1 Department of Obstetrics and Gynaecology, St Antonius Hospital, Koekoekslaan 1, Nieuwegein, 2 Department of Obstetrics and Gynaecology, Academic Medical Centre, Meibergdreef 9, Amsterdam, 3 Department of Obstetrics and Gynaecology, St Elisabeth Hospital, Hilvarenbeekseweg 60, Tilburg, 4 Department of Obstetrics and Gynaecology, Tweesteden Hospital, Dr Deelenlaan 5, Tilburg, 5 Department of Obstetrics and Gynaecology, University Medical Centre, Heidelberglaan 100, Utrecht and 6 Department of Obstetrics and Gynaecology, Maxima Medical Centre, De Run 4600, Veldhoven, The Netherlands
7 To whom correspondence should be addressed at: Department of Obstetrics and Gynaecology, St Antonius Hospital, P.O.Box 2500, 3430 EM Nieuwegein, The Netherlands. Email: p.graziosi{at}antonius.net
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Abstract |
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Key words: curettage/early pregnancy failure/economic evaluation/misoprostol
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Introduction |
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Misoprostol treatment is an alternative to curettage in the treatment of early pregnancy failure, and seems to be effective in 5080% of women (Demetroulis et al., 2001; Graziosi et al., 2004
). Misoprostol is inexpensive, easy to use, available on demand and seems to be safe. Therefore, the use of misoprostol in the management of early pregnancy failure with misoprostol has gained in popularity. Thus far, limited research has been done on the economic aspects of misoprostol versus curettage in the treatment of early pregnancy failure (Hughes et al., 1996
; Doyle et al., 2004
). The increased pressure on health care expenses implies that physicians should consider economic aspects as part of the clinical decision-making process.
We recently performed a multicentre, prospective randomized trial in which misoprostol and curettage were compared (Graziosi et al., 2004). In women allocated to misoprostol, complete evacuation without additional curettage was achieved in just over 50% of the women. As part of this study, patients' specific resource use and health-related benefits were prospectively collected up to 6 weeks after treatment. The aim of the present study was to compare the costs of both strategies. Since the effectiveness of both strategies was found to be equal in both strategies, the economic evaluation was set up as a cost minimization analysis.
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Materials and methods |
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All women aged 1845 years with a diagnosis of early pregnancy failure between 6 and 14 weeks of gestation who had been managed expectantly were eligible for the trial.
A diagnosis of early pregnancy failure was made by transvaginal ultrasonography, and defined as an intrauterine gestational sac (sac diameter >15 or <15 mm, not showing any growth after a 7 day interval) with or without an embryonic pole and absence of cardiac activity. Women with incomplete abortion were not eligible for the study.
After informed consent had been given, randomization was performed using a computer programme with a block randomization sequence. Allocation was concealed until interventions were assigned. Randomization was stratified for previous vaginal birth, duration of amenorrhoea (<10 or >10 weeks), and participating centre.
Curettage consisted of evacuation of the uterus by suction curettage under general anaesthesia in a day care setting, and had to be performed within a week after randomization. Misoprostol treatment was given in an outpatient setting, and consisted of four tablets of 200 µg vaginal misoprostol placed at once in the posterior fornix without additional moistening, by their treating gynaecologist. This procedure was repeated after 24 h if necessary. The dosage scheme for misoprostol was derived from Goldberg et al. (2001). Misoprostol treatment was considered to have failed in cases of persistent bleeding in the presence of a retained product of conception (i.e. a focal hyperechoic intrauterine mass with an anterior posterior diameter >15 mm at sonography), presence of a gestational sac or immediate intervention because of abnormal bleeding or infection was needed. For these categories curettage was planned, and a pathologist examined all tissue. Similarly, curettage was considered to have failed when additional intervention was needed because of abnormal bleeding and signs of retained product of conception were visible at sonography.
Complications were defined as infection, need for transfusion and surgery-related complications such as perforation and cervical tear. Emergency curettage was defined as a curettage that was needed because of heavy bleeding, pain or infection and was therefore not scheduled for. A follow-up visit at the outpatients clinic after 6 weeks was scheduled for each patient.
A complete evacuation rate was considered to be the primary endpoint. Secondary endpoints were complications and costs. The economic evaluation was conducted on an intention-to-treat basis and included all 154 women. Women were asked to complete a questionnaire at 2 days, 2 weeks and 6 weeks after therapy, including use of analgesics or other medication (i.e. anti-emetics), absence from work and consultation of other health professionals.
Costs
The economic analysis was performed from a societal perspective. The mean costs of each treatment were calculated by multiplying used resources and resource unit prices. Standardized unit costs were calculated using the Dutch manual for costing in economic evaluations and standardized costs (Oostenbrink et al., 2002). A distinction was made between costs of medical interventions (direct costs) and costs resulting from productivity losses (indirect costs) (Drummond et al., 1986
). Resource utilization was assessed using individual data in the case record forms. Resources counted were: visits to the outpatient clinic, number of ultrasound scans, misoprostol usage, need for curettage (during working hours versus outside working hours), days of day care, days of hospital admittance, visits to general practitioner or midwives related to early pregnancy failure, and the treatment of complications (blood transfusion, conservative management in cases of perforation, antibiotics and additional hysteroscopy). Furthermore, each woman filled in a questionnaire concerning productivity loss. Productivity loss was valued using Dutch reference data from the handbook of the Dutch Health Council (Oostenbrink et al., 2000
).
Trial-specific resource utilization [costs of pathological examination, blood test (type and cross-match), additional outpatient visits and ultrasonography as needed for the study protocol only] was excluded from the analysis.
Resource unit prices reflected unit costs for staff, materials, equipment, housing and overheads, the latter both at department level and at hospital level. Unit prices were calculated for all medical resources counted for. Since in the Dutch health care system the hospitals charge the patients' insurance company and are managed on a non-profit basis, the calculated costs are an appropriate measure for the societal costs of direct medical care.
Prices were calculated and reported in European euros (). Since all costs were realized in
6 weeks after treatment, correction for differential timing of economic costs was not performed. Direct costs were calculated using data of all patients included in the trial, whereas calculations on total costs were limited to those women who completed the questionnaire.
Cost-minimization analysis
We adopted the cost minimization form of economic analysis, as the clinical trial report showed evacuation rates of 100% after 6 weeks in both groups. In the cost minimization analysis, the costs of a treatment with misoprostol (including the need for concomitant curettage) were compared to the costs of initial treatment with curettage (Gold et al., 1996). For each strategy, we calculated the mean costs. Confidence intervals around the mean cost of each treatment and differences in costs were calculated using bootstrapping. For this purpose, 2000 random samples with replacement were drawn from the distribution of total costs in the two treatment groups.
Sensitivity analysis was performed to explore the effect of plausible chances in key variables on the results of the cost analysis. We first looked at the number of patients with complete evacuation rates after initial misoprostol treatment. Other variables and costs were varied in a univariate sensitivity analysis between +10 and 10%.
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Results |
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All complications occurred in women allocated to curettage. One woman had a uterine perforation that was managed expectantly during clinical observation for 1 day without further complications. One woman needed a transfusion after a haemorrhage of 800 ml during curettage that was treated with uterotonic agents and resulted in clinical observation for 1 day. One woman had an amenorrhoea after curettage, which was due to intrauterine synechia (Asherman syndrome). This woman needed additional hysteroscopic resection in a day care setting.
Follow-up consultation was needed in 28 women allocated to misoprostol strategy and 11 for those allocated to curettage. Visits to a general practitioner or midwife were not needed in both groups.
Resource units used and prices for each treatment are presented in Table III. The number of women allocated to misoprostol therapy and curettage who returned questionnaires on additional medication and lost working days for misoprostol and curettage were 69 (87%) versus 55 (74%) after randomization. There were no significant differences between responders and non-responders with respect to baseline characteristics or treatment allocation between the two groups.
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In the women allocated to misoprostol, the fact whether misoprostol resulted in complete evacuation or not had a strong impact on the direct costs. In the 42 women in whom misoprostol resulted in complete evacuation, the mean direct costs were 137, whereas in the 37 women in whom additional curettage was needed after misoprostol, the mean direct costs were
788. The mean indirect costs in these two groups were
416 and
565 respectively, resulting in mean total costs of
549 and
1360.
Figure 1 shows the results of a sensitivity analysis, in which the impact of different complete evacuation rates after misoprostol is shown. If one only considers direct medical costs, the costs of a strategy with misoprostol are equal to curettage when the complete evacuation rate after misoprostol is 15%. If one also considers productivity losses from lost working time, a complete evacuation rate at which misoprostol becomes less costly than curettage is 31%. Variation of other variables with a range of +10 to 10% did not have an impact on the conclusion, i.e. that the direct costs and total costs of a misoprostol strategy are lower than a curettage strategy, and indirect total costs of both strategies are comparable.
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Discussion |
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The difference in initial success rate after misoprostol of 53% as compared to 96% after curettage is a crucial variable in the present study, and the extent to which the diagnosis of incomplete abortion was made.
The 53% complete evacuation rate of misoprostol in our study is lower as compared to the 6088% success rates described in other trials, using comparable misoprostol treatment protocols and criteria for diagnosis of treatment failure (Creinin et al., 1997; Demetroulis et al., 2001
; Muffley et al., 2002
; Wood and Brain, 2002
). The preceding expectant management and criteria for deciding upon failed misoprostol treatment as used in our study protocol might explain the lower evacuation rate in our study.
The criteria for deciding upon incomplete evacuation using misoprostol in our study were based on ultrasonography (presence of gestational sac, or anteriorposterior diameter of 15 mm) and clinical signs such as persistent bleeding. It must be noted that several studies have shown that the use of ultrasonography, using a threshold level for anteriorposterior diameter in the detection of retained products of conception, has limited value (Luise et al., 2002). The arbitrary limit of 15 mm anteriorposterior diameter and persistent bleeding in our study was present in only a small proportion of women classified as having a failed misoprostol strategy. The other categories (presence of gestational sac, profuse bleeding) clearly needed additional therapy (i.e. curettage) for evacuation.
In the present trial, there was quite extensive diagnostic management of women after they had been treated with misoprostol. It is possible that the diagnosis of incomplete abortion after misoprostol treatment will decrease in routine practice over time resulting in lower costs. Women undergoing medical treatment were more likely to have a further investigation to ensure that all products of conception have been passed, which has been confirmed in another study as well (Hughes et al., 1996). The effects on total costs in our study, however, show that a strategy starting with misoprostol remains cost-reducing.
One study reported on cost of medical management versus curettage for early pregnancy failure (Hughes et al., 1996). Using sensitivity analysis the extra cost of introducing medical methods ranged from a cost saving of £71 to an additional cost of £47 per patient. Interestingly, from publications concerning medical abortion additional costs are observed too (Creinin, 2000
). As compared to our study, the extra expenditure of medical treatment seems due to the concomitant use of mifepristone and misoprostol in these studies as well as costs for in-hospital treatment (Hughes et al., 1996
; Creinin, 2000
). Since in our study mifepristone was not used as pre-treatment and misoprostol was given in an outpatient setting, this resulted in more profound cost savings in the medically treated women.
Recently, a cost-benefit analysis comparing misoprostol treatment to curettage for early pregnancy failure was presented by Doyle et al. (2004) showing that misoprostol treatment remains cost beneficial and the preferred treatment strategy over a wide range of assumptions. This finding is in concordance with our results. There are some limitations in interpretation of our study results. The objective of the analysis was to use unit costs that are representative of hospitals in The Netherlands. However, there is considerable variation in some costs, in particular the hotel costs of a day care admission (Oostenbrink et al., 2002
). Therefore a cost reduction for curettage is expected to come from a strategy using local anaesthesia instead of general anaesthesia.
Furthermore we had a lower rate of returned questionnaires considering lost working days and use of additional medication in the women allocated to curettage as compared to women allocated to misoprostol. The effect of this incomplete response remains speculative. One might hypothesize that evacuation rates and recovery were homogeneous in the curettage group, thus limiting the potential bias of this low response rate. One should also consider that the major components of the cost come from day care admission.
This economic analysis has limited application since it was performed in women with early pregnancy failure after failed expectant management. It is expected that in women without prior expectant management the complete evacuation rate will be higher and therefore in that scenario will be more cost-reducing.
In view of the effectiveness of misoprostol and lower costs of a misoprostol strategy in the treatment of early pregnancy failure, we feel that misoprostol could become the first choice of treatment of early pregnancy failure after initial failed expectant management.
In conclusion, this economic evaluation shows that misoprostol, after failed expectant management, reduces the need for curettage and is a cost-reducing therapy in treatment of early pregnancy failure. The costs and benefits estimated here are based on a follow-up period of 6 weeks. Further follow-up of patients in this trial is essential to see whether events such as future fertility have substantive effect on the results presented here.
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Submitted on October 22, 2004; resubmitted on November 17, 2004; accepted on December 2, 2004.