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Gonadotropin therapy prior to in vitro fertilization was more cost-effective than immediate in vitro fertilization
ARTICLE IN PRESS REPRODUC TIVE ENDOCRINOLOGY & INFERTILIT Y
Gonadotropin therapy prior to in vitro fertilization was more cost-effective than immediate in vitro fertilization Kansal-Kalra S, Milad M, Grobman W. In vitro fertilization (IVF) versus gonadotropins followed by IVF as treatment for primary infertility: a cost-based decision analysis. Fertil Steril 2005; 84: 600 ^ 4.
OBJECTIVE To compare the cost of gonadotropin therapy followed by IVF to directly proceeding with IVF therapy. DESIGN Decision-tree model. SETTING University hospitals in the United States. SUBJECTS Hypothetical cohort of 100,000 women o35 years with unexplained infertility. It was assumed that the women had previously failed 3 cycles of clomiphene citrate with IUI. METHOD Studies addressing cost and e¡ectiveness of these two infertility treatments were gathered using a MEDLINE search, the reference lists of retrieved articles and the registry of the Society for Assisted Reproductive Technology (SART). Cost information gathered before 2003 was adjusted for in£ation. Patients entered the gonadotropin arm or the immediate IVF arm. Those in the gonadotropin arm received 3 cycles of treatment before proceeding to a maximum of 3 cycles of IVF. Those in the IVF arm proceeded directly with up to 3 cycles of IVF. The incidence and cost associated with high order multiple pregnancies and cerebral palsy were also considered. MAIN OUTCOME MEASURES Cost per live birth de¢ned as total cost of treatment divided by
48
Evidence-based Obstetrics and Gynecology (2006) 8, 48 ^ 49 doi:10.1016/j.ebobgyn.2006.03.002
the number of live births in each respective treatment arm. MAIN RESULTS The baseline cost of immediate IVF was higher at $61,930 per live birth compared to $58,401 per live birth when IVF was preceded by gonadotropin therapy. Both intervention strategies resulted in a 480% chance of a live birth, although the gonadtropin arm had a larger number of live births than the immediate IVF arm. Both arms resulted in a similar incidence of singleton and twin pregnancies, but the gonadotropins arm had a higher likelihood of high order multiple pregnancies (HOMP) (4.1%) than the immediate IVF arm (0.8%). Sensitivity analysis determined that if the birth rate in the IVF arm reached 55.1%, or if the birth rate in the gonadotropin arm birth rate decreased by 4%, then the cost of the IVF-¢rst treatment strategy would be equal to that of the gonadotropins-¢rst followed by IVF strategy. CONCLUSION When risk and costs associated with HOMP pregnancies are taken into consideration, immediate IVF is less cost e¡ective than the approach of ovarian stimulation with gonadotropins prior to proceeding with IVF. Overall study quality (out of 10) Topic importance Methodological quality Practical relevance
8 7 7
ARTICLE IN PRESS Commentary Infertility affects about one in six couples at some stage in their lives. The numbers of couples seeking treatment has increased substantially over the last decade. For couples with unexplained primary infertility that have not been helped by clomiphene citrate, treatment with gonadotropins is often the next step prior to IVF. This paper reports the results of a decision-tree model in which a hypothetical cohort of women aged under 35 years was allocated to receive up to three cycles of IVF immediately or up to three cycles of gonadotropins and then, if unsuccessful, proceeding to up to three cycles of IVF. It was assumed that, for all women, three cycles of clomiphene citrate with IUI had already failed to achieve a pregnancy. Data to populate the model were taken from a Medline search from 1991 to 2003, manual searches of the reference lists and from the SARTregistry. Costs were adjusted for inflation where necessary and included costs of treatment, antepartum, intrapartum and neonatal medical costs and costs of cerebral palsy (CP). The outcome of interest was cost per live birth. The results of the stimulation produced lower costs per live birth for women allocated to receive gonadotropins followed by IVF than for women who proceeded directly to IVF ($58,401 and $61,930, respectively). This was due to the higher number of live births (87,590 compared to 80,489, respectively); and to the lower cost of gonadotropins ($3000 per cycle) compared to IVF ($15,000 per cycle). The apparent advantages of undertaking gonadotropins therapy f|rst followed by IVF are, however, complicated by the higher incidence of HOMP at 4.1% in the former strategy compared to 0.8% in the immediate IVF group. Although the model did include the direct medical costs of caring for these pregnancies and births and also those costs related to CP, there are other costs associated with HOMP that were not included. The study took the perspective of the third party payer and only included direct medical costs. Inclusion of other medical costs arising in the community, social and personal costs, and particularly educational costs would have decreased the cost differential.1,2 Although some of these costs would have been included in the CP related cost, it is not clear from the paper how these costs were calculated, whether they represent lifetime costs and whether they are medical costs or broader societal costs. Costs were expressed per live birth.This is a misleading measure of success because a multiple birth counts as a greater suc-
cess than a singleton birth.With the associated poorer outcomes and higher costs associated with HOMP, this approach is clearly inappropriate. A better outcome would have been cost per maternity.Using this endpoint would further decrease the apparent advantage of the gonadotropin-f|rst strategy. Clinicians treating women presenting with primary infertility who have not been helped with clomiphene citrate would consider other prognostic factors, principally female age, in judging whether to recommend gonadotropin treatment prior to IVF. In a more sophisticated model, female age should be included as an important covariate. Sensitivity analyses revealed that fairly small variations in both success rates and costs could make immediate IVF the less costly option. It should be noted that the costs given in this paper represent charges, which vary according to market conditions and customer behaviour, not actual costs, which reflect the organisation and staff|ng of the service. The costs may, therefore, not be generalisable to other centres and other countries. In a systematic review of economic implications of assisted reproductive techniques, it was found that many studies failed to consider the costs associated with multiple pregnancy.3 When they were included they were generally neither long term nor societal in perspective. This study adds to that body of knowledge in which costs of multiple pregnancy are explicitly included. Jane Henderson, MSc National Perinatal Epidemiology Unit, University of Oxford, UK
Literature cited 1. Petrou S, Henderson J, Marlow N, Wolke D, Bracewell M. Pushing the boundaries of viability: the economic impact of extreme preterm birth. Early Hum Dev 2006; 82(2):77^ 84. 2. Stevenson RC, Pharoah PO, Stevenson CJ, McCabe CJ, Cooke RW. Cost of care for a geographically determined population of low birthweight infants to age 8 ^9 years. II. Children with disability. Arch Dis Child Fetal Neonatal Ed 1996; 74:F118 ^21. 3. Garceau L, Henderson J, Davis L- J, Petrou S, Henderson L, McVeigh E, Barlow D, Davidson L. Economic implications of assisted reproductive techniques: a systematic review. Hum Reproduction 2002; 17(12): 3090 ^109.
Evidence-based Obstetrics and Gynecology (2006) 8, 48 ^ 49
49
Gonadotropin therapy prior to in vitro fertilization was more cost-effective than immediate in vitro fertilization Kansal-Kalra S, Milad M, Grobman W. In vitro fertilization (IVF) versus gonadotropins followed by IVF as treatment for primary infertility: a cost-based decision analysis. Fertil Steril 2005; 84: 600 ^ 4.
OBJECTIVE To compare the cost of gonadotropin therapy followed by IVF to directly proceeding with IVF therapy. DESIGN Decision-tree model. SETTING University hospitals in the United States. SUBJECTS Hypothetical cohort of 100,000 women o35 years with unexplained infertility. It was assumed that the women had previously failed 3 cycles of clomiphene citrate with IUI. METHOD Studies addressing cost and e¡ectiveness of these two infertility treatments were gathered using a MEDLINE search, the reference lists of retrieved articles and the registry of the Society for Assisted Reproductive Technology (SART). Cost information gathered before 2003 was adjusted for in£ation. Patients entered the gonadotropin arm or the immediate IVF arm. Those in the gonadotropin arm received 3 cycles of treatment before proceeding to a maximum of 3 cycles of IVF. Those in the IVF arm proceeded directly with up to 3 cycles of IVF. The incidence and cost associated with high order multiple pregnancies and cerebral palsy were also considered. MAIN OUTCOME MEASURES Cost per live birth de¢ned as total cost of treatment divided by
48
Evidence-based Obstetrics and Gynecology (2006) 8, 48 ^ 49 doi:10.1016/j.ebobgyn.2006.03.002
the number of live births in each respective treatment arm. MAIN RESULTS The baseline cost of immediate IVF was higher at $61,930 per live birth compared to $58,401 per live birth when IVF was preceded by gonadotropin therapy. Both intervention strategies resulted in a 480% chance of a live birth, although the gonadtropin arm had a larger number of live births than the immediate IVF arm. Both arms resulted in a similar incidence of singleton and twin pregnancies, but the gonadotropins arm had a higher likelihood of high order multiple pregnancies (HOMP) (4.1%) than the immediate IVF arm (0.8%). Sensitivity analysis determined that if the birth rate in the IVF arm reached 55.1%, or if the birth rate in the gonadotropin arm birth rate decreased by 4%, then the cost of the IVF-¢rst treatment strategy would be equal to that of the gonadotropins-¢rst followed by IVF strategy. CONCLUSION When risk and costs associated with HOMP pregnancies are taken into consideration, immediate IVF is less cost e¡ective than the approach of ovarian stimulation with gonadotropins prior to proceeding with IVF. Overall study quality (out of 10) Topic importance Methodological quality Practical relevance
8 7 7
ARTICLE IN PRESS Commentary Infertility affects about one in six couples at some stage in their lives. The numbers of couples seeking treatment has increased substantially over the last decade. For couples with unexplained primary infertility that have not been helped by clomiphene citrate, treatment with gonadotropins is often the next step prior to IVF. This paper reports the results of a decision-tree model in which a hypothetical cohort of women aged under 35 years was allocated to receive up to three cycles of IVF immediately or up to three cycles of gonadotropins and then, if unsuccessful, proceeding to up to three cycles of IVF. It was assumed that, for all women, three cycles of clomiphene citrate with IUI had already failed to achieve a pregnancy. Data to populate the model were taken from a Medline search from 1991 to 2003, manual searches of the reference lists and from the SARTregistry. Costs were adjusted for inflation where necessary and included costs of treatment, antepartum, intrapartum and neonatal medical costs and costs of cerebral palsy (CP). The outcome of interest was cost per live birth. The results of the stimulation produced lower costs per live birth for women allocated to receive gonadotropins followed by IVF than for women who proceeded directly to IVF ($58,401 and $61,930, respectively). This was due to the higher number of live births (87,590 compared to 80,489, respectively); and to the lower cost of gonadotropins ($3000 per cycle) compared to IVF ($15,000 per cycle). The apparent advantages of undertaking gonadotropins therapy f|rst followed by IVF are, however, complicated by the higher incidence of HOMP at 4.1% in the former strategy compared to 0.8% in the immediate IVF group. Although the model did include the direct medical costs of caring for these pregnancies and births and also those costs related to CP, there are other costs associated with HOMP that were not included. The study took the perspective of the third party payer and only included direct medical costs. Inclusion of other medical costs arising in the community, social and personal costs, and particularly educational costs would have decreased the cost differential.1,2 Although some of these costs would have been included in the CP related cost, it is not clear from the paper how these costs were calculated, whether they represent lifetime costs and whether they are medical costs or broader societal costs. Costs were expressed per live birth.This is a misleading measure of success because a multiple birth counts as a greater suc-
cess than a singleton birth.With the associated poorer outcomes and higher costs associated with HOMP, this approach is clearly inappropriate. A better outcome would have been cost per maternity.Using this endpoint would further decrease the apparent advantage of the gonadotropin-f|rst strategy. Clinicians treating women presenting with primary infertility who have not been helped with clomiphene citrate would consider other prognostic factors, principally female age, in judging whether to recommend gonadotropin treatment prior to IVF. In a more sophisticated model, female age should be included as an important covariate. Sensitivity analyses revealed that fairly small variations in both success rates and costs could make immediate IVF the less costly option. It should be noted that the costs given in this paper represent charges, which vary according to market conditions and customer behaviour, not actual costs, which reflect the organisation and staff|ng of the service. The costs may, therefore, not be generalisable to other centres and other countries. In a systematic review of economic implications of assisted reproductive techniques, it was found that many studies failed to consider the costs associated with multiple pregnancy.3 When they were included they were generally neither long term nor societal in perspective. This study adds to that body of knowledge in which costs of multiple pregnancy are explicitly included. Jane Henderson, MSc National Perinatal Epidemiology Unit, University of Oxford, UK
Literature cited 1. Petrou S, Henderson J, Marlow N, Wolke D, Bracewell M. Pushing the boundaries of viability: the economic impact of extreme preterm birth. Early Hum Dev 2006; 82(2):77^ 84. 2. Stevenson RC, Pharoah PO, Stevenson CJ, McCabe CJ, Cooke RW. Cost of care for a geographically determined population of low birthweight infants to age 8 ^9 years. II. Children with disability. Arch Dis Child Fetal Neonatal Ed 1996; 74:F118 ^21. 3. Garceau L, Henderson J, Davis L- J, Petrou S, Henderson L, McVeigh E, Barlow D, Davidson L. Economic implications of assisted reproductive techniques: a systematic review. Hum Reproduction 2002; 17(12): 3090 ^109.
Evidence-based Obstetrics and Gynecology (2006) 8, 48 ^ 49
49