ajog.org
Editorials
A validated prediction model for IVF: is it clinically applicable? Emily S. Jungheim, MD, MSCI
A
lthough it was not the first in the world, the first live birth after in vitro fertilization (IVF) in the United States in 1981 was a breakthrough because it was the first in the world to use gonadotropins to hyperstimulate the ovaries.1 The innovation of the use of gonadotropins improved oocyte recovery at retrieval thus increasing the number of embryos available for transfer. At the time, IVF embryo implantation rates were poor, and multiple embryo transfer was arguably necessary for IVF to offer a clinically meaningful chance of live birth.2 Three decades later embryo implantation rates after IVF have improved such that, from a societal perspective, the major concern with IVF is not pregnancy rates but rather the risk of multifetal pregnancy associated with the transfer of multiple embryos. In this issue of the American Journal of Obstetrics and Gynecology, Luke et al3 use a clinical prediction model that was built with data from the Society for Assisted Reproductive Technology (SART) Clinic Outcome Reporting System to compare the chance of live birth after 2 sequential cycles of in vitro fertilization with a single embryo transfer (SET) to the chance of live birth after 1 cycle with a double embryo transfer (DET). The authors also compare the risk of multiple births that are associated with each strategy. Not surprisingly, the risk of multiple births that are associated with sequential SET cycles is markedly lower than that associated with 1 DET cycle. What is interesting is that the 2 strategies yield similar live birth rates. Moreover, the model demonstrates that a strategy of 2 sequential SET cycles may yield a higher chance of live birth than 1 DET cycle for some women, while virtually eliminating the risk of multiple births. In discussing the importance of their findings, the authors emphasize that the modern-day challenge of IVF is to “narrow the gap in perinatal outcomes between assisted vs spontaneous pregnancies.” Given that multifetal pregnancies are common after IVF and that they are associated with adverse pregnancy and birth outcomes, it would seem the
From the Department of Obstetrics and Gynecology, Washington University, St. Louis, MO. Received March 9, 2015; accepted March 16, 2015. The author reports no conflict of interest. Corresponding author: Emily S. Jungheim, MD, MSCI. jungheime@wustl. edu 0002-9378/free ª 2015 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.ajog.2015.03.028
See related article, page 676
556 American Journal of Obstetrics & Gynecology MAY 2015
most effective solution to this challenge would be to offer women sequential IVF cycles with 1 embryo being transferred at a time. However, there are a number of barriers to the universal application of this solution. The first of these barriers is the lack of information available to patients regarding their individual chance of live birth and their risk of multifetal pregnancy with SET vs multiple embryo transfer. Currently, many practitioners look to “Guidelines on the number of embryos transferred” from SART and the American Society for Reproductive Medicine (ASRM) to determine how many embryos to transfer after IVF.4 This resource was first presented in 1998 and was revised most recently in 2013 with a new title, “Criteria for number of embryos to transfer: a committee opinion.”5 Over the years the SART/ASRM guidelines have influenced practice by encouraging the transfer of fewer embryos and the application of SET. This has led to a reduction in the rates of higher-order multiple gestation pregnancies that result from IVF.6 Thus, the guidelines have led to an overall improvement in IVF outcomes; however, when it comes to the care of individuals, the guidelines offer little flexibility for the incorporation of patient or clinic-specific information. This information is critical to the determination of an individual’s chance of live birth with IVF, which is the primary concern of many women who contemplate IVF. The most recent SART/ASRM embryo transfer guidelines underscore the importance of programs to develop their own guidelines for the number of embryos transferred based on clinic-specific live and multiple birth rate data, but very few programs have actually done this.4 In the past, publically available information on IVF prognosis has been limited to aggregate-level data collected through SART’s Clinical Outcome Reporting System, which accounts for approximately 90% of IVF clinics in the United States.7 The prognostic information available through the SART website (www.SART.org) is categorized by age and provides the average number of embryos transferred for each age category. The information can be narrowed further by patient diagnosis. The model of Luke et al3 also uses SART Clinical Outcome Reporting System data, but it incorporates a number of additional characteristics, thus allowing for a more individualized approximation of success. Further, the model is built with data from cycles that were limited to the transfer of 1 or 2 embryos, which allowed women to compare their prognosis based on the number of embryos transferred. Although the model by Luke et al3 ultimately can be helpful for women who contemplate IVF, there are limitations that must be considered when applying the tool clinically. First, as the authors acknowledge, many of the SET cycles that are included in the model may have been from women with “better prognosis” because the SART/ASRM committee
ajog.org opinion on the “criteria for number of embryos to transfer” encourages SET for women who meet certain criteria (good quality embryos with excess embryos to freeze).5 On the contrary, there are instances in which women choose SET not because they are good candidates but rather because underlying medical conditions preclude pregnancy with multiple gestations.8 Although these women may not have the best IVF prognosis, if they have >1 embryo to choose from, they may still be better off than women who have only 1 embryo available for transfer. Therefore, as a clinical prediction model, the model may overstate the probability of an individual’s success of IVF with SET. From a societal perspective, the value of the model in the current article is that it can be used to identify clinical scenarios in which a choice (1 vs 2 embryos) has an outcome with markedly different costs to society. When considered from a societal perspective, the choice of SET over DET is easy. But for women who undergo their first IVF cycle, there are a number of factors that may discourage them from choosing SET over a transfer with multiple embryos. These factors include, but are not limited to, the emotional toll of infertility treatment, the time one has available for additional courses of treatment, and the cost of additional cycles of IVF to the individual, which is paid for largely out-of-pocket. In considering these factors, it is not surprising that, if faced with a question such as, “What would be a worse outcome, a twin pregnancy or not getting pregnant and having to go through IVF again?” many would answer “I can’t do this again. I’ll take two.” In other words, it is not the fear of multiples that drives decisions about number of embryos to transfer for many of these women, but rather the fear of not conceiving at all. In practices in which SET criteria are defined clearly and applied with a high chance of live birth, SET is supported by patients.9 Education programs that encourage the use of SET to reduce the risk of multifetal pregnancy after IVF have been found to increase uptake and support for SET.10,11 IVF insurance coverage and shared risk, money-back guarantee programs also improve SET uptake.11 The implementation of education programs on SET is an easy step for most IVF clinics. The problem with the coverage piece is that most women pay for IVF out-of-pocket. Over the years a number of policy makers have called for expanded benefits to cover IVF with SET because it would lead to lower overall perinatal costs and hospital costs for infants who are born through IVF. Despite this, currently, there are only a handful of states with mandates to cover IVF.12 Not since 2001 has any state passed new legislation expanding insurance coverage for the treatment of infertility, and it is unlikely that IVF will be deemed essential in working out the details of the Affordable Care Act,13,14 despite the fact that, since 2001, IVF practice has made huge strides in improving live birth rates and reducing in higher-order multiples. On the other hand, there has been little change in the percentage of twins after IVF.15 Legislation expanding insurance coverage for infertility likely would reduce the risk of multiple births that is
Editorials associated with IVF because women who undergo IVF in states with IVF mandates have fewer embryos transferred and lower twin and higher-order birth rates.12,16,17 Furthermore, insurance coverage for IVF could incorporate a requirement for SET because it has been done successfully elsewhere, leading to lower costs per IVF live birth.18 Perhaps with work like that of Luke et al3 that demonstrates that, for many women, sequential SET is as effective at achieving live birth through IVF as DET (but without the risk of multiple gestations), policy makers and insurers will take notice and update IVF insurance coverage policies. Insurance coverage for IVF with sequential SET would eliminate concerns about higher out-of-pocket costs that are associated with SET, which undoubtedly drive some women to choose multiple embryo transfer. Such an approach would remove the current perverse incentive for individuals to choose an IVF strategy that increases societal costs in an effort to reduce costs borne by the individual. This approach would encourage decisions that improve outcomes for everyone. -
REFERENCES 1. Jones HW Jr. The use of controlled ovarian hyperstimulation (COH) in clinical in vitro fertilization: the role of Georgeanna Seegar Jones. Fertil Steril 2008;90:e1-3. 2. Cohen J, Trounson A, Dawson K, et al. The early days of IVF outside the UK. Hum Reprod Update 2005;11:439-59. 3. Luke B, Brown MB, Wantman E, et al. Application of a validated prediction model for in vitro fertilization: comparison of live birth rates and multiple birth rates with 1 embryo transferred over 2 cycles vs 2 embryos in 1 cycle. Am J Obstet Gynecol 2015;212:676.e1-7. 4. Jungheim ES, Ryan GL, Levens ED, et al. Embryo transfer practices in the United States: a survey of clinics registered with the Society for Assisted Reproductive Technology. Fertil Steril 2010;94: 1432-6. 5. Practice Committee of American Society for Reproductive M, Practice Committee of Society for Assisted Reproductive Technology. Criteria for number of embryos to transfer: a committee opinion. Fertil Steril 2013;99: 44-6. 6. Stern JE, Cedars MI, Jain T, et al. Assisted reproductive technology practice patterns and the impact of embryo transfer guidelines in the United States. Fertil Steril 2007;88:275-82. 7. Society for Assisted Reproductive Technology. SART National Summary, 2015. Available at: http://www.sart.org/frame/detail.aspx? id¼3893. Accessed March 8, 2015. 8. Jungheim ES, Ratts VS, Chang AS, Moley KH, Lanzendorf SE, Odem RR. Encouraging patient-driven single-embryo transfer. Fertil Steril 2008;90:1266-8. 9. Martini S, Van Voorhis BJ, Stegmann BJ, et al. In vitro fertilization patients support a single blastocyst transfer policy. Fertil Steril 2011;96: 993-7. 10. Ryan GL, Sparks AE, Sipe CS, Syrop CH, Dokras A, Van Voorhis BJ. A mandatory single blastocyst transfer policy with educational campaign in a United States IVF program reduces multiple gestation rates without sacrificing pregnancy rates. Fertil Steril 2007;88:354-60. 11. Stillman RJ, Richter KS, Banks NK, Graham JR. Elective single embryo transfer: a 6-year progressive implementation of 784 single blastocyst transfers and the influence of payment method on patient choice. Fertil Steril 2009;92:1895-906. 12. American Society for Reproductive Medicine. State infertility insurance laws, 2015. Available at: http://www.asrm.org/insurance.aspx. Accessed March 8, 2015.
MAY 2015 American Journal of Obstetrics & Gynecology
557
Editorials 13. Omurtag K, Adamson GD. The affordable care act’s impact on fertility care. Fertil Steril 2013;99:652-5. 14. Devine K, Stillman RJ, DeCherney AH. The Affordable Care Act: early implications for fertility medicine. Fertil Steril 2014;101:1224-7. 15. Kulkarni AD, Jamieson DJ, Jones HW Jr, et al. Fertility treatments and multiple births in the United States. N Engl J Med 2013;369: 2218-25.
558 American Journal of Obstetrics & Gynecology MAY 2015
ajog.org 16. Martin JR, Bromer JG, Sakkas D, Patrizio P. Insurance coverage and in vitro fertilization outcomes: a US perspective. Fertil Steril 2011;95: 964-9. 17. Jain T, Harlow BL, Hornstein MD. Insurance coverage and outcomes of in vitro fertilization. N Engl J Med 2002;347:661-6. 18. Velez MP, Connolly MP, Kadoch IJ, Phillips S, Bissonnette F. Universal coverage of IVF pays off. Hum Reprod 2014;29:1313-9.
Editorials
A validated prediction model for IVF: is it clinically applicable? Emily S. Jungheim, MD, MSCI
A
lthough it was not the first in the world, the first live birth after in vitro fertilization (IVF) in the United States in 1981 was a breakthrough because it was the first in the world to use gonadotropins to hyperstimulate the ovaries.1 The innovation of the use of gonadotropins improved oocyte recovery at retrieval thus increasing the number of embryos available for transfer. At the time, IVF embryo implantation rates were poor, and multiple embryo transfer was arguably necessary for IVF to offer a clinically meaningful chance of live birth.2 Three decades later embryo implantation rates after IVF have improved such that, from a societal perspective, the major concern with IVF is not pregnancy rates but rather the risk of multifetal pregnancy associated with the transfer of multiple embryos. In this issue of the American Journal of Obstetrics and Gynecology, Luke et al3 use a clinical prediction model that was built with data from the Society for Assisted Reproductive Technology (SART) Clinic Outcome Reporting System to compare the chance of live birth after 2 sequential cycles of in vitro fertilization with a single embryo transfer (SET) to the chance of live birth after 1 cycle with a double embryo transfer (DET). The authors also compare the risk of multiple births that are associated with each strategy. Not surprisingly, the risk of multiple births that are associated with sequential SET cycles is markedly lower than that associated with 1 DET cycle. What is interesting is that the 2 strategies yield similar live birth rates. Moreover, the model demonstrates that a strategy of 2 sequential SET cycles may yield a higher chance of live birth than 1 DET cycle for some women, while virtually eliminating the risk of multiple births. In discussing the importance of their findings, the authors emphasize that the modern-day challenge of IVF is to “narrow the gap in perinatal outcomes between assisted vs spontaneous pregnancies.” Given that multifetal pregnancies are common after IVF and that they are associated with adverse pregnancy and birth outcomes, it would seem the
From the Department of Obstetrics and Gynecology, Washington University, St. Louis, MO. Received March 9, 2015; accepted March 16, 2015. The author reports no conflict of interest. Corresponding author: Emily S. Jungheim, MD, MSCI. jungheime@wustl. edu 0002-9378/free ª 2015 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.ajog.2015.03.028
See related article, page 676
556 American Journal of Obstetrics & Gynecology MAY 2015
most effective solution to this challenge would be to offer women sequential IVF cycles with 1 embryo being transferred at a time. However, there are a number of barriers to the universal application of this solution. The first of these barriers is the lack of information available to patients regarding their individual chance of live birth and their risk of multifetal pregnancy with SET vs multiple embryo transfer. Currently, many practitioners look to “Guidelines on the number of embryos transferred” from SART and the American Society for Reproductive Medicine (ASRM) to determine how many embryos to transfer after IVF.4 This resource was first presented in 1998 and was revised most recently in 2013 with a new title, “Criteria for number of embryos to transfer: a committee opinion.”5 Over the years the SART/ASRM guidelines have influenced practice by encouraging the transfer of fewer embryos and the application of SET. This has led to a reduction in the rates of higher-order multiple gestation pregnancies that result from IVF.6 Thus, the guidelines have led to an overall improvement in IVF outcomes; however, when it comes to the care of individuals, the guidelines offer little flexibility for the incorporation of patient or clinic-specific information. This information is critical to the determination of an individual’s chance of live birth with IVF, which is the primary concern of many women who contemplate IVF. The most recent SART/ASRM embryo transfer guidelines underscore the importance of programs to develop their own guidelines for the number of embryos transferred based on clinic-specific live and multiple birth rate data, but very few programs have actually done this.4 In the past, publically available information on IVF prognosis has been limited to aggregate-level data collected through SART’s Clinical Outcome Reporting System, which accounts for approximately 90% of IVF clinics in the United States.7 The prognostic information available through the SART website (www.SART.org) is categorized by age and provides the average number of embryos transferred for each age category. The information can be narrowed further by patient diagnosis. The model of Luke et al3 also uses SART Clinical Outcome Reporting System data, but it incorporates a number of additional characteristics, thus allowing for a more individualized approximation of success. Further, the model is built with data from cycles that were limited to the transfer of 1 or 2 embryos, which allowed women to compare their prognosis based on the number of embryos transferred. Although the model by Luke et al3 ultimately can be helpful for women who contemplate IVF, there are limitations that must be considered when applying the tool clinically. First, as the authors acknowledge, many of the SET cycles that are included in the model may have been from women with “better prognosis” because the SART/ASRM committee
ajog.org opinion on the “criteria for number of embryos to transfer” encourages SET for women who meet certain criteria (good quality embryos with excess embryos to freeze).5 On the contrary, there are instances in which women choose SET not because they are good candidates but rather because underlying medical conditions preclude pregnancy with multiple gestations.8 Although these women may not have the best IVF prognosis, if they have >1 embryo to choose from, they may still be better off than women who have only 1 embryo available for transfer. Therefore, as a clinical prediction model, the model may overstate the probability of an individual’s success of IVF with SET. From a societal perspective, the value of the model in the current article is that it can be used to identify clinical scenarios in which a choice (1 vs 2 embryos) has an outcome with markedly different costs to society. When considered from a societal perspective, the choice of SET over DET is easy. But for women who undergo their first IVF cycle, there are a number of factors that may discourage them from choosing SET over a transfer with multiple embryos. These factors include, but are not limited to, the emotional toll of infertility treatment, the time one has available for additional courses of treatment, and the cost of additional cycles of IVF to the individual, which is paid for largely out-of-pocket. In considering these factors, it is not surprising that, if faced with a question such as, “What would be a worse outcome, a twin pregnancy or not getting pregnant and having to go through IVF again?” many would answer “I can’t do this again. I’ll take two.” In other words, it is not the fear of multiples that drives decisions about number of embryos to transfer for many of these women, but rather the fear of not conceiving at all. In practices in which SET criteria are defined clearly and applied with a high chance of live birth, SET is supported by patients.9 Education programs that encourage the use of SET to reduce the risk of multifetal pregnancy after IVF have been found to increase uptake and support for SET.10,11 IVF insurance coverage and shared risk, money-back guarantee programs also improve SET uptake.11 The implementation of education programs on SET is an easy step for most IVF clinics. The problem with the coverage piece is that most women pay for IVF out-of-pocket. Over the years a number of policy makers have called for expanded benefits to cover IVF with SET because it would lead to lower overall perinatal costs and hospital costs for infants who are born through IVF. Despite this, currently, there are only a handful of states with mandates to cover IVF.12 Not since 2001 has any state passed new legislation expanding insurance coverage for the treatment of infertility, and it is unlikely that IVF will be deemed essential in working out the details of the Affordable Care Act,13,14 despite the fact that, since 2001, IVF practice has made huge strides in improving live birth rates and reducing in higher-order multiples. On the other hand, there has been little change in the percentage of twins after IVF.15 Legislation expanding insurance coverage for infertility likely would reduce the risk of multiple births that is
Editorials associated with IVF because women who undergo IVF in states with IVF mandates have fewer embryos transferred and lower twin and higher-order birth rates.12,16,17 Furthermore, insurance coverage for IVF could incorporate a requirement for SET because it has been done successfully elsewhere, leading to lower costs per IVF live birth.18 Perhaps with work like that of Luke et al3 that demonstrates that, for many women, sequential SET is as effective at achieving live birth through IVF as DET (but without the risk of multiple gestations), policy makers and insurers will take notice and update IVF insurance coverage policies. Insurance coverage for IVF with sequential SET would eliminate concerns about higher out-of-pocket costs that are associated with SET, which undoubtedly drive some women to choose multiple embryo transfer. Such an approach would remove the current perverse incentive for individuals to choose an IVF strategy that increases societal costs in an effort to reduce costs borne by the individual. This approach would encourage decisions that improve outcomes for everyone. -
REFERENCES 1. Jones HW Jr. The use of controlled ovarian hyperstimulation (COH) in clinical in vitro fertilization: the role of Georgeanna Seegar Jones. Fertil Steril 2008;90:e1-3. 2. Cohen J, Trounson A, Dawson K, et al. The early days of IVF outside the UK. Hum Reprod Update 2005;11:439-59. 3. Luke B, Brown MB, Wantman E, et al. Application of a validated prediction model for in vitro fertilization: comparison of live birth rates and multiple birth rates with 1 embryo transferred over 2 cycles vs 2 embryos in 1 cycle. Am J Obstet Gynecol 2015;212:676.e1-7. 4. Jungheim ES, Ryan GL, Levens ED, et al. Embryo transfer practices in the United States: a survey of clinics registered with the Society for Assisted Reproductive Technology. Fertil Steril 2010;94: 1432-6. 5. Practice Committee of American Society for Reproductive M, Practice Committee of Society for Assisted Reproductive Technology. Criteria for number of embryos to transfer: a committee opinion. Fertil Steril 2013;99: 44-6. 6. Stern JE, Cedars MI, Jain T, et al. Assisted reproductive technology practice patterns and the impact of embryo transfer guidelines in the United States. Fertil Steril 2007;88:275-82. 7. Society for Assisted Reproductive Technology. SART National Summary, 2015. Available at: http://www.sart.org/frame/detail.aspx? id¼3893. Accessed March 8, 2015. 8. Jungheim ES, Ratts VS, Chang AS, Moley KH, Lanzendorf SE, Odem RR. Encouraging patient-driven single-embryo transfer. Fertil Steril 2008;90:1266-8. 9. Martini S, Van Voorhis BJ, Stegmann BJ, et al. In vitro fertilization patients support a single blastocyst transfer policy. Fertil Steril 2011;96: 993-7. 10. Ryan GL, Sparks AE, Sipe CS, Syrop CH, Dokras A, Van Voorhis BJ. A mandatory single blastocyst transfer policy with educational campaign in a United States IVF program reduces multiple gestation rates without sacrificing pregnancy rates. Fertil Steril 2007;88:354-60. 11. Stillman RJ, Richter KS, Banks NK, Graham JR. Elective single embryo transfer: a 6-year progressive implementation of 784 single blastocyst transfers and the influence of payment method on patient choice. Fertil Steril 2009;92:1895-906. 12. American Society for Reproductive Medicine. State infertility insurance laws, 2015. Available at: http://www.asrm.org/insurance.aspx. Accessed March 8, 2015.
MAY 2015 American Journal of Obstetrics & Gynecology
557
Editorials 13. Omurtag K, Adamson GD. The affordable care act’s impact on fertility care. Fertil Steril 2013;99:652-5. 14. Devine K, Stillman RJ, DeCherney AH. The Affordable Care Act: early implications for fertility medicine. Fertil Steril 2014;101:1224-7. 15. Kulkarni AD, Jamieson DJ, Jones HW Jr, et al. Fertility treatments and multiple births in the United States. N Engl J Med 2013;369: 2218-25.
558 American Journal of Obstetrics & Gynecology MAY 2015
ajog.org 16. Martin JR, Bromer JG, Sakkas D, Patrizio P. Insurance coverage and in vitro fertilization outcomes: a US perspective. Fertil Steril 2011;95: 964-9. 17. Jain T, Harlow BL, Hornstein MD. Insurance coverage and outcomes of in vitro fertilization. N Engl J Med 2002;347:661-6. 18. Velez MP, Connolly MP, Kadoch IJ, Phillips S, Bissonnette F. Universal coverage of IVF pays off. Hum Reprod 2014;29:1313-9.
