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Cryopreservation and delayed embryo transfer–assisted reproductive technology registry and reporting implications

2014; Elsevier BV; Volume: 102; Issue: 1 Linguagem: Inglês

10.1016/j.fertnstert.2014.04.048

1556-5653

Kevin J. Doody,

Assisted Reproductive Technology and Twin Pregnancy

Clinics performing assisted reproductive technology (ART) procedures have collected data via registry and publicly reported pregnancy outcomes for more than 25 years. During this time, the practice of ART has changed considerably with frozen embryo transfer (FET) procedures contributing an increasing proportion of live births. Cycles initiated with the intent of embryo banking for the purpose of fertility preservation have been excluded from these public reports, because pregnancy outcomes are not immediately available. An unintended consequence of the common sense handling of fertility preservation has been that cycles performed with intentional short-term cryopreservation of all embryos for other indications have also been excluded from the report. Over the last few years, cryopreservation with short-term delayed transfer increasingly has been performed for reasons other than fertility preservation. The pregnancy outcomes of these cycles are expected within a reasonable time frame and should be transparently reported. The Society for Assisted Reproductive Technology has collaborated with the Centers for Disease Control and Prevention to “recapture” these cycles for the public reports. This recapture is done by linking the FET cycles to the stimulation cycles from which the embryos were derived and by changing the labels of the outcome success metrics. Stimulations using ART, initiated for the purpose of transferring embryos within 1 year will be included in the report despite any prospective intent to freeze all eggs or embryos. A positive outcome will be reported when a live birth results from the first embryo transfer following stimulation (“primary transfer”). Linkage of ovarian stimulation and egg-retrieval procedures to FET will also allow development of other success metrics to further benefit fertility patients. Clinics performing assisted reproductive technology (ART) procedures have collected data via registry and publicly reported pregnancy outcomes for more than 25 years. During this time, the practice of ART has changed considerably with frozen embryo transfer (FET) procedures contributing an increasing proportion of live births. Cycles initiated with the intent of embryo banking for the purpose of fertility preservation have been excluded from these public reports, because pregnancy outcomes are not immediately available. An unintended consequence of the common sense handling of fertility preservation has been that cycles performed with intentional short-term cryopreservation of all embryos for other indications have also been excluded from the report. Over the last few years, cryopreservation with short-term delayed transfer increasingly has been performed for reasons other than fertility preservation. The pregnancy outcomes of these cycles are expected within a reasonable time frame and should be transparently reported. The Society for Assisted Reproductive Technology has collaborated with the Centers for Disease Control and Prevention to “recapture” these cycles for the public reports. This recapture is done by linking the FET cycles to the stimulation cycles from which the embryos were derived and by changing the labels of the outcome success metrics. Stimulations using ART, initiated for the purpose of transferring embryos within 1 year will be included in the report despite any prospective intent to freeze all eggs or embryos. A positive outcome will be reported when a live birth results from the first embryo transfer following stimulation (“primary transfer”). Linkage of ovarian stimulation and egg-retrieval procedures to FET will also allow development of other success metrics to further benefit fertility patients. Discuss: You can discuss this article with its authors and with other ASRM members at http://fertstertforum.com/doodyk-cryopreservation-delayed-embryo-transfer-art-registry/ Discuss: You can discuss this article with its authors and with other ASRM members at http://fertstertforum.com/doodyk-cryopreservation-delayed-embryo-transfer-art-registry/ In the United States, efforts to record and publicly report assisted reproductive technology (ART) activity began in 1987. This effort tabulated retrospectively collected data forms used to record an overall summary of in vitro fertilization (IVF) clinic activities from cycles performed in 1985 and 1986 (1Medical Research InternationalThe American Fertility Society Special Interest GroupIn vitro fertilization/embryo transfer in the United States: 1985 and 1986 results from the National IVF/ET Registry.Fertil Steril. 1988; 49: 212-215Abstract Full Text PDF Google Scholar). At that time, participation was entirely voluntary but is believed to have been high (2Toner J. Progress we can be proud of: U.S. trends in assisted reproduction over the first 20 years.Fertil Steril. 2002; 78: 943-950Google Scholar). An IVF special interest group within the American Fertility Society (now the American Society for Reproductive Medicine [ASRM]) coordinated this process with the first of many annual reports published beginning in 1988. This special interest group soon became the Society for Assisted Reproductive Technology (SART) and remains affiliated with the ASRM. This initial reporting system evolved into a legally required and highly structured system within a decade. This transformation was a consequence of the passage of the Federal Clinic Success Rate and Certification Act (FCSRCA) in 1992. Sponsored by then-Representative Ron Wyden (Democrat from Oregon), the statute set out to establish a national public reporting framework for the clinical outcomes of ART programs offering IVF and egg-donation services (3Adashi E.Y. Wyden R. Public reporting of clinical outcomes of assisted reproductive technology programs: implications for other medical and surgical procedures.JAMA. 2011; 306: 1135-1136Google Scholar). Specifically, the FCSRCA required that by 1994, “each assisted reproductive technology program shall annually report… pregnancy success rates achieved by such program” through the Centers for Disease Control and Prevention (CDC), and that effective in 1995, the CDC “annually publish and distribute” the same data (4102nd U.S. Congress. Fertility Clinic Success Rate and Certification Act of 1992. Public Law No. 102-493, 42 USC 263a-1 et seq. Washington, DC.Google Scholar). The FCSRCA defined two pregnancy success rate calculations to be annually publicly reported. The first success rate is obtained “by dividing the number of pregnancies which result in live births by the number of ovarian stimulation procedures.” The second defined success rate is calculated “by dividing the number of pregnancies which result in live births by the number of successful oocyte retrieval procedures.” Additionally, the FCSRCA specified that other success rate definitions could be developed in consultation with appropriate consumer and professional organizations. Success rate calculations for frozen embryo transfer (FET) and donor egg procedures were developed under this third guideline. The CDC collaborated with SART to collect this information beginning in 1995. In 1997, the CDC submitted to Congress the first federally mandated annual report (5Centers for Disease Control and Prevention. Annual ART success rates reports. Available at: http://www.cdc.gov/art/ART.htm. Accessed March 23, 2014.Google Scholar). The format of the clinic summary report (CSR) and national summary report of ART outcomes has remained fundamentally unchanged since that time. The CDC and SART ART success reports have since become easily available to the public over the Internet. Although the format of the published outcome report has not been previously revised, the practice of ART in the United States has evolved significantly. The first pregnancy after cryopreservation, thawing, and transfer of a human embryo was reported in 1983. When the first national results were tabulated for the 1985/1986 report, seven clinical pregnancies had resulted from FET (1Medical Research InternationalThe American Fertility Society Special Interest GroupIn vitro fertilization/embryo transfer in the United States: 1985 and 1986 results from the National IVF/ET Registry.Fertil Steril. 1988; 49: 212-215Abstract Full Text PDF Google Scholar). This number represented slightly 10% of the nearly 12,000 deliveries reported. In 2012, the proportion of births resulting from FET continued to increase, with 15,408 reported by SART. This number accounted for nearly one third of ART births nationwide. This increase in proportion of births resulting from embryo cryopreservation has occurred as a result of dramatic improvements in laboratory technology (including quality assurance and vitrification) and is additionally a consequence of widespread adoption of a strategy to reduce multiple gestations by decreasing the number of embryos that are transferred when fresh. Initially, cryopreservation with subsequent FET was viewed merely as a supplement to fresh transfer. Availability of supernumerary embryos suitable for cryopreservation was considered a “bonus.” More recently, however, it has been recognized that in some circumstances cryopreservation of all fertilized eggs/embryos might be desirable. Embryo banking has been the primary strategy for fertility preservation in women for whom gonadotoxic chemotherapy is planned. Less commonly, embryo banking for fertility preservation is also performed at the request of women who are wishing to delay pregnancy for 1 or more years, but are concerned regarding the possible impact of the delay on ultimate fertility. Assisted reproductive technology procedures done for the purpose of embryo banking traditionally have been excluded from the national and clinic summary success reports because pregnancy outcomes are not expected within the required reporting time frame. Fertility preservation is not the only widely accepted indication for cryopreservation of all fertilized eggs/embryos. It has been suggested that severe ovarian hyperstimulation syndrome (OHSS) can be nearly eliminated by a strategy that includes segmentation of the IVF process such that embryo replacement is avoided during the cycle of ovarian stimulation and egg retrieval (7Devroey P. Polyzos N. Blockeel C. An OHSS-free clinic by segmentation of IVF treatment.Hum Reprod. 2011; 26: 2593-2597Google Scholar). Although cryopreservation of all embryos and avoidance of a fresh transfer is a well-accepted means of reducing the risk of OHSS in a patient with an unexpectedly high response to stimulation, the term “embryo banking” does not generally apply. Embryo banking cycles have been defined more rigorously by the CDC since 2000 (8Federal Register: September 1, 2000 (Vol. 65, No. 171). DOCID: FR Doc 00-22425.Google Scholar). Specifically, to qualify as “embryo banking,” a cycle must be initiated with the intent of cryopreserving all embryos for later use. The designation “does not apply to cycles initiated with the intent to transfer embryos but for which all embryos were subsequently cryopreserved regardless of the reason” (6Assisted reproductive technology in the United States: 1995 results generated from the American Society for Reproductive Medicine/Society for Assisted Reproductive Technology Registry.Fertil Steril. 1998; 69: 389-398Google Scholar). The time frame for “later use” was not defined. The annual SART Registry report first included a separate tabulation of embryo banking cycles in 1996 (9Assisted reproductive technology in the United States: 1996 results generated from the American Society for Reproductive Medicine/Society for Assisted Reproductive Technology Registry.Fertil Steril. 1999; 71: 798-807Google Scholar). At that time, only 311 of more than 65,000 cycles carried this designation. The low percentage remained stable over the next 4 reporting years. After implementation of the more rigorous definition requiring prospective intent, the number of embryo banking cycles significantly declined, even as the overall number of ART cycles increased. In 2001, only 85 embryo banking cycles were reported out of a total of 108,130 ART procedures (10Assisted reproductive technology in the United States: 2001 results generated from the American Society for Reproductive Medicine/Society for Assisted Reproductive Technology registry.Fertil Steril. 2007; 87: 1253-1266Google Scholar). Over the next decade, embryo banking cycles became increasingly common for reasons other than fertility preservation. Accumulation of eggs/embryos over multiple cycles has been suggested as a strategy for managing low responder patients (11Cabo A. Garrido N. Crespo J. Remohi J. Pellicer A. Accumulation of oocytes: a new strategy for managing low-responder patients.Reprod Biomed Online. 2012; 24: 424-432Google Scholar). Preimplantation genetic screening (PGS) with trophectoderm biopsy is used increasingly by some clinics despite a requirement for freezing/vitrification of embryos to allow time for genetic analysis (12Scott K. Hong K. Scott R. Selecting the optimal time to perform biopsy for preimplantation genetic testing.Fertil Steril. 2013; 100: 608-614Google Scholar). Embryonic/endometrial asynchrony might also be handled by cryopreservation and delayed ET (13Shapiro B.S. Daneshmand S.T. Garner F.C. Aguirre M. Hudson C. Thomas S. Evidence of impaired endometrial receptivity after ovarian stimulation for in vitro fertilization: a prospective randomized trial comparing fresh and frozen-thawed embryo transfer in normal responders.Fertil Steril. 2011; 96: 344-348Abstract Full Text Full Text PDF Scopus (508) Google Scholar, 14Maruta Y. Oku H. Morimoto Y. Tokuda M. Murata T. Sugihara K. et al.Freeze-thaw programmes rescue the implantation of day 6 blastocysts.Reprod Biomed Online. 2005; 11: 428-433Google Scholar). In contrast to fertility preservation, these embryo banking cycles are accompanied by the expectation of an immediate or near-immediate pregnancy outcome. However, because the rules for reporting banking cycles adopted by SART and the CDC were geared toward fertility preservation, the outcomes of these “other” embryo banking cycles have also been excluded from both the national and clinic summary reports. In 2012, more than 13% of the 165,955 ART cycles were excluded from the success reports (15Society for Assisted Reproductive Technology (SART). SART CORS. Available at: https://www.sartcorsonline.com/rptCSR_PublicMultYear.aspx?ClinicPKID=0.html. Accessed May 28, 2014.Google Scholar). Although ART cycles were excluded from the report for other reasons (egg banking, egg thaw cycles, egg donor cycles without transfer and embryo thaw cycles with no associated ET), embryo banking is by far the most common reason for reporting exclusion. In 2012, nearly 14,000 excluded cycles were designated as embryo banking, representing 8.2% of the total ART cycles nationwide. A relatively small number of outlier clinics have been reported to account for the majority of these excluded cycles. It is for these outlier clinics that the current reporting system is most problematic. The exclusion of these cycles has been criticized as leading to decreased transparency (16Kushnir V.A. Vidali A. Barad D.H. Gleicher N. The status of public reporting of clinical outcomes in assisted reproductive technology.Fertil Steril. 2013; 100: 736-741Google Scholar). Public reporting of health care outcomes is premised on the tenets of transparency and accountability, with consumers of medical services in mind. The decision to perform fresh transfer, or alternatively, to “freeze all,” should be made according to what is ideal for the patient, her pregnancy, and her offspring and should not be significantly influenced by the reporting concerns (17Meldrum D.R. Pregnancies and deliveries per fresh cycle are no longer adequate indicators of in vitro fertilization program quality: how should registries adapt?.Fertil Steril. 2013; 100: 620-621Google Scholar). The Society for Assisted Reproductive Technology has identified the need to distinguish true fertility preservation from “short-term” embryo banking and has collaborated with the CDC to make changes to data collection to implement a solution that will abide by both the letter and the spirit of the FCSRCA (18Doody K. Ball G.D. Schattman G. Coddington III, C. Toner J.P. Goldfarb J. Reporting of clinical outcomes in assisted reproductive technology.Fertil Steril. 2013; 100: e25Google Scholar, 19Ball D. Coddington C. Doody K. Schattman G. Toner J. Van Voorhis B. et al.The playing field is changing.Fertil Steril. 2014; 101: e29Google Scholar). The principles of the new report are that [1] Embryo banking for fertility preservation will continue to be excluded from the CSR, as there is no immediate expected cycle outcome; and [2] Cryopreservation of all eggs or embryos with intent for embryo transfer within 12 months of cycle start will not be considered the same as embryo banking. This treatment paradigm is more appropriately referred to as “delayed transfer” because the intended outcome is the same as a fresh transfer. It is anticipated that short-term autologous delayed transfer will in some cases have prospective intent (e.g., PGS or planned multiple cycles for egg/embryo accumulation), but additionally it will include “freeze-all” cycles initiated with intent to transfer fresh (e.g., endometrial receptivity concerns, risk of OHSS, inability to obtain sperm). Because outcomes from “delayed transfer” cycles are available in a short time frame, they will be included in the CSR, independent of the intent at the initiation of the cycle. An important feature of the data collection is that it will link all ETs to the cycle(s) from which the embryo(s) originate. The report “labels/category titles” for autologous (nondonor egg) cycles will change from “fresh” and “frozen” to “primary” and “subsequent” to allow linkage of delayed ETs to cycle starts. Each individual embryo transferred and each ET procedure will be linked/assigned to the egg-retrieval procedure(s) from which it was derived. All cycle starts are included in the denominator of the outcome report. The outcome of the first ET following stimulation will be included in the numerator of the outcome statistic. This transfer can occur within 1 year of the cycle start or the following year, if within 12 months of cycle start. The outcome will be reported in the year of cycle start if possible. However, if the transfer is significantly delayed, the cycle start and outcome will in some cases be reported in the year following. Lack of embryos (or lack of genetically normal embryos following PGS/PGD) available for transfer will result in a negative outcome for the cycle. Lack of ET within 12 months of cycle start will result in a negative outcome reported for the cycle. The definition of ART delineated in the FCSRCA encompasses egg freezing (4102nd U.S. Congress. Fertility Clinic Success Rate and Certification Act of 1992. Public Law No. 102-493, 42 USC 263a-1 et seq. Washington, DC.Google Scholar); thus, data must be collected, and pregnancy outcomes following oocyte cryopreservation must be appropriately reported. Short-term cryopreservation of eggs will be handled in exactly the same fashion as short-term cryopreservation of embryos. The outcome of the first transfer resulting from thawing of eggs, embryos, or a combination of both will be the reported primary transfer outcome. It is foreseen that, infrequently, more than one stimulation cycle could be conducted in the same patient with different designations prior to a primary transfer. A cycle intended to achieve a pregnancy in the short term may be preceded or followed by a cycle intended for fertility preservation. Rules have been devised in anticipation of this occurrence. Any cycle designated as intended for fertility preservation will be reclassified if the retrieved eggs result in an ET within the reporting time frame (within 12 months of cycle start). It is the intention of the SART validation committee to audit clinics that are outliers. Clinics with a high percentage of fertility preservation cycles will have on-site visits with review of medical records to confirm the prospective intent of these cycles. Disingenuous designation of fertility preservation will result in clinic sanction. The emphasis on public reporting of ART cycle outcomes has numerous negative unintended consequences. The current cycle-centered approach encourages clinics to maximize the pregnancy rate per cycle. One of the most effective ways to do this is through the transfer of multiple embryos. The many disadvantages and risks of the resulting twin pregnancies and higher-order multiple gestations are well known. It has been suggested that a cumulative performance metric, termed “total reproductive potential” (TRP), might result in increased use of single ET and hence better obstetrical and neonatal outcomes (20Jones Jr., H.W. Jones D. Kolm P. Cryopreservation: a simplified method of evaluation.Hum Reprod. 1997; 12: 548-553Google Scholar). Although the term has been used in varying ways, the general concept is that this statistic would reflect the cumulative live-birth rate per initiated cycle. Indeed, it can be argued that this statistic fully satisfies the wording of the FCSRCA primary definition of success (live births per stimulation procedure), as the initial definition did not consider separately the outcome of the subsequent FETs. This metric would be calculated by counting in the numerator as a success the first live birth following ovarian stimulation. Thus, it makes no difference whether the success is achieved in the first ET after stimulation or any subsequent frozen transfer. No single success metric is perfect. Even FET cycles carry associated burdens of expense and effort. Additionally, an unintended consequence of this TRP metric could be more-aggressive ovarian stimulation (with attendant risk of OHSS) for the purpose of maximizing egg numbers. The SART Registry Committee believes the benefits of reporting a TRP statistic outweigh the potential disadvantages. Fortunately, the above reporting paradigm shift, whereby data collection allows linkage of FETs to stimulation cycles will greatly facilitate the implementation of reporting of a TRP outcome measure. The precise definition and calculation of TRP needs careful consideration. One concern is that the primary ET and subsequent transfer(s) can occur in different calendar/reporting years. As a result, the reported TRP will consistently change (increase) after the initial publication of outcomes for a given reporting year. One possible option for handling this concern is to publish a preliminary TRP initially, with a secondary “finalization” the following year. Very few additional pregnancies are anticipated to occur later than 12 months after the primary transfer. Another issue to be addressed through registry rules is the recognition that FETs can involve eggs/embryos collected via various retrieval procedures (and different calendar years). Although SART believes that the consumer of fertility services would benefit from inclusion of a TRP statistic in the report, specific details with regard to implementation have not yet been finalized. The SART plans also include the reporting of outcomes “per patient.” This metric would reflect success per individual patient cumulatively over all stimulation cycles/fresh and frozen transfers within a clinic. This metric is useful to the patient that might desire estimation of the ultimate chance of live birth with ART treatment. Reporting of this statistic would encourage adoption of strategies to reduce patient “drop-out.” These strategies might include less-intensive stimulation/monitoring and lower patient cost. Although this outcome metric is likely to be greatly appreciated by patients, the handling of treatment cycles occurring over multiple calendar years needs to be considered and carefully addressed to avoid underestimation of the likelihood of success. Additionally, reporting of outcomes per patient may enhance access to care for those patients with a low chance of pregnancy per cycle that are willing to undergo multiple ART attempts. In conclusion, the federal government and SART have decided that public report cards should complement nonpublic efforts to improve patient safety and the quality of care. This noble goal is more likely to be achieved if reports are accurate, meaningful, and current. Information should be verified and selectively audited to correct mistakes. External data review and on-site validation is required to prevent “gaming the system.” Public report cards are not going away. Indeed, they are likely to become more common and will cover individual physicians as well as institutions/clinics (21Steinbrook R. Public report cards: cardiac surgery and beyond.N Engl J Med. 2006; 355: 1847-1849Google Scholar). The FCSRCA was intended to allow patients to estimate the chance of success with ART treatment within a specific clinic. This law will likely remain unchanged, but administrative rules will be added/modified to more appropriately apply the legislated intent. The above considerations notwithstanding, well-intentioned public reporting of ART clinical outcomes is accompanied by error and unintended consequences. Although the ART reporting system was not intended to be used by the public to directly compare outcomes among centers, it is widely used that way. Commercial attempts have even been made to “rank” ART programs using publicly reported data. Such ranking is inappropriate given that reports have made no effort to stratify the “severity” of infertility by criteria other than age (3Adashi E.Y. Wyden R. Public reporting of clinical outcomes of assisted reproductive technology programs: implications for other medical and surgical procedures.JAMA. 2011; 306: 1135-1136Google Scholar). Variation in clinic-specific case mix is well recognized. Furthermore, until now, some ART cycles involving very short-term cryopreservation of eggs and or embryos have been excluded from the public clinic-specific reports. Lag in appropriate handling of these “delayed transfer” cycles has resulted in decreased transparency for consumers of fertility services. A minority of clinics have high numbers of ART stimulations that are not included in the current public report because they are categorized as “embryo banking.” Most of these cycles should be included in the clinic summary report because pregnancy outcomes are expected within a short time frame. In recognition of that fact, plans are in place to improve the public reporting system. Increased transparency will be achieved by reporting the outcome of all stimulations conducted with the intent of achieving pregnancy in the short term. The most common reasons for cryopreservation and delayed transfer are PGD/PGS, egg/embryo accumulation for poor responders and embryo/endometrial asynchrony. Other possible benefits of delayed transfer may also be considered. Cryopreservation of all embryos retrieved should be performed if indicated without concern of public reporting of outcomes. This will be achieved by linking the outcome of the first (primary) transfer to the prior stimulation(s)/retrieval. The annual SART and CDC reports will continue to strive to improve the clinic and national summary reports to make the rates more transparent and meaningful to consumers of fertility services. The current cycle-centered report will be supplemented with patient-centered data. A patient-anchored approach will better approximate the “true” live-birth rate per cycle by including potential future births due to the subsequent transfer of frozen embryos. Moreover, by ordering and linking the outcomes of sequential cycles in a given patient, the cumulative live-birth rate of consecutive cycles could also be established (live birth per patient). In that the “true” live-birth rate of a single cycle and the cumulative live-birth rate of consecutive cycles are of intense interest to consumers, the development of such metrics for public report deserves further effort. The level of difficulty and complexity involved in such a shift in reporting cannot be underestimated. The most important aspect of the report is that the format take into consideration the needs of the patient. An average patient has difficulty understanding the multiple numerators and denominators inherent in a detailed report (22Chetkowski J. Consumer-friendly reporting of in vitro fertilization outcomes.Fertil Steril. 2014; 101: e7Google Scholar). We must do our best to make the report patient friendly. At present, these reports are best understood by the patient in consultation with her physician.