An economic comparison of a laparoscopic electrocautery strategy and ovulation induction with recombinant FSH in women with clomiphene citrate-resistant polycystic ovary syndrome

M. van Wely1,3, N. Bayram1, F. van der Veen1 and P.M.M. Bossuyt2

1 Center for Reproductive Medicine, Department of Obstetrics and Gynaecology (H4-205), and 2 Department of Clinical Epidemiology and Biostatistics, Academic Medical Center, University of Amsterdam, P.O.Box 22700, 1100 DE Amsterdam, The Netherlands

3 To whom correspondence should be addressed. Email: m.vanwely{at}amc.uva.nl


    Abstract
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
BACKGROUND: Recombinant FSH (rFSH) is the current standard treatment for ovulation induction in women with polycystic ovary syndrome (PCOS) that do not respond to clomiphene citrate. Ovulation induction with rFSH is known to be costly due to the necessity of daily injections and intensive monitoring. An alternative strategy, starting with electrocautery of the ovaries, may be a less costly option. METHODS: An economic evaluation was set up alongside a multicentre randomized clinical trial comparing laparoscopic electrocautery of the ovaries, followed by clomiphene citrate and rFSH when anovulation persisted, and treatment with rFSH in 168 women with clomiphene citrate-resistant PCOS. Data on resources used for treatment and productivity loss were collected prospectively up to an eventual ongoing pregnancy with a time horizon of 12 months. RESULTS: At 12 months the ongoing pregnancy rates were 67% for both the electrocautery strategy and rFSH treatment. Mean total costs per woman were {euro}5308 for the electrocautery strategy and {euro}5925 for treatment with rFSH, resulting in a mean difference of {euro}617 (95% CI: –{euro}382 to {euro}1614). CONCLUSIONS: The total treatment costs up to an ongoing pregnancy are comparable for rFSH treatment and an alternative strategy starting with electrocautery. Due to a lower number of multiple pregnancies, the electrocautery strategy can be expected to result in lower total costs when costs of the delivery are included.

Key words: cost minimization/gonadotrophin/laparoscopic electrocautery/ovulation induction/PCOS


    Introduction
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
Polycystic ovary syndrome (PCOS) is estimated to affect ~7% of women (Balen and Michelmore, 2002Go). Most women with PCOS who seek treatment or counselling do so because of infertility due to chronic anovulation. The drug of first choice in these women is clomiphene citrate. Those 20% of women who do not ovulate on the maximal dose of 150 mg are referred to as clomiphene citrate resistant (Imani et al., 1998Go). In clomiphene citrate-resistant women, ovulation induction with gonadotrophins is a well-established treatment. At present, recombinant FSH (rFSH) is widely used.

Laparoscopic electrocautery of the ovaries is an alternative treatment for women with clomiphene citrate-resistant PCOS. In previous studies, electrocautery of the ovaries was shown to result in resumption of regular ovulatory function (Gjonnaess, 1984Go; Farquhar et al., 2004Go).

We recently conducted a randomized clinical trial to compare the effectiveness of a treatment strategy entailing electrocautery of the ovaries followed by clomiphene citrate and rFSH when anovulation persisted, versus ovulation induction with rFSH alone (Bayram et al., 2004Go). We chose to study this electrocautery strategy, rather than laparoscopic electrocautery of the ovaries only, for two reasons. First, uncontrolled studies have shown that some anovulatory women may respond again to clomiphene citrate after electrocautery of the ovaries (Gjonnaess, 1984Go; Greenblatt and Casper, 1987Go; Armar et al., 1990Go; Merchant, 1996Go; Felemban et al., 2000Go). Second, it seems logical to attempt ovulation induction with rFSH in women who still fail to ovulate after electrocautery and clomiphene citrate, before proceeding to the costly and burdensome procedure of IVF.

Primary outcome of the trial was ongoing pregnancy rate with a time horizon of 12 months. The electrocautery strategy was found to be equivalent to ovulation induction with rFSH alone with ongoing pregnancy rates of 67% for both strategies. The major difference between the two strategies was a lower number of multiple pregnancies in the group first treated with electrocautery and clomiphene citrate prior to rFSH.

As the two arms of the study produced similar results apart from the differences in multiple pregnancy rates, costs may play an important role in deciding which treatment to give to a patient. Ovulation induction with rFSH is known to be costly due to the necessity of daily injections and intensive monitoring to prevent ovarian hyperstimulation and multiple pregnancies. Electrocautery of the ovaries is supposed to be a less costly and less burdensome treatment option, as it essentially involves a single operation only. In order to make an economic comparison of the electrocautery strategy and ovulation induction with rFSH, we collected prospective data during the trial to calculate the costs of both treatment strategies.


    Materials and methods
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
Patients
Women with chronic anovulation, World Health Organization type II (Rowe, 1993), polycystic ovaries on transvaginal ultrasonography and not responding to 150 mg clomiphene citrate were eligible for the trial. Women with other causes of infertility, including severe male subfertility and maternal age >40 years were excluded. Consenting women were randomly assigned on a 1:1 basis to receive either a treatment strategy entailing laparoscopic electrocautery of the ovaries followed by clomiphene citrate and rFSH when anovulation persisted or to ovulation induction with rFSH.

Before randomization, all women underwent a diagnostic laparoscopy such that women with a tubal obstruction and/or adhesions could be excluded from the trial. Immediately following the diagnostic laparoscopy, patients were randomized by using a computer program with block randomization, stratified for Center. Participating centres called the Center for Reproductive Medicine in the Academic Medical Center, which acted as the trial co-ordination centre. The trial took place in 29 Dutch hospitals (Bayram et al., 2004Go).

Electrocautery was performed using an Erbotom ICC 350 Unit (Erbe BV, The Netherlands) and done with a bipolar insulated needle-electrode. Depending on the size of the ovary, we created 5–10 punctures on each ovary distributed randomly over the surface. Clomiphene citrate was given when anovulation persisted within 8 weeks following electrocautery or if anovulation recurred during follow-up. Women who did not ovulate on 150 mg clomiphene citrate received rFSH as described below.

Patients randomized to gonadotrophins were treated with rFSH (follitropin alpha, Gonal-F; Serono Benelux BV, The Netherlands), administered in a chronic low-dose step-up protocol. rFSH was given until six ovulatory cycles were reached within 1 year. Details on these treatment regimens have been published elsewhere (Bayram et al., 2004Go).

In both treatment arms, follicle development was monitored by transvaginal ultrasonography at weekly intervals or more frequently if indicated by follicle growth. The surgical procedures were performed in a day care setting.

Costs
The cost analysis was performed from a societal perspective. A distinction was made between costs of medical interventions (direct costs) and costs resulting from productivity losses (indirect or time costs). Standardized unit costs were calculated for the Academic Medical Center based on actual expenses made during the study, using year 2000 prices. Subsequently, unit costs were applied to resource use observed in all trial centres.

Resource utilization was documented using individual patient data in the case record forms. For each patient, we measured and registered duration of the diagnostic laparoscopy, duration of the electrocautery of the ovaries, hospital stay, transvaginal ultrasonography, endocrine screening, rFSH use, and visits to the outpatient clinic. In addition, each woman was sent a questionnaire for details on associated direct costs of professional care, and on indirect costs such as transportation and productivity loss. These questionnaires were sent 2, 12 and 24 weeks after the diagnostic laparoscopy. The mean results from the rFSH group were used to estimate the costs of professional care and indirect costs of rFSH treatment in the electrocautery strategy.

Resource unit prices reflected the unit of staff, materials, equipment, housing, depreciation, and overheads. Productivity loss was valued using Dutch reference data from the handbook of the Dutch Health Council (Oostenbrink et al., 2000Go). Costs are expressed in euro ({euro}).

Analysis
Given the equivalence between the two strategies in terms of ongoing pregnancy rate—the primary outcome measure—our analysis focused on the cost difference between the two strategies within a time horizon of 12 months. Costs were expressed as means per woman. For the electrocautery strategy, weighted means reflecting the subsequent treatments were determined. All outcomes were analysed according to the intention-to-treat principle.

To explore the effect of plausible changes in key variables, a sensitivity analysis was performed. Key variables considered were number of outpatient clinic visits and number of endocrine screens. A scenario analysis was performed to evaluate the costs in a scenario without a diagnostic laparoscopy. Delivery costs were also estimated on basis of the literature.


    Results
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
From February 1998 to October 2001, 213 eligible women with clomiphene citrate-resistant PCOS were invited to participate in the study. Five of these women became pregnant while waiting for laparoscopy, one had a language barrier and three were too obese to undergo general anaesthesia. A further 27 did not give informed consent.

At laparoscopy, nine women were excluded for the following reasons: one had endometriosis, five had adhesions, two had tubal occlusions and in one woman electrocautery was not feasible. Of the 168 included women, 83 were randomly allocated to the electrocautery strategy and 85 to rFSH (Figure 1). Baseline characteristics of the two groups appeared to be equally distributed (Table I).



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Figure 1. Flowchart.

 

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Table I. Baseline characteristics

 
Within a time span of 12 months, 67% of the women allocated to the electrocautery strategy and 67% of the women in the rFSH group reached an ongoing pregnancy [relative risk (RR) 1.01, 95% CI: 0.81 to 1.24]. This resulted in a live birth rate of 64% with the electrocautery strategy versus 60% after ovulation induction with rFSH (RR 1.1, 95% CI: 0.84 to 1.35).

Average use of resources for the electrocautery strategy and the rFSH group are presented in Table II, as well as unit prices. The mean (SD) operation time of the laparoscopic procedure was 19 (7) min and of the electrocautery procedure 20 (10) min. The mean (SD) number of outpatient visits as well as the transvaginal ultrasonographies for women allocated to the electrocautery strategy and rFSH were 18 (8) and 12 (9) respectively.


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Table II. Average use of resources for the electrocautery strategy and recombinant (r)FSH treatment and unit prices

 
In five of the 35 women treated at the Academic Medical Center, the anaesthetist recommended a 24 h stay as the body mass index (BMI)>35 kg/m2 was considered to be associated with an increased surgical risk. This practice was not seen in the other participating centres whether the BMI was >35 kg/m2 or not.

The questionnaires on domiciliary care and productivity loss were returned by 78 women (94%) treated with the electrocautery strategy and by 74 women (87%) who were treated primarily with rFSH. The general practitioner was visited on average almost two times in both groups. Professional domiciliary care and visits to medical specialists elsewhere were never reported. Of all women in the study, 115 (68%) were employed at the start of the treatment. Mean (SD) productivity losses were 7.4 (3.5) days in women allocated to the electrocautery strategy and 5.9 (4.0) days in women allocated to rFSH treatment. On average, women took 3 days off to recover from the laparoscopic procedure as well as an additional half a day for each visit to the outpatient clinic.

The composition of the costs is shown in Table III. The mean (SD) direct medical costs until an ongoing pregnancy or during a treatment time of 1 year were {euro}4664 ({euro}1967) for women allocated to the electrocautery strategy versus {euro}5418 ({euro}3785) for women allocated to rFSH treatment respectively. The mean (SD) 12 months total costs until an ongoing pregnancy were {euro}5308 ({euro}2211) for the electrocautery strategy versus {euro}5925 ({euro}4063) for rFSH treatment. Although both direct and total costs were lower in the electrocautery strategy group these differences were not significantly different from zero. The mean difference in direct medical costs was {euro}754 (95% CI –{euro}149 to {euro}1649). The difference in total costs was {euro}617 (95% CI –{euro}382 to {euro}1614).


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Table III. Mean cost ({euro}) per woman per cost category

 
Scenario and sensitivity analyses
In this trial, all women underwent a diagnostic laparoscopy. In a more realistic scenario, a diagnostic laparoscopy would not be required for ovulation induction with rFSH. In that case the mean (SD) direct medical costs for rFSH treatment would be {euro}4864 ({euro}3638) and the mean total costs {euro}5371 ({euro}4022). The resulting costs difference compared to the electrocautery strategy would be lower: {euro}200 for direct medical costs and {euro}63 for total costs respectively.

Sensitivity analyses showed that the cost difference in both groups was sensitive to changes in the number of monitoring visits (including transvaginal ultrasonography). A decrease of ≥40% in monitoring visits during rFSH treatment would be necessary to make ovulation induction with rFSH less expensive than the electrocautery strategy. However, such a decrease in monitoring visits is not an option, as intensive monitoring during rFSH treatment is absolutely required to prevent multiple follicular development and the development of multiple pregnancies.

The risk for these complications after electrocautery of the ovaries is almost nil. The same accounts for women treated with clomiphene citrate. Hence monitoring can safely be minimized in women treated with electrocautery and clomiphene citrate, making the electrocautery strategy less expensive. In order to investigate the effect of such limited monitoring, we performed a scenario analysis in which we compared the electrocautery strategy with limited monitoring and ovulation induction with rFSH without a preceding laparoscopy. The number of monitoring visits was limited to only one after electrocautery, and one when it was decided to administer clomiphene citrate. Furthermore, we registered a monitoring visit at the occurrence of a pregnancy and a miscarriage. According to this scenario, the mean differences in direct and total costs were {euro}1978 and {euro}2110 respectively in favour of the electrocautery strategy.


    Discussion
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
This study compared the costs of ovulation induction with an electrocautery strategy versus those of rFSH treatment in women with clomiphene citrate-resistant PCOS. The mean total costs per woman until an ongoing pregnancy were slightly lower for women assigned to the electrocautery strategy, with substantial between-patient variability and without statistical significance, {euro}5308 versus {euro}5925. A scenario without a diagnostic laparoscopy preceding rFSH treatment led to almost equivalent costs of the two treatment regimens.

This economic evaluation represents the costs in The Netherlands. It should be realized that costs of laparoscopic electrocautery and rFSH may differ between countries, and therefore our results cannot unconditionally be generalized to all circumstances.

In our study, all women had a diagnostic laparoscopy to rule out tubal obstructions and adhesions. As a consequence, the costs of ovulation induction with rFSH without a preceding diagnostic laparoscopy could only be calculated by subtracting the costs of the diagnostic laparoscopy and the associated costs of hospital stay. This seems justified since laparoscopy itself did not lead to any complications.

A diagnostic laparoscopy is not a standard procedure before ovulation induction with rFSH. In our trial, nine women were excluded at laparoscopy, one had endometriosis, five had adhesions, two had tubal occlusions and in one woman electrocautery was not feasible. The tubal occlusions could have been detected by hysterosalpingography but the endometriosis and adhesions would not have been diagnosed without a laparoscopy. Therefore, in six of the 177 women (3.4%) that underwent a diagnostic laparoscopy, an aberration was found that would have had a negative impact on rFSH treatment. Such a low percentage of women does not seem to support the standard use of a diagnostic laparoscopy preceding rFSH treatment.

For the electrocautery strategy, the main cost item was monitoring. The costs of rFSH treatment were associated with the use of rFSH ampoules and the monitoring. Ovulation induction with rFSH is known to require intensive monitoring (Bayram et al., 2004Go; van Wely et al., 2003Go). However, a less intensive monitoring can be realized in the electrocautery strategy. A scenario analysis with limited monitoring after the laparoscopic electrocautery and during clomiphene citrate treatment resulted in considerably lower costs for this strategy. Although we cannot exclude that the reduction in monitoring after electrocautery reduces the success rate, we feel that this is unlikely, as in uncontrolled studies with limited monitoring, comparable and sometimes even higher pregnancy rates were found. Basal body temperature measurements by the patient herself should be sufficient. In the scenario analysis we also reduced the monitoring during clomiphene citrate treatment to a minimum of two visits to explore the cost reduction. Monitoring during clomiphene citrate treatment is not recommended by the Dutch Society for Obstetrics and Gynaecology nor by the National Institute of Clinical Excellence of the British National Health Service (http://www.nvog.nl/files/02_anovulatie_en_kinderwens.pdf and http://www.nice.org.uk/pdf/CG011niceguideline.pdf).

The indirect or time costs made up only 10% of the total. There were productivity losses in both treatment groups. As the women included in the study were healthy women with a fertility problem, the productivity losses were limited. Women usually took 3 days off to recover from the laparoscopic procedure and were absent for half a day for the outpatient clinic visits.

Ovarian failure and post-operative adhesion formation have been described to occur after electrocautery and could in theory lead to extra use of medical resources. As we limited the time horizon for our trial to 12 months, we could not study the possible long-term effect of laparoscopic electrocautery on ovarian function. However, the high pregnancy rate after additional clomiphene citrate and rFSH suggests that postoperative adhesion formation is not a significant problem.

We had defined our economic evaluation as a cost minimization analysis as the electrocautery strategy was equivalent to ovulation induction with rFSH with respect to the ongoing pregnancy rate. Women allocated to the electrocautery strategy, however, had a significantly lower risk for multiple pregnancies (RR 0.11, 95% CI: 0.01 to 0.88). All multiple pregnancies resulted from ovulation induction with rFSH. Of the 104 babies born, nine were twins and one was a triplet. One twin was born after successful secondary rFSH treatment in the electrocautery strategy group. The other nine multiple pregnancies were born after primary rFSH treatment.

As the endpoint of our trial was an ongoing pregnancy and not a delivery, this study does not allow for a precise estimate of the cost differences between singleton and multiple deliveries. In an attempt to explore the cost consequences of multiple pregnancies, we extracted data on costs of delivery and hospital stay of mother and child from the literature. Several studies have assessed the costs of IVF and many point to the large contribution of multiple pregnancies. In one study, the hospital charges for deliveries at a hospital in Boston were determined from 1986 to 1991 (Callahan et al., 1994Go). It was calculated that the costs of hospital delivery were multiplied by 1.9 per child for a twin pregnancy and 3.7 per child for a triplet pregnancy. In another study the costs of assisted reproduction for a Health Maintenance Organization in the USA was calculated (Hidlebaugh et al., 1997Go): there were almost equal costs per infant born for a singleton and twin pregnancy and a 5-fold increase per infant for a triplet pregnancy. In a Swedish study the costs of single and multiple pregnancies were compared based on 1995 data following assisted reproduction (Wolner-Hanssen and Rydhstroem, 1998Go). Sweden has a health care system comparable to that in The Netherlands. According to these calculations the costs of twin pregnancies would be 7.7 times as high as the costs of singleton pregnancies.

As an approximation, we extrapolated the Swedish data for hospital care of the mother, delivery and neonatal care, to the year 2000. The costs per twin would then be {euro}22 117 versus {euro}2879 per singleton.

Based on these data, we estimated the direct medical costs per term pregnancy including treatment and delivery costs for a woman allocated to rFSH to be {euro}14 489. These costs are comparable to those previously found on ovulation induction with FSH in clomiphene citrate-resistant women with PCOS (Fridstrom et al., 1999Go). The estimated direct medical cost per term pregnancy including treatment and delivery costs for a woman allocated to the electrocautery strategy was {euro}11 301, which is 22% lower than in women allocated to rFSH treatment. However, it should at this point be realized that, if multiple pregnancies after rFSH treatment could be prevented, the costs per delivery would be similar in both treatment groups.

In summary, it can be concluded that the mean treatment costs until an ongoing pregnancy are comparable for a strategy that starts with an electrocautery strategy compared to the standard therapeutic strategy that relies on rFSH. Yet due to the risk of multiple pregnancies with rFSH treatment, the electrocautery strategy can be expected to result in lower delivery costs and therefore lower total costs.


    References
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
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Submitted on January 6, 2004; accepted on April 22, 2004.