A cost comparison of infertility treatment for clomiphene resistant polycystic ovary syndrome Fridstrom M, Sjoblom P, Granberg M, Hillensjo T

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1 A cost comparison of infertility treatment for clomiphene resistant polycystic ovary syndrome Fridstrom M, Sjoblom P, Granberg M, Hillensjo T Record Status This is a critical abstract of an economic evaluation that meets the criteria for inclusion on NHS EED. Each abstract contains a brief summary of the methods, the results and conclusions followed by a detailed critical assessment on the reliability of the study and the conclusions drawn. Health technology The study compared ovulation induction cycles (OI) and in vitro fertilisation (IVF) cycles in the treatment of infertile women with clomiphene resistant polycystic ovary syndrome (PCOS). Type of intervention Treatment. Economic study type Cost-effectiveness analysis. Study population The study population was defined as patients referred to hospital because of clomiphene resistant anovulation and infertility due to PCOS. The study sample was drawn from all women referred to Huddinge University Hospital with clomiphene resistant anovulation and infertility due to PCOS. Clomiphene resistance was defined as three cycles with clomiphene citrate 150mg daily, without ovulation or several clomiphene induced ovulatory cycles without conception. PCOS was defined as oligomenorrhea/amenorrhea and/or hirsutism in combination with polycystic ovaries defined by ultrasound. Women with both PCOS and tubal damage and couples with combined PCOS and male factor infertility were excluded from the study. Setting The setting was tertiary care. The economic study was carried out at Huddinge University Hospital, Sweden. Dates to which data relate The effectiveness and resource use data related to women recruited to the study between 1993 and The price year used was Source of effectiveness data The source of effectiveness data was a single study. Link between effectiveness and cost data Data on use of services was collected prospectively from the same patient sample as the effectiveness data. Study sample Page: 1 / 6

2 No power calculations to determine sample size were reported. Twenty-eight infertile women with clomiphene polycystic ovary syndrome, referred to a university clinic, were prospectively randomised to OI or IVF. This sample comprised all eligible couples referred to the clinic. Of these, 15 were randomised to the OI group and 13 to the IVF group. Two couples withdrew after starting treatment (OI group). The authors did not report details of participants who were referred to the clinic but who were not eligible for the study. Study design A single-centre randomised controlled trial design was used. Prospective randomisation in blocks of ten was carried out. Further details of the randomisation process (e.g. sealed envelope or telephone randomisation) were not reported. For the 2 women who were randomised to OI and who withdrew from the study, the treatment cycles prior to withdrawal were included in the analysis. The authors reported that couples were offered at least 3 treatment cycles and analyses of data were also reported for 5 treatment cycles. The authors also reported the number of pregnancies and deliveries. The authors did not report whether these time periods corresponded to the scheduled or actual length of treatment and follow-up and did not report whether the investigators or researchers, clinic staff or patients were masked to treatment allocation. Analysis of effectiveness The analysis was based on intention to treat. The following health outcomes were used in the analysis: number of pregnancies per started cycle, per completed cycle, per converted cycle and per cycle with embryo transfer (ET) of frozen/thawed embryos; total number of pregnancies for all cycles; and, total number of deliveries. Groups were shown to be comparable in terms of age (27 versus 29 years), infertility duration (4.5 versus 5.0 years) and body mass index (29 versus 28 kg/m^2). Effectiveness results The following outcomes were reported: number of pregnancies: per started cycle, OI = 4/41 (10%), IVF = 8/30 (27%), (non-significant); per completed cycle, OI = 4/26 (15%), IVF = 8/16 (50%), (p=0.03); per converted cycle, OI = 1/8 (13%), IVF = 0/1, (non-significant); per cycle with ET of frozen/thawed embryos, OI = 0/1, IVF = 2/8 (25%), (non-significant); total number of pregnancies, all cycles, OI = 5/42 (12%), IVF = 10/38 (26%), (non-significant). Number of deliveries: OI = 5, IVF = 9, (non-significant). Two of the IVF patients developed moderate hyperstimulation. One patient in the IVF group had a miscarriage after replacement of frozen/thawed embryos and two patients delivered prematurely. Clinical conclusions The authors reported that the number of pregnancies per completed cycle was greater in the IVF group than in the OI group. Measure of benefits used in the economic analysis The outcomes were reported in a disaggregated way and this was, thus, a cost consequences analysis. Page: 2 / 6

3 Direct costs The authors did not report the quantities of resource used. The cost estimates were derived from service use and local price data. The following median costs were used in the analysis: Drugs, OI = Sek 7,319 (range: 3,315-29,340), IVF = Sek 8,842 (range: 4,449-14,384). Treatment, OI = Sek 3,365 (range: 1,346-14,151), IVF = Sek 8,767 (range: 2,019-12,132). Costs of cycles with ET of frozen/thawed embryos, drugs, and treatments, OI = Sek 7,264, IVF = Sek 7,079 (range: 5,067-8,248). Maternity care, including duplex pregnancies, OI = Sek 5,171, IVF = Sek 4,947. Delivery, OI = Sek 13,652, IVF = Sek 13,085. Ovarian hyperstimulation syndrome OI = 0, IVF = Sek 9,749. Miscarriage OI = 0, IVF = Sek 6,216. The treatment costs included doctor's consultations, biochemical analyses, semen analyses and preparation, embryo culture, ovum pick-up and embryo transfer, if applicable. The authors reported the median costs in each group for the following: costs per started cycle (defined as drug costs plus treatment costs), cost per obtained pregnancy, cost per obtained pregnancy including ET of frozen thawed embryos, cost per term pregnancy excluding ET of frozen thawed embryos, cost per term pregnancy including ET of frozen thawed embryos. The authors stated explicitly that the costs of the first counselling of the couples, before randomisation, were not included in the analysis. Patient income-loss due to clinic visits or sick leave and costs of neonatal intensive care were also excluded from the analysis. All costs were based on prices in Sweden in The authors did not report whether discounting of the longer term costs was necessary or conducted. Statistical analysis of costs The Mann-Whitney U-test was used for between group comparisons and frequencies were compared with Fisher's exact test. The authors presented the data as medians and ranges. Indirect Costs Indirect costs were not included. Currency Swedish kroner (Sek). No currency conversions were reported. Sensitivity analysis No sensitivity analyses were reported. Estimated benefits used in the economic analysis See effectiveness results above. Cost results The total cost per couple of each intervention were not reported. The following median costs were reported: per started cycle OI = Sek 12,454, (range: 4,661-42,938) and IVF = Sek 16,772, (range: 6,678-24,186); per obtained pregnancy OI = Sek 120,912 and IVF = Sek 60,623; per obtained pregnancy including ET of frozen/thawed embryos OI = Sek 122,365 and IVF = Sek 54,138; Page: 3 / 6

4 per term pregnancy excluding ET of frozen/thawed embryos OI = Sek 139,335 and IVF = Sek 85,704; and per term pregnancy including ET of frozen/thawed embryos OI = Sek 140,778 and IVF = Sek 82,496. The authors did not report any statistical or sensitivity analysis of the cost data. The time period for treatment and follow-up costs was not reported. The costs include the costs of care for ovarian hyperstimulation syndrome, miscarriage and IVF for patients randomised to the OI group. The authors did not report any costs of treatment failure in the IVF group or the costs for related events such as the use of neonatal intensive care. Synthesis of costs and benefits Costs and benefits were not combined. Authors' conclusions The authors' concluded that, for a group of obese women with clomiphene resistant PCOS, IVF seems to be a costeffective treatment. CRD COMMENTARY - Selection of comparators A justification was given for the comparator used, namely that OI represented a lower cost treatment used for infertile couples living in regions where IVF is not included in public health coverage. You, as a user of this database, should decide if the comparators represent current practice in your own setting. Validity of estimate of measure of effectiveness The analysis was based on a controlled randomised trial, which was appropriate for the study question. The authors did not report whether any process was used to mask study participants (clinic staff or patients) or investigators to treatment allocation. Knowledge of treatment allocation may bias the perception and reporting of outcomes. The authors indicated that all eligible patients were enrolled in the trial, although they do not report details of the number of couples excluded in total or by reason for exclusion. Demographic and clinical characteristics of the study population and excluded patients were not reported, making it difficult to assess whether the study sample was representative of the study population. The authors noted that half the patients in the study had a high body mass index, which has a detrimental impact on treatment outcomes. The authors restricted their conclusion to apply to women who are overweight. The patient groups were shown to be comparable at analysis. Data for all the couples randomised and starting treatment were reported, including those who withdrew before the end of the study. Appropriate statistical analyses were undertaken to take account of potential biases and confounding factors. However, the authors did not report any estimates of the sample size required to detect statistically significant differences or the power of the sample size used to detect statistically significant differences. It is, thus, not possible to assess whether the lack of statistically significant differences between groups was due to lack of power or equivalence in outcomes. Validity of estimate of measure of benefit The authors did not specify a summary measure of health benefit for comparison with costs. The authors reported the median cost per obtained pregnancy and per term pregnancy for each group but did not report the incremental costeffectiveness ratios for OI versus IVF, which are necessary to draw conclusions about relative cost-effectiveness. The analysis was therefore categorised as a cost consequences study. Validity of estimate of costs The perspective for the analysis was not reported, but the authors indicated that the full range of costs was not included in the analysis as the costs of the initial counselling of the couples (before randomisation), patient income-loss due to clinic visits or sick leave, and the costs of neonatal intensive care were excluded. The exclusion of these costs may have Page: 4 / 6

5 led to under estimation of the costs in each group. In particular the difference in costs could be underestimated if there were differences in adverse events that increased patient costs and use of neonatal intensive care. The authors did not report the total mean cost per person for all stages of care, or the incremental costs of the intervention. The authors reported median costs. However, the cost estimate of interest in economic evaluation is the mean cost, since this includes information about the distribution of costs. The authors did not report any statistical or sensitivity analyses of resource use, prices or costs. Other issues The authors did comment on the findings of other studies, and discussed the generalisability of the results to different populations, but noted the problems of evaluating costs in alternative settings. The study enrolled infertile women with clomiphene resistant polycystic ovary syndrome, a large proportion of whom had a high body mass index and this was reflected in the authors' conclusions. The authors reported difficulties in assessing the costs of different procedures (as these vary both regionally and annually), and, deciding which costs should be included in the analyses. The dependence of the prognosis on the severity of the disease and the age of the women, which affects success rates and costs of treatments, was also outlined as a problem. Implications of the study The authors state that, for infertile women with clomiphene resistant polycystic ovary syndrome who are overweight, IVF is a cost-effective treatment. Source of funding Supported by the Swedish Medical Research Council (Grant No 12644) and funds from the Karolinska Institute. Bibliographic details Fridstrom M, Sjoblom P, Granberg M, Hillensjo T. A cost comparison of infertility treatment for clomiphene resistant polycystic ovary syndrome. Acta Obstetricia et Gynecologica Scandinavica 1999; 78(3): PubMedID Indexing Status Subject indexing assigned by NLM MeSH Clomiphene /therapeutic use; Cost-Benefit Analysis; Direct Service Costs /statistics & numerical data; Drug Costs /statistics & numerical data; Drug Resistance; Female; Fertility Agents, Female /therapeutic use; Fertilization in Vitro /economics /methods; Humans; Infertility, Female /etiology; Ovulation Induction /economics /methods; Polycystic Ovary Syndrome /complications /drug therapy; Pregnancy; Pregnancy Outcome /economics; Prospective Studies; Treatment Outcome AccessionNumber Date bibliographic record published 30/09/2002 Date abstract record published 30/09/2002 Page: 5 / 6

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