1 Infertility Centre, University Hospital Gent, and 2 Centre for Reproductive Medicine, Middelheim Hospital, Antwerpen, Belgium
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Abstract |
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Key words: cost-effectiveness/decision-analytic model/health-economics/IVF-ICSI/single embryo transfer
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Introduction |
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The cost-effectiveness studies of recombinant gonadotrophins illustrate the methodology used in health-economics. Since a prospective economic evaluation of a sufficiently large group of real patients is almost impossible to perform in practice, a mathematical simulation is used. A decision-analytic model, called a Markov model (Briggs and Sculpher, 1998) consists of a tree structure in which each arm corresponds to a certain outcome occurring with a certain probability. Probabilities for each arm as well as estimates of costs for each particular outcome are obtained from meta-analyses, randomized trials, national registries, insurance data and expert opinions. A computer program allows a high number of virtual patients enter the tree model and calculates the final outcomes and corresponding costs. Since the input parameters can be varied, the impact of each individual parameter on the output can be studied. This so-called sensitivity analysis has the limitation that only one parameter can be varied at a time, in contrast to the Monte Carlo method (Doubilet et al., 1985
) where distributions of all parameters are taken into account at once.
We developed a simple reproducible decision-analytic model in Microsoft Excel to investigate the cost-effectiveness of single embryo transfer (SET). Elective SET unquestionably is the only effective measure to reduce the incidence of twins following assisted reproduction techniques (ART) (Dhont, 2001; Gerris et al., 2001
). Although this principle has already been acknowledged both from a medical and an ethical point of view (ESHRE Campus Course Report, 2001
), the cost-effectiveness of SET has not yet been established using real pregnancy rates. Wølner-Hanssen and Rydhstroem have calculated the cost-effectiveness of SET using hypothetical pregnancy rates, no exact data on the success of SET being available at that time (Wølner-Hanssen and Rydhstroem, 1998
). It can be anticipated that by performing SET the number of ART cycles needed to obtain a pregnancy will be increased. Of paramount importance, therefore, is the question to what extent SET would influence the success rate of ART. Only a health-economic analysis taking into account all possible variables can answer this question (Meltzer, 2001
). Another aspect is that many infertile couples deliberately opt for a twin pregnancy to short-cut their costly and unpredictable efforts to establish a family. In comparing SET with double embryo transfer (DET), there are various costs to consider: direct and indirect; short and long-term; and those that are measurable and non-measurable. These latter costs are especially difficult to calculate.
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Materials and methods |
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In our simulation we had to agree on certain presumptions. Every patient remained in the group to which she was originally assigned (all SETs or all DETs but no mixing of SET and DET) and the pregnancy rates remained constant for each cycle. In the model we also put the limit at one successful pregnancy, except when embryos are frozen (they belong to the original cycles and all should be used to calculate the cost/effectiveness of the procedure). We also assumed that pregnancies obtained by frozenthawed embryos are all singletons. We restricted our exercise to three cycles, relying on the fact that the pregnancy rates remained constant during at least the first three treatment cycles (Croucher et al., 1998).
Finally, we also selected a group of patients with a good prognosis because all available data on SET have been obtained in young patients with good embryo quality. We therefore assumed that there were no cancelled stimulation cycles, no retrievals without oocytes and no fertilization failures, and that in this patient population all women had a transfer. This is a very important point to realize, since this model therefore does not allow the ability to test a realistic situation, in which the transfer of one or two embryos may be chosen depending on patients age, number of previous cycles, and embryo quality.
Our model therefore strictly compared SET and DET in the same patient group and cannot be used to evaluate an optimal and individualized transfer strategy.
Our model started running at the time of embryo transfer and ended with the birth of the child. For simplicitys sake we entered 1000 women in each group.
Table I summarizes the estimates used in the model. These estimates were obtained from the literature where available. The cost of course is a very local variable and we based our estimates on the costs from the Gent University Hospital in 2001. IVF costs in Table I
are the global costs (both patients and societal), calculated from our own programme, averaging all cycles performed in 2001 (both IVF and ICSI), including the stimulation by a short protocol with urinary gonadotrophins, ultrasound monitoring and oocyte retrieval procedure. Pregnancy costs are calculated from an average number of prenatal consultations and hospitalization, whereas vaginal delivery and Caesarean section costs include both the procedure and hospital stay. We do not account for perinatal mortality and morbidity, but rather for the number of days of admission in a neonatal care unit. Costs of neonatal intensive care are also obtained from our own university hospital (2001). Pregnancy outcome data are taken from the regional register of perinatal activities in Flanders (SPE, 2000
).
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Results |
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Table III shows the different results using pregnancy rates for SET and DET as obtained from the four studies discussed above. Whichever pregnancy rate is used in the model, there are no substantial differences regarding the costs per child born between the four data sets. Statistical comparison of these figures is impossible since we have not used the Monte Carlo simulation in which confidence intervals around the estimates are entered in the model.
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Discussion |
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It is probable that the differences in the figures obtained by the four different studies are due to the nature of the studies themselves. The study by Gerris et al. used very rigorous criteria to perform SET (only when at least two top quality embryos were available) (Gerris et al., 1999). Criteria to perform SET were different in the Martikainen study (Martikainen et al., 2001
), and the two other studies comparing SET with DET (Vilska et al., 1999
; De Sutter et al., 2000
) were not randomized, but left the choice to the couple. Therefore, in the two latter studies SET was performed on demand, even when no top quality embryos were available. It is clear that both the level of counselling and the evaluation of the embryo quality (Van Royen et al., 1999
, 2001
) will influence the degree of application of SET in an IVF programme. A distinction should therefore be made between these studies and a theoretical model, such as discussed, which tests a virtual population of 100% good prognosis patients (in whom top quality embryos will be available). In reality, embryo transfer strategy will be individualized, taking into account patients prognostic factors and the availability of one or more top quality embryos. In each cycle the choice between SET and DET will be made in order to obtain the ideal trade-off between a maximum chance of pregnancy and a minimal risk for a twin pregnancy. An optimized strategy implies that SET will be performed when at least one top quality embryo is available, and DET when no top quality embryos are obtained.
An important question is whether changing the cost of the IVF procedure itself and of neonatal intensive care would influence the results of the analysis. Performing a sensitivity analysis for different ranges of costs of the IVF procedure on the one hand, and of neonatal care on the other hand, the differences in cost-effectiveness between SET and DET never exceed 10% (data not shown). Of course, in doing this exercise, we assume that in countries where IVF is more expensive, neonatal critical care is more expensive as well, and vice versa.
Many cost-effectiveness studies on ART have been published previously. One study (Neumann et al., 1994) calculated the cost of a successful delivery after IVF (independent of the fact whether it was a singleton or a multiple pregnancy) to be US$66 667 for the first cycle up to US$114 286 by the sixth cycle. These seemingly high costs can be explained by the fact that the data used in this study dated from the pre-ICSI era when delivery rates for IVF were lower than today (from 12% in the first cycle to 7% in the sixth). It has been estimated (Collins, 2001
) that for 2001 the median projected cost for an IVF delivery would be US$56 419 in the US and US$20 522 in other countries. Another study (Callahan et al., 1994
) showed that hospital charges (per baby) are doubled for twins compared with singletons, both for the mother and the child(ren). All studies show that the cost of ART is significantly increased by multiple pregnancies. It is well known from the literature that twins lead to a higher maternal and neonatal morbidity and mortality, (The ESHRE Capri Workshop Group, 2000
; for review). When comparing ART pregnancies with spontaneous controls, we have previously shown that for ART pregnancies the incidence of Caesarean section is significantly increased (Dhont et al., 1999
). Moreover, some authors have demonstrated that ART twin pregnancies have more pregnancy complications and a more adverse perinatal outcome than spontaneous twins (Bernasko et al., 1997
; Daniel et al., 2000
; Lynch et al., 2002
). For all these reasons the cost of an ART twin pregnancy is a multiple of that of an ART singleton pregnancy, which is already much more expensive than a spontaneous singleton pregnancy. The ESHRE Capri Workshop Group calculated the cost of a twin delivery after ART to be four times higher than that of an ART singleton delivery (ESHRE Capri Workshop Group, 2000
). Obviously, the differences between all these data and the costs used in the present study do not only depend on local economical variables, but also on the success rates of IVF used to calculate these costs.
Regarding SET and DET, only one group has calculated the theoretical cost of pregnancies after SET compared with DET (Wølner-Hanssen and Rydhstroem, 1998). The method they used to calculate the costs was different from ours and in 1998 no data from trials comparing SET with DET were available. However, these authors reached a similar conclusion to ours, namely that although more treatments might be needed to achieve a similar take-home baby rate after transfer of one compared with two embryos, the lower twin pregnancy rate of the former approach causes it to be more cost-efficient than the latter.
Very recently a prediction model for selecting patients for SET in IVF has been published (Hunault et al., 2002). In this study, in common with other studies (Coetsier and Dhont, 1998
; Strandell et al., 2000
; Engmann et al., 2001
), which also ran a database analysis, they conclude that applying SET in a good-prognosis subgroup of patients drastically diminishes the twin rate without compromising singleton pregnancy rates. It seems that more and more authors are becoming convinced of the value of SET, at least on the basis of theoretical speculations. The present analysis suggests that the SET strategy is defendable not only medically and ethically, but also economically.
In conclusion, our calculations show that the cost per child born is not different whether the SET or the DET approach is used. DET is more effective in terms of child per cycle rate, but SET is as cost-effective per child born. It is clear that the twins originating from DET increase the indirect and long-term costs, which are not calculated in the present model. Twins have a perinatal mortality of 25/1000 versus singletons 6/1000 (SPE, 2000) and it is well documented that the long-term morbidity is much higher with twins than with singletons (Wølner-Hanssen and Rydhstroem, 1998
). There is more need for hospitalization, special education and training due to cerebral palsy and other handicaps following preterm birth (Petterson et al., 1990
). Twins have a 6-fold increased risk of mortality (Luke and Keith, 1992
) and a 13-fold increased risk of handicap (Yokoyama et al., 1995
). The present model only calculates the economic costs of neonatal care, but does not cipher the economic impact of mortality and long-term morbidity. The message is clear: although DET leads to more children in fewer cycles, economically SET and DET are break-even; and in the long-term SET is definitely more advantageous than DET. The final validity of all these assumptions remains to be proven in a health-economic impact study comparing SET with DET in a real clinical setting.
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Notes |
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References |
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Briggs, A. and Sculpher, M. (1998) An introduction to Markov modeling for economic evaluation. Pharmacoeconomics, 13, 397409.[ISI][Medline]
Callahan, T.L., Hall, J.E., Ettner, S.L., Christiansen, C.L., Greene, M.F. and Crowley, W.F. (1994) The economic impact of multiple-gestation pregnancies and the contribution of assisted-reproductive techniques to their incidence. New Engl. J. Med., 331, 244249.
Coetsier, T. and Dhont, M. (1998) Avoiding multiple pregnancies in in-vitro fertilization: whos afraid of single embryo transfer? Hum. Reprod., 13, 26632670.
Collins, J. (2001) Cost-effectiveness of in vitro fertilization. Semin. Reprod. Med., 19, 279289.[ISI][Medline]
Croucher, C.A., Lass, A., Margara, R. and Winston, R.M. (1998) Predictive value of the results of a first in-vitro fertilization cycle on the outcome of subsequent cycles. Hum. Reprod., 13, 403408.[ISI][Medline]
Daniel, Y., Ochshorn, Y., Fait, G., Geva, E., Bar-Am, A. and Lessing, J.B. (2000) Analysis of 104 twin pregnancies conceived with assisted reproductive technologies and 193 spontaneously conceived twin pregnancies. Fertil. Steril., 74, 683689.[ISI][Medline]
Daya, S. and Gunby, J. (1999) Recombinant versus urinary follicle stimulating hormone for ovarian stimulation in assisted reproduction. Hum. Reprod., 14, 22072215.
Daya, S., Ledger, W., Auray, J.P., Duru, G., Silverberg, K., Wikland, M., Bouzayen, R., Howles, C.M. and Beresniak, A. (2001) Cost-effectiveness modelling of recombinant FSH versus urinary FSH in assisted reproduction techniques in the UK. Hum. Reprod., 16, 25632569.
De Sutter, P., Coetsier, P., Van der Elst, J. and Dhont, M. (2000) Elective single embryo transfer in IVF/ICSI: an analysis of 126 cases. 16th Annual Meeting of the European Society of Human Reproduction and Embryology. Hum. Reprod., 15 (Abs. Bk 1), O-157, p.63.
De Vries, M.J., De Sutter, P. and Dhont, M. (1999) Prognostic factors in patients continuing in vitro fertilization or intracytoplasmic sperm injection treatment and dropouts. Fertil. Steril., 72, 674678.[ISI][Medline]
Dhont, M. (2001) Single embryo transfer. Semin. Reprod. Med., 19, 251258.[ISI][Medline]
Dhont, M., De Sutter, P., Ruyssinck, G., Martens, G. and Bekaert, A. (1999) Perinatal outcome of pregnancies after assisted reproduction: a case-control study. Am. J. Obstet. Gynecol., 181, 688695.[ISI][Medline]
Doubilet, P., Begg, C.B., Weinstein, M.C., Braun, P. and McNeil, B.J. (1985) Probabilistic sensitivity analysis using Monte Carlo simulation: a practical approach. Med. Decis. Making, 5, 157177.[Medline]
Engmann, L., Maconochie, N., Tan, S.L. and Bekir, J. (2001) Trends in the incidence of births and multiple births and the factors that determine the probability of multiple birth after IVF treatment. Hum. Reprod., 16, 25982605.
ESHRE Campus Course Report (2001) Prevention of twin pregnancies after IVF/ICSI by single embryo transfer. Hum. Reprod., 16, 790800.
ESHRE Capri Workshop Group (2000) Multiple gestation pregnancy. Hum. Reprod., 15, 18561864.
Gerris, J., De Neubourg, D., Mangelschots, K., Van Royen, E., Van de Meerssche, M. and Valkenburg, M. (1999) Prevention of twin pregnancy after in-vitro fertilization or intracytoplasmatic sperm injection based on strict criteria: a prospective randomized clinical trial. Hum. Reprod., 14, 25812587.
Gerris, J., Van Royen, E., De Neubourg, D., Mangelschots, K., Valkenburg, M. and Ryckaert, G. (2001) Impact of single embryo transfer on the overall and twin-pregnancy rates of an IVF/ICSI programme. R.B.M. Online, 2, 172177.
Hunault, C.C., Eijkemans, M.J.C., Pieters, M.H.E.C., te Velde, E.R., Habbema, J.D.F., Fauser, B.C.J.M. and Macklon, N.S. (2002) A prediction model for selecting patients undergoing in vitro fertilization for elective single embryo transfer. Fertil. Steril., 77, 725732.[ISI][Medline]
Luke, B. and Keith, L.G. (1992) The contribution of singletons, twins and triplets to low birth weight, infant mortality and handicap in the United States. J. Reprod. Med., 37, 661666.[ISI][Medline]
Lynch, A., McDuffie, R., Murphy,J., Faber, K. and Orleans, M. (2002) Preeclampsia in multiple gestation: the role of assisted reproductive technologies. Obstet. Gynecol., 99, 445451.
Martikainen, H., Tiitinen, A., Tomas, C., Tapanainen, J., Orava, M., Tuomivaara, L., Vilska, S., Hydén-Granskog, C., Hovatta, O. and the Finnish ET Study Group (2001) One versus two embryo transfer after IVF and ICSI: a randomized studyHum. Reprod, 16, 19001903.
Meltzer, M.I. (2001) Introduction to health economics for physicians. Lancet, 358, 993998.[ISI][Medline]
Mol, B.W.J., Bonsel, G.J., Collins, J.A., Wiegerinck, M.A.H.M., van der Veen, F. and Bossuyt, P.M.M. (2000) Cost-effectiveness of in vitro fertilization and embryo transfer. Fertil. Steril., 73, 748754.[ISI][Medline]
Neumann, P.J., Gharib, S.D. and Weinstein, M.C. (1994) The cost of a successful delivery with in vitro fertilization. New Engl. J. Med., 331, 239243.
Out, H.J., Mannaerts, B.M.J.L., Driessen, S.G.A.J. and Coelingh Bennink, H.J.T. (1996) Recombinant follicle stimulating hormone (rFSH, Puregon) in assisted reproduction: more oocytes, more pregnancies. Results from five comparative studies. Hum. Reprod. Update, 2, 162171.
Petterson, B., Stanley, F. and Henderson, D. (1990) Cerebral palsy in multiple births in Western Australia. Am. J. Med. Genet., 37, 346351.[ISI][Medline]
Philips, Z., Barraza-Llorens, M. and Posnett, J. (2000) Evaluation of the relative cost-effectiveness of treatments for infertility in the UK. Hum. Reprod., 15, 95106.
Silverberg, K., Daya, S., Auray, J.P., Duru, G., Ledger, W., Wikland, M., Bouzayen, R., OBrien, M., Falk, B. and Beresniak, A. (2002) Analysis of the cost effectiveness of recombinant versus urinary follicle-stimulating hormone in in vitro fertilization/intracytoplasmic sperm injection programs in the United States. Fertil. Steril., 77, 107113.[ISI][Medline]
SPE (2000) Perinatale activiteiten in Vlaanderen 2000. In Bekaert et al. Studiecentrum voor Perinatale epidemiologie.
Strandell, A., Bergh, C. and Lundin, K. (2000) Selection of patients suitable for one-embryo transfer may reduce the rate of multiple births by half without impairment of overall birth rates. Hum. Reprod., 15, 25202525.
Sykes, D., Out, H.J., Palmer, S.J. and van Loon, J. (2001) The cost-effectiveness of IVF in the UK: a comparison of three gonadotrophin treatments. Hum. Reprod., 16, 25572562.
Tummers, P., De Sutter, P. and Dhont, M. (2002) Miscarriage risk in singleton versus twin pregnancies after IVF. 18th Annual Meeting of the European Society of Human Reproduction and Embryology. Hum. Reprod., 17 (Abstract Bk 1), O-216, p. 75.
Van Royen, E., Mangelschots, K., De Neubourg, D., Valkenburg, M., Van de Meerssche, M., Ryckaert, G., Eestermans, W. and Gerris, J. (1999) Characterization of a top quality embryo, a step towards single embryo transfer. Hum. Reprod., 14, 23452349.
Van Royen, E., Mangelschots, K., De Neubourg, D., Laureys, I., Ryckaert, G. and Gerris, J. (2001) Calculating the implantation potential of day 3 embryos in women younger than 38 years of age: a new model. Hum. Reprod., 16, 326332.
Vilska, S., Tiitinen, A., Hydén-Granskog, C. and Hovatta, O. (1999) Elective transfer of one embryo results in an acceptable pregnancy rate and eliminates the risk of multiple birth. Hum. Reprod., 14, 23922395.
Wølner-Hanssen, P. and Rydhstroem, H. (1998) Cost-effectiveness analysis of in-vitro fertilization estimated costs per successful pregnancy after transfer of one or two embryos. Hum. Reprod., 13, 8894.[Abstract]
Yokoyama, Y., Shimizu, T. and Hayakawa, K. (1995) Incidence of handicaps in mutiple births and associated factors. Acta Genet. Med. Gemellol., 44, 8191.[Medline]
Submitted on May 15, 2002; accepted on July 19, 2002.