Human Reproduction, Vol.30, No.9 pp. 2038 –2047, 2015 Advanced Access publication on July 13, 2015 doi:10.1093/humrep/dev162

ORIGINAL ARTICLE Early pregnancy

Cost-effectiveness of salpingotomy and salpingectomy in women with tubal pregnancy (a randomized controlled trial)

1 Centre for Reproductive Medicine, Academic Medical Centre, University of Amsterdam, Amsterdam, The Netherlands 2Department of Obstetrics and Gynaecology, Academic Medical Centre, University of Amsterdam, Amsterdam, The Netherlands 3Sahlgrenska University Hospital, Go¨teborg, Sweden 4University College London Hospital, London, UK 5King’s College Hospital, London, UK 6Wake Forest University School of Medicine, Winston-Salem, NC, USA 7Penn Fertility Care, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA 8Onze Lieve Vrouwe Gasthuis, Amsterdam, The Netherlands 9Antonius Hospital, Nieuwegein, The Netherlands 10Ma´xima Medical Centre, Veldhoven, The Netherlands 11School of Paediatrics and Reproductive Health, University of Adelaide, Adelaide, SA, Australia

*Correspondence address. E-mail: [email protected]

Submitted on November 23, 2014; resubmitted on March 12, 2015; accepted on June 1, 2015

study question: Is salpingotomy cost effective compared with salpingectomy in women with tubal pregnancy and a healthy contralateral tube? summary answer: Salpingotomy is not cost effective over salpingectomy as a surgical procedure for tubal pregnancy, as its costs are higher without a better ongoing pregnancy rate while risks of persistent trophoblast are higher.

what is known already: Women with a tubal pregnancy treated by salpingotomy or salpingectomy in the presence of a healthy contralateral tube have comparable ongoing pregnancy rates by natural conception. Salpingotomy bears the risk of persistent trophoblast necessitating additional medical or surgical treatment. Repeat ectopic pregnancy occurs slightly more often after salpingotomy compared with salpingectomy. Both consequences imply potentially higher costs after salpingotomy. study design, size, duration: We performed an economic evaluation of salpingotomy compared with salpingectomy in an international multicentre randomized controlled trial in women with a tubal pregnancy and a healthy contralateral tube. Between 24 September 2004 and 29 November 2011, women were allocated to salpingotomy (n ¼ 215) or salpingectomy (n ¼ 231). Fertility follow-up was done up to 36 months post-operatively. participants/materials, settings, methods: We performed a cost-effectiveness analysis from a hospital perspective. We compared the direct medical costs of salpingotomy and salpingectomy until an ongoing pregnancy occurred by natural conception within a time horizon of 36 months. Direct medical costs included the surgical treatment of the initial tubal pregnancy, readmissions including reinterventions, treatment for persistent trophoblast and interventions for repeat ectopic pregnancy. The analysis was performed according to the intention -to-treat principle. main results and the role of chance: Mean direct medical costs per woman in the salpingotomy group and in the salpingectomy group were E3319 versus E2958, respectively, with a mean difference of E361 (95% confidence interval E217 to E515). Salpingotomy resulted in a marginally higher ongoing pregnancy rate by natural conception compared with salpingectomy leading to an incremental cost-effectiveness ratio E40 982 (95% confidence interval 2E130 319 to E145 491) per ongoing pregnancy. Since salpingotomy resulted in more additional treatments for persistent trophoblast and interventions for repeat ectopic pregnancy, the incremental cost-effectiveness ratio was not informative. †

The ESEP Group members are listed in the Appendix.

& The Author 2015. Published by Oxford University Press on behalf of the European Society of Human Reproduction and Embryology. All rights reserved. For Permissions, please email: [email protected]

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F. Mol1,*, N.M. van Mello 2, A. Strandell 3, D. Jurkovic4, J.A. Ross 5, T.M. Yalcinkaya6, K.T. Barnhart 7, H.R. Verhoeve 8, G.C. Graziosi 9, C.A. Koks 10, B.W. Mol11, W.M. Ankum 2, F. van der Veen1, P.J. Hajenius 2, and M. van Wely 1, for the European Surgery in Ectopic Pregnancy (ESEP) study group†

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Cost-effectiveness of tubal pregnancy interventions

limitations, reasons for caution: Costs of any subsequent IVF cycles were not included in this analysis. The analysis was limited to the perspective of the hospital.

wider implications of the findings: However, a small treatment benefit of salpingotomy might be enough to cover the costs of subsequent IVF. This uncertainty should be incorporated in shared decision-making. Whether salpingotomy should be offered depends on society’s willingness to pay for an additional child. study funding/competing interest(s): Netherlands Organisation for Health Research and Development, Region Va¨stra Go¨taland Health & Medical Care Committee.

trial registration number: ISRCTN37002267. Key words: ectopic pregnancy / laparoscopy / randomized controlled trial / cost-effectiveness / surgery

Materials and Methods

Ectopic pregnancy affects 1– 2% of all pregnant women (Barnhart, 2009). Most ectopic pregnancies are located in the Fallopian tube, and surgery is generally accepted as the treatment of first choice (Hajenius et al., 2007). Historically, surgical treatment involved a radical approach, i.e. salpingectomy, to achieve rapid haemostasis since tubal rupture was usually present. From 1957 onwards, the concept of preservation of the tube was propagated over ablative surgery to maintain women’s fertility (Miller, 1957). Nowadays, early diagnosis has enabled conservative surgery by salpingotomy. Salpingotomy preserves the tube, but carries the risks of persistent trophoblast and repeat tubal pregnancy in the same tube. Salpingectomy minimizes these risks, but leaves only one tube available for conception, which might reduce fertility potential. We recently completed the European Surgery in Ectopic Pregnancy (ESEP) study, an international multicentre randomized controlled trial to compare the effectiveness of salpingotomy with salpingectomy in women with tubal pregnancy (Mol et al., 2014). We randomly assigned women with a laparoscopically confirmed tubal pregnancy and a healthy contralateral tube to either salpingotomy or salpingectomy. A healthy tube was defined as a tube with a normal macroscopic aspect during surgery. To assess fertility after surgery, researchers contacted the participants every 6 months for 36 months. If an ongoing pregnancy did not occur, follow-up ended at the last date of contact, or at the moment when either IVF or reconstructive tubal surgery was done. This trial showed a non-significantly higher rate of ongoing pregnancy by natural conception within a time horizon of 36 months after salpingotomy compared with salpingectomy. However, there were significantly more women with persistent trophoblast and there was a slightly higher but non-significant repeat ectopic pregnancy rate after salpingotomy. As the two arms of the trial had comparable ongoing pregnancy rates, but showed differences in persistent trophoblast and repeat ectopic pregnancy rates, costs may then play an important role in deciding which treatment should prevail. Salpingotomy incurs additional costs of routine post-operative blood tests (serum hCG) to detect persistent trophoblast in a significant number of women. If present, this adds the costs of systemic methotrexate treatment and occasional surgical re-intervention. A higher rate of repeat ectopic pregnancy also implies higher costs. Salpingectomy is supposed to be a less costly treatment option, as it usually involves a single operation, and a repeat ectopic pregnancy in the same tube occurs very rarely. The aim of this study was to calculate the costs of both treatments and provide an economic evaluation of salpingotomy compared with salpingectomy.

Study design The economic evaluation was conducted alongside the ESEP study. This trial was an international multicentre randomized controlled trial that compared salpingotomy and salpingectomy in women with a tubal pregnancy and a healthy contralateral tube (Mol et al., 2014). Women were eligible for the trial if they had a presumptive diagnosis of tubal pregnancy and were scheduled for surgery. At surgery, the presence of a tubal pregnancy had to be confirmed. Women were not eligible if the condition of the contralateral tube was so abnormal according to the surgeon, that future pregnancy was unlikely in case the woman was randomly assigned to salpingectomy (e.g. hydrosalpinx, severe peri tubal adhesions or malformations). Salpingotomy and salpingectomy were performed following local procedural standards used in the participating hospitals. Salpingotomy was converted to salpingectomy and laparoscopy was converted to open surgery when clinically necessary. Serum hCG was followed weekly until it became undetectable in both study groups, to detect persistent trophoblast. Women were contacted every 6 months for a period of 36 months to assess fertility. A total of 450 women were enrolled in the trial between 24 September 2004 and 29 November 2011. Four women from one hospital were excluded owing to the inability of that hospital to provide any data on these women. Thus, of 446 women, 215 were randomly allocated salpingotomy and 231 were randomly allocated to salpingectomy. In February 2013, the trial was completed. Twenty-four women (5.4%) were lost to fertility follow-up, 11 (5.1%) in the salpingotomy group and 13 (5.6%) in the salpingectomy group (P-value 0.82). Ongoing pregnancy by natural conception was comparable in both groups. The cumulative ongoing pregnancy rate was 60.7% after salpingotomy and 56.2% after salpingectomy (fecundity rate ratio 1.06; 95% CI, 0.81– 1.38; Log rank test P-value 0.678). Persistent trophoblast occurred more frequently in the salpingotomy group than in the salpingectomy group: 14 (7%) versus 1 (,1%); rate ratio 15; 95% CI 2.0 – 113.4. Repeat ectopic pregnancy occurred in 18 women (8%) in the salpingotomy group versus 12 (5%) in the salpingectomy group (rate ratio 1.6; 95% CI 0.8 – 3.3).

Economic evaluation For the cost analysis we used data from the 446 randomized women. The economic evaluation was designed as a cost-effectiveness analysis, with ongoing pregnancy by natural conception as the clinical outcome (Briggs and O’Brien, 2001). Since comparable cumulative ongoing pregnancy rates were found after salpingotomy and salpingectomy, the secondary outcome measures persistent trophoblast and repeat ectopic pregnancy became relevant for clinical decision-making and were therefore also evaluated as clinical outcomes in this analysis.

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Introduction

2040 The cost analysis was performed from a hospital perspective. Because in the Dutch Health Care system the hospitals bill the patient’s insurance company and are managed on a non-profit basis, these calculated costs were an appropriate measure of the societal cost of direct medical care. In this study only costs of medical interventions (direct costs) were taken into account. In this study we also included costs of repeat ectopic pregnancy although we did not observe a significant difference in repeat ectopic pregnancy rate between salpingotomy and salpingectomy. In a cost-effectiveness analysis, all actual costs are included also of rare events where it is virtually impossible to reach adequate power to prove statistical difference. Costs of repeat ectopic pregnancy were therefore included in both groups.

Resource utilization was documented using individual patient data from the case record form. For each patient, we registered and measured the duration of surgery to perform salpingotomy or salpingectomy, conversions to salpingectomy and/or open surgery, blood transfusions, hospital stay, re-admittances and re-interventions, additional systemic methotrexate treatment or laparoscopic salpingectomy to treat persistent trophoblast, and interventions for repeat ectopic pregnancy. Duration of surgery was defined as time spent in the operating theatre calculated as the interval between the start of general anaesthesia induction and the end of the anaesthesia. The number of disposable bipolar cutting forceps for complete salpingectomy was assumed to equal the number of salpingectomies performed. We used one type of bipolar cutting forceps for unit cost reference (Cutting forcepsw, ACMI USA). The number of serum hCG measurements to detect persistent trophoblast were calculated for salpingotomy (weekly serum hCG until undetectable level) and for salpingectomy (one serum hCG measurement post-operatively at the post-operative consultation in the outpatient clinic). Missing data for duration of surgery and serum hCG monitoring after salpingotomy were imputed using the multiple method (Manca and Palmer, 2005). Resource utilization in terms of diagnostic work-up for the index ectopic pregnancy or any suspected repeat ectopic pregnancy and subfertility work-up or assisted reproductive technology (ART) was not taken into account.

Unit costs Unit costs were estimated with different methods and sources, all according to recent guidelines on costing and health care services (Table I). Recourse unit prices reflected the use of medical staff, materials, equipment, housing, depreciation and overheads. Costs were expressed in euro (E). Standardized unit costs were calculated for the Academic Medical Centre Amsterdam, The Netherlands based on actual expenses made during the trial, using the most recently available unit prices of the year 2009. Subsequently, unit costs were applied to resource use observed in all participating centres.

Statistical analysis All outcomes were analysed according to the intention-to-treat principle. Costs were calculated by multiplying the quantity of resource use and unit costs. Costs were expressed as means and medians per woman. We split costs into four categories: initial surgery, readmission (for other reasons than persistent trophoblast), persistent trophoblast and repeat ectopic pregnancy. The difference in total direct medical costs was expressed as a mean difference. Costs were combined with the clinical outcomes by calculating incremental cost-effectiveness ratios (ICER). An ICER was defined as the ratio of the difference in costs and the difference in effectiveness between two interventions, which reflects the costs needed to obtain one extra unit in health outcome. We calculated ICERs for ongoing pregnancy by natural conception,

persistent trophoblast and repeat ectopic pregnancy. So, the reported ICERs reflect the costs needed to gain one ongoing pregnancy by natural conception, or to prevent one case of persistent trophoblast, or to prevent one case of repeat ectopic pregnancy. For the outcome ongoing pregnancy by natural conception, contingency table analysis was used to calculate the difference in effectiveness compared with survival analysis in the original paper. Statistical uncertainty around the difference in mean costs and ICERs was expressed with 95% CI, estimated by 1000 bootstrap replications. Bootstrapping is based on generating multiple data sets, using sampling with replacement from the original data and calculating the statistic of interest in each set (Barber and Thompson, 2000). Uncertainty of the ICERs was visualized by plotting a cost-effectiveness plane and cost-effectiveness acceptability curves (Black, 1990). Salpingectomy was the reference strategy (in the origin of the cost-effectiveness plane). Cost-effectiveness acceptability curves visualized the increasing probability that salpingotomy is cost-effective for the measured effect when increasing the willingness-to-pay threshold.

Sensitivity and scenario analysis To explore the effect of plausible changes in key variables, a sensitivity analysis was performed. Key variables comprised unit costs of hospital admission and unit costs of use of the operating theatre. Model 1 assumes an overall 30% higher admission costs and operating theatre costs, whereas model 2 assumes an overall 30% lower costs to reflect different cost levels in other countries of hospital types, for example general hospitals. A scenario analysis was performed to evaluate the costs in a scenario in which women return the next day for surgery in a day-care surgery unit compared with the current situation with immediate hospital admission and waiting for an operation room to become available (model 3). Such a scenario would be possible in women diagnosed with tubal pregnancy who are haemodynamically stable and relatively asymptomatic, suggesting a low suspicion of impending tubal rupture. Other scenarios were: a scenario in which disposable bipolar cutting forceps are replaced by re-usable materials (model 4), a scenario with limited serum hCG monitoring after salpingotomy using a serum hCG clearance curve and in which no serum hCG monitoring is done after salpingectomy (model 5), and a scenario with only a home urinary pregnancy test 6 weeks after salpingotomy and no serum hCG monitoring after salpingectomy (model 6). In view of model 5 and 6, women had (weekly) serum hCG monitoring after salpingotomy and salpingectomy in the trial. It is realistic to propose that post-operative serum hCG measurement is not required after salpingectomy since the risk of persistent trophoblast was ,1%. After salpingotomy, persistent trophoblast can be detected early by plotting a single serum hCG measurement within the first week after surgery in the standard serum hCG clearance curve after salpingotomy (Hajenius et al., 1995). All statistical, economic and simulation analyses were performed using SPSS version 19.0 (Chicago, IL, USA) and MICROSOFT EXCEL 2003.

Ethical approval One institutional review board in each country approved the study protocol, after which the boards of directors of all other participating centres provided local approval. Participants provided written informed consent.

Results Resource use Initial admission Laparoscopy was attempted in all women (Table II). Both after salpingotomy and salpingectomy, three women (1%) had a conversion to open surgery. Reasons for these conversions were impaired vision because

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Resource use

Mol et al.

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Cost-effectiveness of tubal pregnancy interventions

Table I Cost analysis: units of resource use, unit costs, valuation method and volume source. Unit

Unit cost (euro)

Valuation method (source)

............................................................................................................................................................................................. Initial admission First admission day*

Day

794

Direct costs from academic hospital

Additional hospital stay

Day

638

Direct costs from academic hospital

Laparoscopy start up

Standard associated costs of operation

355

Direct costs from academic hospital

Theatre

Minute

5.66

Direct costs from academic hospital

Material

177

Direct costs from academic hospital

Disposable cutting forceps

Material

343

Direct costs from academic hospital

Blood transfusion

Gift

208

Direct costs from academic hospital

Re-laparoscopy with salpingectomy

Procedure

1450

Direct costs from academic hospital

Post-operatively Serum hCG measurement order

Measurement

12.90

Dutch costing guideline^

Serum hCG measurement

Measurement

10.36

Dutch Health Authority fares$

Consultation by telephone

Consultation

52

Direct costs from academic hospital

Consultation outpatient clinic

Consultation

138

Direct costs from academic hospital

Hospital admission

Day

638

Direct costs from academic hospital

Diagnostic laparoscopy*

Procedure

525

Direct costs from academic hospital

Laparoscopic salpingectomy

Procedure

1450

Direct costs from academic hospital

Surgical exploration at trocar site*

Procedure

525

Direct costs from academic hospital

20

Dutch Health Authority fares$ fares

Readmission

Persistent trophoblast Systemic methotrexate Kidney, liver function lab tests

Measurement

Methotrexate dosage

Milligram

Day care methotrexate

Day

Serum hCG measurement order

Measurement

12.90

Dutch costing guideline

Serum hCG measurement

Measurement

10.36

Dutch Health Authority fares$ fares

Consultation by telephone

Consultation

52

Direct costs from academic hospital

1450

Direct costs from academic hospital

638

Direct costs from academic hospital

0.21 547

Pharmaco therapeutic compass# Direct costs from academic hospital

Salpingectomy Salpingectomy by laparoscopy

Procedure

Hospital admission

Day

Repeat ectopic pregnancy Laparoscopic salpingotomy (E1750) plus 1 admission day (E794)

Procedure

2544

Direct costs from academic hospital

Laparoscopic salpingectomy (E1450) plus one admission day (E794)

Procedure

2244

Direct costs from academic hospital

Single dose methotrexate

Procedure

697

Direct costs from academic hospital

Multiple dose methotrexate

Procedure

2787

Direct costs from academic hospital

Expectant management

Procedure

200

Direct costs from academic hospital

*Duration of surgery mean 30 min. ^ Reference Dutch Costing Guideline (Hakkaart-van Roijen et al., 2010). # Pharmaco therapeutic compass (College voor Zorgverzekeringen, 2011). $ Hospital pricelist of Dutch Health Authority 2012 (Nederlandse Zorg Autoriteit, www.nza.nl).

of intra-abdominal adhesions or blood clots, or technical difficulties with laparoscopy in obese women. In the salpingotomy group, 43 women (20%) had a conversion to salpingectomy because of persistent uncontrollable bleeding. The mean duration of surgery of the procedures was 90 min for salpingotomy and 75 min for salpingectomy (mean difference 215 min; 95% CI 222 to 28).

In the salpingotomy group, two women (1%) had an immediate re-laparoscopy with salpingectomy for suspected bleeding compared with no re-interventions after salpingectomy. Fourteen (7%) women allocated to salpingotomy and seven (3%) allocated to salpingectomy had one or more units of blood transfusion. The total numberof units packed cellstransfused was 32 after salpingotomy compared with 17 after salpingectomy.

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Conversion to open surgery materials

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Mol et al.

Table II Resource use. Salpingotomy (n 5 215)

Salpingectomy (n 5 231)

........................................................................................ Initial admission Duration of the surgery—mean in 90 (39) minutes (SD)

75 (32)

Conversion to open surgery

3 (1%)

3 (1%) 43 (20%)

NA

Re-laparoscopy with salpingectomy for suspected bleeding

2 (1%)

NA

Blood transfusion

14 (7%)

7 (3%)

Blood transfusion: total no. units

32

17

Serum hCG measurements including consultation by telephone

691

141

Consultations outpatient clinic

215

231

Readmission

15 (5%)

5 (2%)

Repeat laparoscopy with salpingectomy for suspected bleeding

1 (,1%)

0

Other surgical reintervention

4 (2%)

2 (1%)

Readmission onlya

10 (5%)

3 (1%)

Readmission days—no.

38

18

Persistent trophoblast

14 (7%)

1 (

Cost-effectiveness of salpingotomy and salpingectomy in women with tubal pregnancy (a randomized controlled trial).

Is salpingotomy cost effective compared with salpingectomy in women with tubal pregnancy and a healthy contralateral tube?...
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