ART outcome reporting of delayed embryo transfers: oocyte/embryo accumulation cycles

A novel challenge to ART outcome reporting has been the notion of delayed (≤1 year) fresh-thawed embryo transfer (also referred to as “short-term banking”) in the wake of “oocyte/embryo accumulation cycles.” As currently applied, the term refers to the sequential accumulation of autologous oocytes or embryos by way of multiple initiated cycles followed by a single (multibatch) frozen-thaw embryo transfer. Reliant on multiple minimal stimulation cycles, this paradigm aims to capitalize on the prospect of enhanced endometrial receptivity. In addition, this approach seeks to reduce the dropout rates of poor-prognosis patients displaying poor ovarian responsiveness and/or poor embryo quality. As such, the practice of delayed embryo transfer differs fundamentally from the “freeze all” practice of “long-term (≥1 year) banking” of oocytes or embryos for the purpose of preserving fertility in the face of cancer therapy or social reasons wherein the initiated cycles are excluded from any and all ART outcome calculations. An exception to the preceding statement, 1 enunciated by the updated SART guidelines, is the case wherein 1 or more embryos slated for “long-term banking” have been transferred within the reporting year or immediately thereafter. Under these circumstances, the relevant initiated cycle and the linked “early” transfer will be included in outcome calculations and the reporting thereof in the CSR.

The potential clinical use of oocyte/embryo accumulation cycles notwithstanding, the practice has proven incommensurate with consumer-friendly ART reporting paradigms. Indeed, as pointed out by Kushnir et al, the coupling of multiple oocyte retrievals with a single (multibatch) frozen-thaw embryo transfer increases the exclusion (from ART outcome calculations) of initiated cycles wherein oocyte retrievals are not associated with subsequent fresh embryo transfers. Indeed, as recently as 2010, excluded and thus unreported initiated cycles accounted for 7.4% of stimulation cycles. More importantly, this constellation gave rise to seemingly improved rates for ART outcomes expressed on a per cycle initiated or on a per fresh embryo transfer basis. Lower rates of fresh cycle cancellation reporting may well constitute an additional reporting aberration.

In seeking to address this challenge to ART outcome reporting, SART considered but rejected as inadequate the notion of merely listing the number of delayed embryo transfer cycles. In effect, such an arrangement would have required the creation of a separate reporting category for oocyte/embryo accumulation cycles and perhaps other forms of “short-term” if not ”long-term” banking. As viewed by advocates, a separate reporting category would indicate “…the average number of cycles performed and average number of embryos generated and transferred” thereby allowing “normal prognosis couples to have a more accurate estimation of their success rate, and low prognosis couples…see the actual experience reported by their respective center.” The SART decision notwithstanding, The 2011 ART Fertility Clinic Success Rates Report of the CDC will include the total number of “short-term” and “long-term” embryo banking cycles reported. At present, the National ART Surveillance System is unable to distinguish between “short-term” and “long-term” banking cycles.

SART also considered the prospect of substituting the current cycle centered reporting system with one focused on a patient-centered paradigm. The latter system, advocated by many, one capable of more faithfully representing the total reproductive potential of any one initiated cycle, could have readily handled the challenges posed by the coupling of multiple oocyte retrievals with a single multibatch frozen-thaw cycle. Indeed, present day data may well make it possible to implement the total reproductive potential reporting paradigm if deemed desirable. Moreover, this approach stands to enhance the prevalence of elective single embryo transfers. Though familiar with and sympathetic to this option, SART elected to forego this potential solution in recognition of the perceived complexity of its implementation and the open ended nature of its life cycle. Instead, SART elected to “link” 1 or more dated oocyte retrievals carried out during autologous nondonor cycles with their attendant first or “primary” (fresh or frozen) embryo transfer and if need be, with a “subsequent” (frozen) transfer of the residual complement of embryos. Under this arrangement, the ART outcome of the “primary” transfer will be accounted for in the numerator. By the same token, all cycles initiated will be accounted for in the denominator. Actual reporting of ART outcomes will take place during the cycle start year if at all possible. In those cases wherein the “primary” transfer is significantly delayed, the ART outcome of the index cycle may well be reported the year following the cycle start. Indeed, failure to transfer within a year of cycle start will be reported as a negative ART outcome in the year following the cycle start. There is every reason to believe that the SART-instituted linkage of delayed embryo transfers to cycle starts (applicable to all cycles with start dates on or after Jan. 1, 2014) will enhance the all-important validity and use of the public reporting of ART outcomes.

The above notwithstanding, the newly implemented SART guidelines may be associated with unintended and/or unforeseen relative shortcomings. First, consideration must be given to the possibility that the projected reduction in the reported pregnancy rates per initiated cycle or oocyte retrieval may lead to a decrease in the initiation of oocyte/embryo accumulation cycles. Other varieties of minimal stimulation cycles may be similarly affected. Second, the new reporting rules may have little or no effect on the inflated ART outcome rates expressed on a per fresh embryo transfer basis. Third, the linking of initiated cycles to a primary transfer may be complicated by the possibility that such pairing may straddle sequential calendar years. Conceivably, this eventuality might be minimized by extending the reporting period and delaying the deadline thereof. Fourth, the added levels of complexity inherent in the new SART guidelines may well increase the challenges associated with its enforcement as well as with its auditing functions. It will likely be a year or 2 before clarity emerges as to the functionality of the newly minted reporting paradigms and as to the potential need for modifications.

ART outcome reporting of delayed embryo transfers: additional clinical indications

Yet another challenge to the reporting of ART outcomes has been the proliferation of other examples of autologous delayed (ie, frozen-thawed) embryo transfers apart and distinct from oocyte/embryo accumulation cycles. Reference is being made to an assortment of circumstances wherein the conclusion of an initiated cycle is a delayed (≤1 year) frozen-thawed rather than a fresh embryo transfer. Potential indications for deferred (“freeze all”) embryo transfers include the short-term banking of embryos pending the receipt of PGD/PGS results or the removal of a heretofore unrecognized endometrial polyp. Other indications for short-term banking include patients at increased risk for the ovarian hyperstimulation syndrome, the inability to secure sperm, or the prospect of a nonreceptive endometrium. Either way, these variants of short-term banking, not unlike oocyte/embryo accumulation cycles, are liable to increase the representation of excluded cycles and the attendant distortions thereof. Recognizing the need in course correction, SART has resolved to restore transparency by “linking” all oocyte retrievals to the eventual embryo transfer whether they are fresh or frozen-thawed embryos. In this context, the decision to delay the embryo transfer can be made either at cycle start or at any time during the cycle prior to embryo transfer. Moreover, if and when oocyte retrieval is not followed by a fresh embryo transfer, the reason(s) dictating this course of action would have to be furnished (eg, “freeze for biopsy”).

In the absence of transfer because of universal (thaw-associated) embryonic loss or universal embryo aneuploidy, the ART outcome of the cycle in question will be reported as negative during the relevant reporting year.

Universal prospective reporting of cycle starts?

Prospective reporting of initiated cycles (within 4 days of cycle start) constitutes an expectation of the FCSRCA as articulated in the regulatory framework thereof. Instituted by SART in 1999, prospective reporting was designed to capture any and all cycle starts and thus ensure the integrity of the denominator with consumer-friendly public reporting in mind. At the time of this writing, prospective reporting by SART members is required and monitored but is neither reported nor enforced. Still, as recently as 2011, 53% of cycles reported to SART were prospectively reported. Given the latest update of the SART guidelines, the notion of prospective reporting now appears more important than ever. This sentiment was recently affirmed by Kushnir et al when stating that the only statistically correct way to prevent data manipulation such as cycle exclusion is “outcome reporting based on prospective data collection at cycle start, and calculation of success rates based on intention to treat.” In this regard, cancellations or conversions before oocyte retrieval and/or transfer are particularly disconcerting. Examples of the latter include but are not limited to poor responders, poor blastocyst development, or universal aneuploidy in fresh embryos. Going forward, it is the intention of SART to work towards improving the overall prevalence of prospective reporting. As a first step towards universal compliance, the percent of prospectively reported cycles will henceforth be included in the CSR beginning in 2014. Additional measures may follow suit.

Reporting ART outcome per embryo transfer?

In yet another effort to update the current reporting paradigm, the prospect of reporting cycle outcomes on a per embryo transfer basis has been proposed. Under this arrangement, fresh and frozen-thawed embryo transfers would be combined thereby eliminating any and all distinctions between these transfer modalities. In arguing the case for a per embryo transfer reporting paradigm, proponents have emphasized the unique value of reporting the implantation rate (as well as delivery rate) per embryo transfer. The latter, it was argued, constitutes the “single best index of program quality” and as such would be welcomed by prospective patients. It is further argued by advocates that reporting ART outcomes per embryo transfer will acknowledge recent progress, reinforce the ongoing quest for excellence, incentivize the optimization of ART outcomes, and promote the responsible stewardship of medical resources. Finally, the projection has been made that reporting ART outcomes per embryo transfer will discourage the transfer of multiple embryos (and thus births) in that ART outcomes reported per embryo transfer stand to be adversely affected.

The possibility and promise of ART outcome reporting per embryo transfer notwithstanding, this approach constitutes a departure from the letter and the spirit of the FCSRCA mandate according to which success rates are to be expressed on the basis of the “number of ovarian stimulation procedures attempted” and the “number of successful oocyte retrieval procedures performed”. Moreover, as pointed out by Kushnir et al, per embryo transfer reporting will not address the “exclusion” of cycles initiated in poor-prognosis patients wherein the failure to transfer will only drive up the pregnancy/fresh or frozen-thawed embryo transfer rates. Initiated cycles likely to be excluded from the denominator of ART outcome measures could include cases of poor ovarian stimulation, poor egg yield, poor embryo yield, failure to fertilize, absent/poorly developed blastocysts, and absent fresh euploid blastocysts. Stated differently, ART outcome reporting per embryo transfer is bound to favor patients with good prognosis thereby undermining the notion of affording all patients with a reasonable estimate of success. It is possible that the latter concerns could have been addressed by the creation of a separate reporting category for “short-term banking” in the face of “oocyte/embryo accumulation cycles” and related forms of delayed transfer. However, for the foreseeable future, this possibility has been ruled out by SART. All told, these considerations argue against the possibility that ART outcome reporting per embryo transfer is likely to be implemented anytime soon.

Reporting risk-adjusted ART outcomes?

Ranking, rating, or otherwise directly comparing ART programs is not undertaken at present by either SART or the CDC in recognition of the variance in the clinic-specific case mix. However, as argued by Kushnir et al, prospective patients do in fact compare ART outcomes between clinics the inadvisability of the practice notwithstanding. Moreover, it is not outside the realm of possibility that self-paying (uninsured and underinsured) prospective patients and possibly even insured counterparts may welcome meaningful clinic-specific comparative data. Assuming one is willing to entertain such modification, consideration could be given to the possibility of stratifying patients and thus clinics by the nature and severity of the cognate infertility. Candidate variables could include but need not be limited to age, body mass index, duration of infertility, or the number of failed ART and/or medicated intrauterine insemination (IUI) cycles. Consideration could also be given to adjusting as per the functional ovarian reserve (eg, metaphase II oocyte yield) and possibly as per the circulating levels of (uniformly assayed) follicle-stimulating hormone and antimullerian hormone at cycle start. Such correction could, by leveling the playing field (ie, correcting for adverse patient selection), allow for a more meaningful comparison of clinic-specific performance.

The notion of risk adjustment of clinical outcomes is hardly a new one. Indeed, by statutory requirement, risk adjustment is (or will be) routinely used for the datasets populating all of the governmental “Compare” websites such as the “Physician Compare,” “Nursing Home Compare,” and “Hospital Compare” to name a few. Other long-established registries such as the New York and Pennsylvania. State cardiac registries routinely rely on risk adjustment in the evaluation of physicians and hospitals. Some of the same applies to the Society of Thoracic Surgeons National Database. As such, these observations suggest that given the political will, the notion of comparing and reporting risk-adjusted ART outcomes is well within the realm of possibility. Complex, costly, and not without widely recognized shortcomings, such initiatives would have to be considered carefully, validated thoroughly, and phased in progressively. Deemed unlikely to materialize any time soon, the prospect of risk-adjusting ART outcomes should nevertheless remain on the proverbial table so that the relevant national conversation may proceed apace.

Reporting perinatal ART outcomes?

In the final analysis, the live term birth of a singleton infant weighing in excess of 2500 g constitutes the ultimate success in the pursuit of ART. In this regard, SART and the CDC are in complete harmony with the Birth Emphasizing a Successful Singleton at Term (BESST) outlook according to which a “single, term gestation, live infant per initiated cycle is the most relevant standard of success.” At present, little is being done in the way of public reporting of the perinatal outcomes of ART the availability of gestational age and birthweight data notwithstanding. Instead, reporting of the ART outcome data in question are presently limited to peer-reviewed venues. Joshi et al concluded that the proportion of favorable perinatal outcomes of live-born neonates increased from 38.6% in 2000 to 45.5% in 2008. Similarly, Kissin et al report that “the highest chance of good perinatal outcome is associated with a single embryo transfer” was noted for patients younger than 35 years of age. It would seem highly desirable and eminently doable that some of the same data (and perhaps additionally derived information) could populate appropriate fields in the CSR and in the national annual report.

Reporting concordance with ASRM embryo transfer guidelines?

Since 1998, at variable intervals, the ASRM Practice Committee has issued recommended limits for the numbers of embryos to transfer. The last such set of guidelines was issued in January of 2013. Although nonbinding, the ASRM guidelines have been and are widely viewed as representing the “Best Practice” standard for ART. Subject to these assumptions, it stands to reason that voluntary compliance with the ASRM guidelines could be viewed as 1 proxy measure of the quality of an ART clinic. Given that the full complement of data required for the analysis of clinic-specific compliance with the ASRM guidelines may not be at hand, pursuit of such possibility will require the accession of SART and the CDC as well as a close review of the attendant logistic and financial burdens which such transition might entail.