Elective Single-Embryo Transfer — Has Its Time Arrived?
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《新英格兰医药杂志》
Since its introduction in 1978,1 human in vitro fertilization has rapidly become one of the most successful and widely used techniques in the treatment of infertility. Worldwide, an estimated 1.2 million children have been born as a result of in vitro fertilization, and approximately 1 percent of newborns in the United States are now conceived through the use of assisted reproductive technology.2 The ubiquitous practice of transferring multiple embryos in a single cycle resulted from historically poor pregnancy rates after the transfer of single embryos. As clinical and scientific advances, including refinements in ovarian-stimulation protocols and in culture techniques, have led to improved implantation rates (the chance of clinical pregnancy per embryo) and, consequently, higher live-birth rates, attention has increasingly turned to the predominant risk posed by in vitro fertilization: multiple gestations.
Multifetal pregnancies, and most notably triplet or higher-order multiple gestations, are associated with a significantly increased risk of adverse clinical outcomes, primarily owing to prematurity and its short-term and long-term sequelae. Neonatal mortality is four times as great among twins as it is among singletons,3 and twins are at increased risk for long-term disability, including cerebral palsy. The balance of risk and benefit is intrinsic to all medical practice, and optimization of the outcomes of in vitro fertilization requires minimization of risk while maintaining or improving success rates, generally defined as the percentage of embryo-transfer procedures resulting in live births.
During the past decade, voluntary and, in some countries, legislative guidelines targeted at limiting the number of embryos transferred have been promulgated in an effort to reduce the incidence of multiple gestations after assisted-reproduction techniques. Legislative guidelines, although potentially effective in minimizing specific risks, can be overly simplistic with respect to the nuances of clinical care. For example, if the transfer of more than two embryos is proscribed irrespective of the patient's age, any possible benefit of in vitro fertilization will be severely curtailed for women over, say, 41 years of age. Furthermore, legislative regulations run the risk of politicizing reproductive health and autonomy.
In the United States, the Society for Assisted Reproductive Technology (SART) and the American Society for Reproductive Medicine (ASRM) published guidelines in 1998 that limited the number of embryos transferred according to the characteristics of individual patients and cycles.4 A recent analysis of data from the assisted reproductive technology registry of the Centers for Disease Control and Prevention5 indicates a decline in the rate of triplet or higher-order multiple gestations in the years after publication of the SART and ASRM guidelines. However, the incidence of twin pregnancies remained relatively static. The SART and ASRM guidelines were revised in 20046 in an effort to address this problem and to reduce further the incidence of triplets conceived through in vitro fertilization.
In this issue of the Journal, Thurin et al. report the results of a randomized, double-blind, multicenter trial comparing a strategy of transferring two fresh embryos on a single occasion (double-embryo transfer) with a strategy of transferring a single fresh embryo, followed, if the first transfer is unsuccessful, by a subsequent frozen-and-thawed embryo.7 It is important to note that eligibility criteria limited this trial to patients with the most favorable in vitro fertilization prognosis, specifically young women under 36 years of age (mean age, 30.9 years) who were undergoing their first in vitro fertilization cycle (more than 77 percent of the participants) or their second and who had a minimum of two available embryos of good morphologic quality. These inclusion criteria were met by slightly more than one third of consecutive in vitro fertilization cycles at the 11 participating Scandinavian clinics.
The per-protocol analysis predictably demonstrated a significantly higher rate of live births in the fresh-embryo cycle after double-embryo transfer than after single-embryo transfer (43.4 percent vs. 29.6 percent). After subsequent single thawed-embryo cycles in the single-embryo-transfer patients who failed to conceive after undergoing fresh-embryo transfer, however, the cumulative rate of live births in the single-embryo-transfer group increased to 38.8 percent, similar to the result for fresh double-embryo-transfer cycles. Notably, the strategy of a single-embryo transfer with subsequent transfer of a frozen-and-thawed embryo resulted in a marked reduction in the rate of multiple births as compared with double-embryo transfer (0.8 percent vs. 33.1 percent). Although this study did not demonstrate equivalence of the two treatment protocols with respect to live-birth rates, the results suggested that any reduction in the live-birth rate with single-embryo transfer was unlikely to exceed 11.6 percentage points, a decrease in treatment efficiency that is arguably justified by the striking reduction in multiple gestations.
The authors acknowledge some of the factors that could limit the acceptability of single-embryo transfer for patients and their physicians. Given the lower success rate inherent in the transfer of one rather than two fresh embryos, the increased likelihood of having to undergo the subsequent transfer of frozen-and-thawed embryos entails some inconvenience and stress. Indeed, 38 women in the group undergoing single-embryo transfer (representing more than 17 percent of frozen-and-thawed embryo cycles), a proportion of whom might have conceived after double-embryo transfer, received no subsequent thawed embryos, because none had survived the freezing-and-thawing process. In general, from 50 percent to 75 percent of cryopreserved embryos survive thawing.
The authors also point out that the acceptability of single-embryo transfers is likely to be greater when there is insurance coverage for in vitro fertilization, given the additional cost of undergoing subsequent in vitro fertilization attempts. Needless to say, the drawbacks of single-embryo transfers must be balanced against the risks (and costs) associated with multiple pregnancies.
This provocative study raises the question of whether the authors' results can be translated to the practice of in vitro fertilization in the United States. It is not possible to infer complete comparability between the study population and the population of patients undergoing in vitro fertilization in the United States. For example, it is common practice in the United States to treat young infertile women with "low-tech" options such as ovulation induction combined with intrauterine inseminations, often for several cycles, before proceeding to in vitro fertilization; a history of previous treatment failures with methods other than in vitro fertilization might be expected to reduce the implantation and pregnancy rates with subsequent in vitro fertilization. This speculative consideration notwithstanding, the strategy of single-embryo transfer is not far removed from the current SART and ASRM guidelines. Although the guidelines advise that for women less than 35 years of age "no more than 2 embryos should be transferred," it states that for women with a highly favorable prognosis ("first cycle of [in vitro fertilization]" and "good quality embryos"), "consideration should be given to transferring only a single embryo," particularly if excess embryos can be cryopreserved.6 These criteria for patients with a very favorable prognosis essentially match the inclusion criteria in the study by Thurin and colleagues.
In 2001, women less than 35 years of age underwent approximately 47 percent of the in vitro fertilization cycles in the United States, and 75 percent of the cycles were first or second attempts.2 Although the proportion with "good quality" embryos is not known, this would suggest that on the order of 30 percent of cycles could be considered for single-embryo transfer — a rate similar to that reported by Thurin et al. Given the current rate of survival of embryos after freezing and thawing, single-embryo transfer seems most attractive for patients who meet these favorable criteria and who have a minimum of two additional good-quality embryos to freeze.
This intriguing study underscores the need to monitor trends in the outcomes of in vitro fertilization, to develop techniques to identify and select embryos with the highest potential for implantation, and to optimize protocols for embryo cryopreservation so as to reduce embryo loss and narrow the gap in pregnancy rates between transfers of fresh and thawed embryos. The education of patients regarding the risk of twin as well as higher-order multiple pregnancy, along with improved insurance coverage for assisted reproductive therapies, would probably enhance acceptance of a single-embryo-transfer approach for appropriate candidates.
Source Information
From the Center for Reproductive Medicine and Infertility, Weill Medical College of Cornell University, New York.
References
Steptoe PC, Edwards RG. Birth after reimplantation of a human embryo. Lancet 1978;2:366-366.
National Center for Chronic Disease Prevention and Health Promotion, American Society for Reproductive Medicine, Society for Assisted Reproductive Technology. 2001 Assisted reproductive technology success rates: national summary and fertility clinic reports. Atlanta: Centers for Disease Control and Prevention, December 2003.
Martin JA, Park MM. Trends in twin and triplet births: 1980-97. Natl Vital Stat Rep 1999;47:1-16.
Guidelines on number of embryos transferred: ASRM Practice Committee report. Birmingham, Ala.: American Society for Reproductive Medicine, January 1998.
Jain T, Missmer SA, Hornstein MD. Trends in embryo-transfer practice and in outcomes of the use of assisted reproductive technology in the United States. N Engl J Med 2004;350:1639-1645.
Guidelines on the number of embryos transferred: SART/ASRM Practice Committee report. Birmingham, Ala.: American Society for Reproductive Medicine, September 2004.
Thurin A, Hausken J, Hillensj? T, et al. Elective single-embryo transfer versus double-embryo transfer in in vitro fertilization. N Engl J Med 2004;351:2392-2402.(Owen K. Davis, M.D.)
Multifetal pregnancies, and most notably triplet or higher-order multiple gestations, are associated with a significantly increased risk of adverse clinical outcomes, primarily owing to prematurity and its short-term and long-term sequelae. Neonatal mortality is four times as great among twins as it is among singletons,3 and twins are at increased risk for long-term disability, including cerebral palsy. The balance of risk and benefit is intrinsic to all medical practice, and optimization of the outcomes of in vitro fertilization requires minimization of risk while maintaining or improving success rates, generally defined as the percentage of embryo-transfer procedures resulting in live births.
During the past decade, voluntary and, in some countries, legislative guidelines targeted at limiting the number of embryos transferred have been promulgated in an effort to reduce the incidence of multiple gestations after assisted-reproduction techniques. Legislative guidelines, although potentially effective in minimizing specific risks, can be overly simplistic with respect to the nuances of clinical care. For example, if the transfer of more than two embryos is proscribed irrespective of the patient's age, any possible benefit of in vitro fertilization will be severely curtailed for women over, say, 41 years of age. Furthermore, legislative regulations run the risk of politicizing reproductive health and autonomy.
In the United States, the Society for Assisted Reproductive Technology (SART) and the American Society for Reproductive Medicine (ASRM) published guidelines in 1998 that limited the number of embryos transferred according to the characteristics of individual patients and cycles.4 A recent analysis of data from the assisted reproductive technology registry of the Centers for Disease Control and Prevention5 indicates a decline in the rate of triplet or higher-order multiple gestations in the years after publication of the SART and ASRM guidelines. However, the incidence of twin pregnancies remained relatively static. The SART and ASRM guidelines were revised in 20046 in an effort to address this problem and to reduce further the incidence of triplets conceived through in vitro fertilization.
In this issue of the Journal, Thurin et al. report the results of a randomized, double-blind, multicenter trial comparing a strategy of transferring two fresh embryos on a single occasion (double-embryo transfer) with a strategy of transferring a single fresh embryo, followed, if the first transfer is unsuccessful, by a subsequent frozen-and-thawed embryo.7 It is important to note that eligibility criteria limited this trial to patients with the most favorable in vitro fertilization prognosis, specifically young women under 36 years of age (mean age, 30.9 years) who were undergoing their first in vitro fertilization cycle (more than 77 percent of the participants) or their second and who had a minimum of two available embryos of good morphologic quality. These inclusion criteria were met by slightly more than one third of consecutive in vitro fertilization cycles at the 11 participating Scandinavian clinics.
The per-protocol analysis predictably demonstrated a significantly higher rate of live births in the fresh-embryo cycle after double-embryo transfer than after single-embryo transfer (43.4 percent vs. 29.6 percent). After subsequent single thawed-embryo cycles in the single-embryo-transfer patients who failed to conceive after undergoing fresh-embryo transfer, however, the cumulative rate of live births in the single-embryo-transfer group increased to 38.8 percent, similar to the result for fresh double-embryo-transfer cycles. Notably, the strategy of a single-embryo transfer with subsequent transfer of a frozen-and-thawed embryo resulted in a marked reduction in the rate of multiple births as compared with double-embryo transfer (0.8 percent vs. 33.1 percent). Although this study did not demonstrate equivalence of the two treatment protocols with respect to live-birth rates, the results suggested that any reduction in the live-birth rate with single-embryo transfer was unlikely to exceed 11.6 percentage points, a decrease in treatment efficiency that is arguably justified by the striking reduction in multiple gestations.
The authors acknowledge some of the factors that could limit the acceptability of single-embryo transfer for patients and their physicians. Given the lower success rate inherent in the transfer of one rather than two fresh embryos, the increased likelihood of having to undergo the subsequent transfer of frozen-and-thawed embryos entails some inconvenience and stress. Indeed, 38 women in the group undergoing single-embryo transfer (representing more than 17 percent of frozen-and-thawed embryo cycles), a proportion of whom might have conceived after double-embryo transfer, received no subsequent thawed embryos, because none had survived the freezing-and-thawing process. In general, from 50 percent to 75 percent of cryopreserved embryos survive thawing.
The authors also point out that the acceptability of single-embryo transfers is likely to be greater when there is insurance coverage for in vitro fertilization, given the additional cost of undergoing subsequent in vitro fertilization attempts. Needless to say, the drawbacks of single-embryo transfers must be balanced against the risks (and costs) associated with multiple pregnancies.
This provocative study raises the question of whether the authors' results can be translated to the practice of in vitro fertilization in the United States. It is not possible to infer complete comparability between the study population and the population of patients undergoing in vitro fertilization in the United States. For example, it is common practice in the United States to treat young infertile women with "low-tech" options such as ovulation induction combined with intrauterine inseminations, often for several cycles, before proceeding to in vitro fertilization; a history of previous treatment failures with methods other than in vitro fertilization might be expected to reduce the implantation and pregnancy rates with subsequent in vitro fertilization. This speculative consideration notwithstanding, the strategy of single-embryo transfer is not far removed from the current SART and ASRM guidelines. Although the guidelines advise that for women less than 35 years of age "no more than 2 embryos should be transferred," it states that for women with a highly favorable prognosis ("first cycle of [in vitro fertilization]" and "good quality embryos"), "consideration should be given to transferring only a single embryo," particularly if excess embryos can be cryopreserved.6 These criteria for patients with a very favorable prognosis essentially match the inclusion criteria in the study by Thurin and colleagues.
In 2001, women less than 35 years of age underwent approximately 47 percent of the in vitro fertilization cycles in the United States, and 75 percent of the cycles were first or second attempts.2 Although the proportion with "good quality" embryos is not known, this would suggest that on the order of 30 percent of cycles could be considered for single-embryo transfer — a rate similar to that reported by Thurin et al. Given the current rate of survival of embryos after freezing and thawing, single-embryo transfer seems most attractive for patients who meet these favorable criteria and who have a minimum of two additional good-quality embryos to freeze.
This intriguing study underscores the need to monitor trends in the outcomes of in vitro fertilization, to develop techniques to identify and select embryos with the highest potential for implantation, and to optimize protocols for embryo cryopreservation so as to reduce embryo loss and narrow the gap in pregnancy rates between transfers of fresh and thawed embryos. The education of patients regarding the risk of twin as well as higher-order multiple pregnancy, along with improved insurance coverage for assisted reproductive therapies, would probably enhance acceptance of a single-embryo-transfer approach for appropriate candidates.
Source Information
From the Center for Reproductive Medicine and Infertility, Weill Medical College of Cornell University, New York.
References
Steptoe PC, Edwards RG. Birth after reimplantation of a human embryo. Lancet 1978;2:366-366.
National Center for Chronic Disease Prevention and Health Promotion, American Society for Reproductive Medicine, Society for Assisted Reproductive Technology. 2001 Assisted reproductive technology success rates: national summary and fertility clinic reports. Atlanta: Centers for Disease Control and Prevention, December 2003.
Martin JA, Park MM. Trends in twin and triplet births: 1980-97. Natl Vital Stat Rep 1999;47:1-16.
Guidelines on number of embryos transferred: ASRM Practice Committee report. Birmingham, Ala.: American Society for Reproductive Medicine, January 1998.
Jain T, Missmer SA, Hornstein MD. Trends in embryo-transfer practice and in outcomes of the use of assisted reproductive technology in the United States. N Engl J Med 2004;350:1639-1645.
Guidelines on the number of embryos transferred: SART/ASRM Practice Committee report. Birmingham, Ala.: American Society for Reproductive Medicine, September 2004.
Thurin A, Hausken J, Hillensj? T, et al. Elective single-embryo transfer versus double-embryo transfer in in vitro fertilization. N Engl J Med 2004;351:2392-2402.(Owen K. Davis, M.D.)