexate or further surgery. Long-term clinical effectiveness was defined as the occurrence of intrauterine pregnancy following the treatment of tubal pregnancy, either spontaneously, or after treatment with IVF-ET. The reference spontaneous intrauterine pregnancy rate after salpingectomy was assumed to be 39%3. Assuming a relative risk of 1.2 for conservative surgery compared with salpingectomy5, the spontaneous intrauterine pregnancy rate after conservative surgery was assumed to be 47%. IVF-ET was assumed to be performed in all couples who remained childless three years after surgery for ectopic pregnancy. Subsequent continuing intrauterine pregnancy rates of IVF-ET for tubal infertility for the first, second and third cycle were assumed to be 16%, 15% and 14%, respectively9. Intrauterine pregnancy rates were the sum of spontaneous intrauterine pregnancy rate after surgical treatment for ectopic pregnancy and the continuing intrauterine pregnancy rate of additional IVF-ET. The repeat ectopic pregnancy rate after salpingectomy was assumed to be 10.4%3. Accepting a relative risk of 1.43,4, the estimated repeat rate of ectopic pregnancy after conservative surgery was assumed to be 146%3.

Costs

The costs of each treatment were calculated by multiplying used resources and resource unit prices. A distinction was made between costs of medical interventions (direct costs) and costs resulting from productivity losses (indirect costs)6. Another distinction was made between short term costs—costs made until complete elimination of trophoblast—and long term costs: short term costs plus costs resulting from repeat ectopic pregnancies or additional infertility treatment.

For short term direct costs, resources counted were laparoscopic surgery, number of conversions to open surgery, hospital stay in days, number of complications, number of serum hCG measurements, and number of interventions for persistent trophoblast. Each woman was supposed to make one visit to the outpatient clinic after discharge. To calculate short term indirect costs, literature data on absence from work after laparoscopic surgery were used10,11. For long term costs, resources counted were surgery for repeat ectopic pregnancy, and the diagnosis and treatment of subsequent infertility.

Resource unit prices reflected unit costs for staff, materials, equipment, housing, depreciation, and overheads, the latter at both a department level and a hospital level. Unit prices were calculated for laparoscopic surgery, conversion from laparoscopy to open surgery (both with a fixed component and a time-dependent component), hospital stay, complications (pneumonia, urinary tract infection, thromboembolism, blood transfusion), serum hCG measurements, intervention for persistent trophoblast and visits to the outpatient clinic. The age and sex stratified price of productivity loss was calculated for The Netherlands12. Prices of treatment of repeat tubal pregnancy were calculated directly in the present study. Prices of diagnosis and treatment of infertility were obtained from the Dutch literature13. Productivity loss for a couple undergoing one IVF-ET cycle for infertility treatment was assumed to be one week. Prices were calculated in Dutch guilders (hfl), but are reported in British pounds sterling (£1 = hfl 2.52).

In order to make allowance for the differential timing of economic costs, we assumed a discount rate of 5%. The mean interval until treatment for infertility was assumed to be three years.

Economic evaluation

Short-term costs and effectiveness of salpingectomy and conservative surgery were compared with bootstrapping techniques. Random bootstrap samples were drawn with replacement from the full sample of patients undergoing salpingectomy and patients undergoing conservative surgery (2000 replications). Based on these bootstrap samples, we calculated 95% CI of the costs of both treatments. Furthermore, the 95% CI of the mean difference in short term costs between the two treatments was calculated using bootstrapping techniques.

The spontaneous intrauterine pregnancy rate after salpingectomy was lower than after conservative surgery5. Therefore, salpingectomy (without additional IVF-ET) was regarded as the reference for the analysis of long term cost effectiveness. Conservative surgery was compared with salpingectomy with three additional cycles of IVF-ET in case of infertility, as the central economic issue in the decision for salpingectomy or conservative surgery concerns the balance between additional costs of persistent trophoblast after conservative surgery and the additional cost of future infertility treatment after salpingectomy. Differences in costs and effectiveness between these two treatments and the reference treatment were expressed as cost effectiveness ratios. These are ratios of incremental costs to incremental effectiveness. These cost effectiveness ratios express the additional costs that have to be made for one additional pregnancy.

Threshold and sensitivity analysis

Threshold-analysis was performed in order to determine the required increase in spontaneous pregnancy rate after conservative laparoscopic surgery that would render this treatment as cost effective as laparoscopic salpingectomy with three cycles of IVF-ET for subsequent infertility. Sensitivity analysis was performed to explore the effect of variation of several factors on the results of the threshold analysis: intervention for persistent trophoblast, the risk of repeat ectopic pregnancy after conservative surgery, the costs of IVF-treatment, and the IVF success rate.

RESULTS

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. METHODS
  5. RESULTS
  6. DISCUSSION
  7. References

One hundred and fifteen consecutive women were included in the study with no exclusions. Thirty-nine women (34%) underwent laparoscopic salpingectomy and 76 (66%) conservative laparoscopic surgery. Baseline characteristics of the women are presented in Table 1. The mean gestational age and clinical symptoms in each group showed no significant differences. The mean serum hCG concentration was significantly higher in women treated by salpingectomy. These women also had significantly more adhesions and more tubal ruptures.

Table 1.  Baseline characteristics. Values are numbers unless stated otherwise
 Salpingectomy (n= 39)Conservative surgery (n= 76)P
  1. *χ2 test; Mann-Whitney U test; Student's t test; Fisher's exact test

Clinical symptoms  X2= 2.4; P = 044*
None814 
Abdominalpain513
Vaginalbleeding1214
Abdominal pain and vaginal bleeding1435 
Scrum hCG (IU/L): median (range)3800 (150-80,000)2160 (140-34,000)P = 0.01
Gestational age (days): mean (SD)50 (10)52(11)I =−0.77; P= 0.44
Peritubal adhesions: n (%)18 (46)20 (26)X2= 3.73; P= 0.04*
Tubal rupture: n (%)6 (15)2(3)P = 0.02

Effectiveness

Intervention for persistent trophoblast was necessary in 18 women (15%): in one after salpingectomy and in 17 after conservative surgery. Fifteen women were treated as outpatients with four doses of methotrexate (1 mg/kg intramuscularly), alternating with leucovorin rescue (0.1 mg/kg orally). One woman underwent salpingectomy, and one was managed expectantly. One woman, in whom methotrexate failed, required open salpingectomy. After these treatments the serum hCG concentration declined below 2 IU/L in all women. Therefore, the short term effectiveness of both treatments was 100%.

Spontaneous intrauterine pregnancy rates until three years after salpingectomy and conservative surgery were assumed to be 39% and 47%, respectively. The intrauterine pregnancy rate after salpingectomy with additional FVF treatment was assumed to be 63% (39% spontaneous pregnancy rate plus three additional IVF-cycles in couples who did not achieve a spontaneous intrauterine pregnancy within three years of the initial ectopic pregnancy).

Economic costs

Resource units used for each treatment and their prices are presented in Table 2. The distributions of the number of hospital days per patient and the number of hCG measurements per patient appeared to be skewed and were tested for statistical significance using nonparametric tests. However, from an economic perspective, we were interested in the mean number of used resources. The mean number of hospital days per patient was 2.8 in the patients treated with salpingectomy and 3.0 in the patients treated with conservative surgery. The mean number of serum hCG measurements for the two groups were 2 and 4, respectively. Table 3 shows the short term costs per patient for salpingectomy and conservative surgery. The mean direct and indirect costs of salpingectomy were £1221 and £333, respectively (total £1554 [95% CI £1501–1656]). For conservative surgery these costs were £1391 and £396, respectively (total £1787 [95% CI £1683–1930]), an increase in costs of £243 compared with salpingectomy. The mean difference in short term costs was £233 [95% CI £80–371].

Table 2.  Resources used for laparoscopic salpingectomy and conservative surgery and their unit prices. Values are numbers unless stated otherwise
 Salpingectomy(n= 39)Conservative surgery(n= 76)PUnit price (£)
  1. *Student's t test; Mann-Whitney U test; χ2test

Operation time (min): mean (SD)77 (22)64(27)t =−2.4;P = 0.018*306 + 3.56/min
Conversions laparoscopy - open surgery01 416 + 3.56/min
Hospital stay/patient (days): median (range)3 (2-5)3 (2.8)P = 0.64189
Patients with blood transfusions10 77
No. of serum hCO measurements/patient: median (range)2 (1-8)4 (2.8)t = 5.9;P < 0.00115
Patients with interventions for persistent trophoblast117X2= 7.6 P= 0.006 J812
Hospital visits after discharge per patient11 57
Mean number of days of work10,111010 36
Repeat ectopic pregnancy rate (%)1015 1554/1787§
Infertility investigations and treatment (%)3,4,1261 3276
Table 3.  Total costs and effectiveness per treatment for long term outcome. Costs are given in pounds sterling (£) and rates (%) in parentheses
 Salpingectomy (reference)Conservative surgerySalpingectomy with subsequent IVF-ET
 Cost (E) Rate (%)Cost (E) Rate (%)Cost (E) Rate (%)
Total short term costs155417871554
Costs of repeat ectopic pregnancy143225143
Cost of infertility treatment  3761
Total costs169720125458
Intrauterine pregnancy rate (assumed3–5)(39)(47)(63)
Incremental costs (extra costs compared with reference) 3253761
Incremental intrauterine pregnancy rate (compared with reference) (8)(24)
Incremental cost effectiveness ratio (cost per subsequent intrauterine pregnancy) 406315,629

Long term costs are also presented in Table 3. The mean total cost of salpingectomy was £1697 per patient, the cost of conservative surgery was £2012 per patient, and the mean of laparoscopic salpingectomy with additional IVF treatment for subsequent infertility was £5458 per patient.

Economic evaluation

From the short term perspective, salpingectomy was as effective as conservative surgery, but less costly (Table 3). In the long term we assumed the spontaneous intrauterine pregnancy rate after conservative surgery to be 8% higher than after salpingectomy. The incremental cost effectiveness ratio of conservative surgery compared with the reference treatment (salpingectomy without subsequent IVF-ET) is £4063 per subsequent continuing intrauterine pregnancy ([£2012 −£1687] / [47%− 39%]), whereas the incremental cost-effectiveness ratio of laparoscopic salpingectomy with additional IVF treatment for infertility compared with this reference strategy is £15,629 per subsequent continuing intrauterine pregnancy ([£5448 −£1697] / [63%− 39%]).

Threshold and sensitivity analysis

Threshold analysis revealed that the spontaneous intrauterine pregnancy rate after conservative surgery should be at least 41.2%— an increase of 2.2% compared with salpingectomy — to make this treatment as cost-effective as salpingectomy with additional IVF treatment. At this threshold difference, the increase in spontaneous pregnancy rate and the reduced need for subsequent IVF-ET balances the additional short term cost of conservative surgery. A rate difference of 2.2% is equivalent to a pregnancy rate ratio of 1.06 with conservative surgery compared with salpingectomy, which is within the 95% confidence interval of the pregnancy rate ratio reported by Job-Spira et al.5.

Figure 1 shows the results of the sensitivity analysis. The effect of several variables on the calculated threshold is plotted. Variation of the proportion of patients needing interventions for persistent trophoblast between 5% and 40% causes a shift in the threshold between 0.7% and 3.7%. Variation of the repeat ectopic pregnancy rate after conservative laparoscopic surgery between 10.7% and 20% varies the threshold between 1.8% and 2.7%. Reducing the costs of IVF treatment to £1192 per IVF cycle would make conservative laparoscopic surgery cost effective at a difference in spontaneous pregnancy rate of 4.1%. IVF costs of £6360 per cycle would require a difference in spontaneous pregnancy rate of only 0.9% to make the two treatments equally cost effective. Variation of the success rate of three cumulative IVF cycles between 22% and 47% causes a threshold shift between 1.8% and 2.8%.

image

Figure 1. Sensitivity analysis on long term cost-effectiveness. The dots represent the threshold value of 2.2% calculated under baseline assumptions, required to make conservative surgery and salpingectomy with subsequent IVF-ET equally cost effective. Below this threshold salpingectomy with IVF-ET is more cost effective, whereas above this threshold conservative surgery is more cost effective. Each line indicates the range of threshold values that occurs after variation of one of the assumptions.

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DISCUSSION

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. METHODS
  5. RESULTS
  6. DISCUSSION
  7. References

This study compares laparoscopic salpingectomy and conservative surgery for the treatment of tubal pregnancy from an economic perspective. Salpingectomy is the preferred treatment in patients with tubal pregnancy who do not desire future fertility. From the long term perspective, salpingectomy appears to be less effective and less costly than conservative surgery. Threshold analysis showed that the spontaneous pregnancy rate after conservative surgery should be at least 41.2%, an increase of 2.2% compared with salpingectomy, to make it as cost effective as laparoscopic salpingectomy with additional IVF-ET in case of infertility. In other words, the benefit of conservative surgery should be an increase in spontaneous intrauterine pregnancy rate of 2.2% to justify the additional costs caused by persistent trophoblast. If conservative surgery is less effective, it is preferable from an economic point of view to allocate the available resources to future infertility treatment.

The direct short term costs presented in our study are based on used resource units counted in a nonrandomised study. Potential bias caused by a more severe clinical picture in women undergoing salpingectomy could influence the results. This bias would favour the costs and effectiveness of conservative treatment, and therefore mask any difference. Despite this potential bias, our study shows salpingectomy to be less costly in the short term.

The mean number of serum hCG measurements after salpingectomy was two, whereas theoretically one measurement would suffice. Apparently, more serum hCG measurements were performed than strictly required, thereby illustrating that cost calculations should be based on real observations rather than on theoretical assumptions.

The success rate of IVF-ET is supposed to be 39% after three cycles. One could argue that the IVF-ET success rate is higher in women with a history of tubal pregnancy. However we could not find an IVF-ET success rate for such women documented in the literature. The sensitivity analysis shows that an increase of the IVF-ET success rate to 47% only marginally affects the calculated threshold (i.e. the threshold would rise from 2.2% to 2.8%). Furthermore, we assumed IVF-ET to be available for all women who became infertile after salpingectomy, in accordance with the situation in The Netherlands. The fact that IVF-ET is not universal and not always available to infertile women, for instance for women in the National Health Service in the United Kingdom, puts a different complexion on the matter. Absence of the possibility of IVF-ET hampers the comparison between conservative surgery and salpingectomy with IVF-ET, and makes preservation of fertility more important.

This study compared effectiveness and economic costs, whereas psychological costs were not taken into account. Our model assumed women who failed to conceive after salpingectomy to be treated with IVF-ET. The fact that IVF-ET is a very demanding treatment is an additional argument in favour of conservative surgery as compared with salpingectomy with IVF-ET.

Although conservative surgery has been employed for almost forty years, its long term effectiveness has never been compared with salpingectomy in a randomised clinical trial14. Available information from cohort studies suggests that there is a slight improvement in fertility rate after conservative surgery, and an increased rate of repeat ectopic pregnancy; but the strength of this evidence is weakened by methodological shortcomings. Therefore, the most important conclusion to be drawn from the present analysis is not that conservative surgery is superior to salpingectomy, but that better evidence is required in the comparison of conservative laparoscopic surgery and salpingectomy. Well designed randomised controlled trials comparing salpingectomy and conservative surgery are therefore urgently needed. Such trials should focus on the 2.2% difference in spontaneous pregnancy rate after conservative surgery.

Acknowledgements

This study was supported by grant OG 93/007 from the Dutch Health Insurance Funds Council, Amstelveen, The Netherlands.

References

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. METHODS
  5. RESULTS
  6. DISCUSSION
  7. References