Comprehensive chromosome screening withsynchronous blastocyst transfer: time for aparadigm shift*

Recently, the nature of assisted reproductive technology(ART) laboratory investigation has been shifting. Tradition-ally, it has focused on optimizing the culture milieu or assur-ing fertilization; now, a variety of new technologies areavailable to assess the reproductive potential of individualembryos. Perhaps most prominent has been the resurgenceof embryonic aneuploidy screening. The validation of24-chromosome testing platforms has led to a variety ofstudies demonstrating higher implantation and delivery rates.These findings are now translating to changes in the para-digm of ART practice.

Caution is prudent in times of change, and methodicalanalyses are needed. Evaluation logically focuses on efficacyin terms of enhanced implantation and delivery rates. Otherfactors, such as safety, cost, and accessibility also deservethoughtful consideration. Evaluations of these endpointsshould take into account the caliber of the data supportingthe ‘‘new paradigm,’’ in parallel with the data supportingthe current ‘‘standard of care,’’ and both should be evaluatedwith the same level of rigor.

Several investigators have recently expressed concernsabout the implementation of comprehensive chromosomalscreening (CCS) in clinical practice. Fortunately, an ever-growing literature is available to provide clinicians and scien-tists with the information they need to evaluate many of thecritical issues. Some of the major issues and questionsinclude:

1. Efficacy of 24-chromosome embryonic aneuploidyscreening. Multiple studies provide class I data demon-strating higher implantation and delivery rates following24-chromosome aneuploidy screening. In distinct contrastto fluorescent in-situ hybridization-based preimplantationgenetic screening studies in which every randomizedcontrolled trial (RCT) showed either no improvement oractive detriment, every RCT involving 24-chromosomescreening has demonstrated benefit (1–3).

2. What magnitude of improvement in clinical outcomes isnecessary to justify screening? Answering this questioninevitably involves a subjective decision that will bemade by patients after counseling by the clinicians caringfor them. Given that aneuploidy rates vary from 25% inwomen in their late twenties to 85% for those in theirmid-forties, the opportunity for enhancing outcomes willbe greatly affected by the age of the female partner andher intrinsic ovarian responsiveness. It is unlikely that im-provements will be made in direct proportion to the aneu-ploidy rate, as many other factors affect delivery rates.Women with high embryonic arrest rates are unlikely toattain the full benefit of screening. Still, the magnitude ofthe enhanced outcomes seen in the RCTs is substantial.

3. The cost of CCS may be burdensome. Although substantialcosts are associated with CCS, even in proportion, they are

*This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/3.0/).

660

lower than the costs of additional ART cycles. A definitivecost-effectiveness study has not been published to date.Although enhanced delivery rates should translate to fewertreatment cycles, that question must await more detailedanalyses before conclusions may be drawn. Additionally,savings attributable to decreased pregnancy losses and thecare provided to ongoing aneuploid gestations would needto be considered. Given that, and the impact on transfer or-der discussed below, it is unlikely that cost effectiveness willlimit implementation of embryonic aneuploidy screening.

4. Implementation of CCS may actually increase the risk formultiple gestations unless transfer order is reduced. Thatvery fact has already been established in a randomizedcontrolled trial (2). In fact, it is a mathematical certainty.As implantation rates increase, if there is no decrease intransfer order, then multiple gestation rates will inevitablyrise. However, it is not reasonable to assume that transferorder would remain the same. For the first time, there areclass I data demonstrating eSET after CCS is as effectiveas double-embryo transfer of unscreened embryos (2).All prior RCTs comparing elective single-embryo transfer(eSET) versus double-embryo transfer found poorer per-transfer outcomes with eSET. If CCS is used, that is nolonger true. Equivalent delivery rates are maintained whilevirtually eliminating the risk of twins. The paradigm usingCCS and eSET produced an average gain in birth weight ofapproximately 650 grams. No other single intervention inobstetrics has produced such a dramatic enhancement inbirth weight, which is known to be highly correlatedwith the health of the child. Of course, the transfer oftwo screened embryos would further increase pregnancyrates, but at the cost of quite elevated twin rates; thus, itshould be discouraged. Armed with these data, utilizationof eSET in our program has risen from less than 6% toapproximately 60% over a 4-year interval.

5. Embryo cryopreservation is essential to the application ofCCS. This is an excellent point, as it is true inmany, but notall, programs. Analyses can be completed in as little as4 hours, and several programs now have testing labora-tories within their facilities. However, that may not benecessary. Data from RCTs demonstrate equivalent deliv-ery rates following the transfer of fresh or vitrified CCSscreened blastocysts (2). Furthermore, data now demon-strate meaningfully better obstetrical outcomes in concep-tions following the transfer of cryopreserved embryos.

6. Some subpopulations may not benefit from aneuploidyscreening. The studies to date have focused on infertilenormal responders. No class I data address the impact ofCCS in women who are low responders or have recurrentpregnancy loss. An RCT to determine the impact of CCSin women at risk for low response to gonadotropin stimu-lation has been registered (NCT01977144) and is currentlyunderway. Within the general ART population, individualswho might typically be considered candidates for two-embryo transfer should be offered CCS. Given that theeSET rate was 8.8% in the recently released 2012 Societyfor Assisted Reproductive Technology (SART) data, itwould appear that this type of screening is appropriate

VOL. 102 NO. 3 / SEPTEMBER 2014

Use your smartphone

Fertility and Sterility®

for very large numbers of patients. Even those patientswho desire eSET attain increased delivery rates if theeuploid embryos are selected for transfer. Althoughmany of these patients already have excellent deliveryrates, it is difficult to imagine a scenario in which the in-creases in implantation rates seen in the RCTs done todate would not be a compelling reason to screen.

7. The need to culture to the blastocyst stage to safely biopsyembryos increases the number of futile cycles because ofembryonic arrest prior to blastulation. This issue isextremely important and represents a widely held belief,but it is not supported by data. In this case, two importantfacts may have been disregarded: (1) The in vivo environ-ment on day 3 is not physiologic given that humanembryos are not in the endometrial cavity on the thirdday of development. Moreover, significant differencesexist between the intra-endometrial and intra-tubal envi-ronments at that time. The real question is which of the twononphysiologic environments (intra-endometrial versusin vitro laboratory) allow a given embryo to attain itshighest reproductive potential. To date, the RCTs favorextended culture to the blastocysts. Definitive studies inlow responders have not yet been done; (2) This mode ofreasoning also completely disregards the issue of syn-chrony. Data, as opposed to speculation, now indicatethat active management of the time of transfer improvesoutcomes in those patients whose embryos are slow toblastulate (4). Of course, it is not possible to know onday 3 when any single embryo will blastulate. By failingto place embryos into extended culture, clinicians andembryologists lose the opportunity to determine if the em-bryos blastulate synchronously with endometrial develop-ment. This lost opportunity removes the ability to transfervitrified embryos the following month when synchronymay be assured. Therefore, day-3 transfer might actuallyresult in a reproductively competent embryo failing toimplant. This outcome is of particular concern in patientswith diminished ovarian reserve with very few embryos.Hopefully, class I data will become available to resolvethis issue in the near future.

8. The use of CCS allows some programs to manipulate theirdata and create inaccuracies in the SART/Centers for Dis-ease Control and Prevention reporting system. Factors thatare important to the fidelity of the reporting system areimportant and legitimate concerns. The prior reportingsystem was not designed to reliably capture outcomesfrom cycles requiring deferment of transfer to thefollowing month. Fortunately, the leadership at SARThas recently restructured the system to achieve greaterclarity and accuracy. This adjustment is not the firstadjustment for the SART/Centers for Disease Control andPrevention reporting system, and it is unlikely to be thelast. The key point is that the system remains committed

VOL. 102 NO. 3 / SEPTEMBER 2014

to fair and accurate reporting and has done an excellentjob in addressing this issue. Perhaps most important, im-plementation of new technologies or procedures shouldnot be based on consideration of the reporting system,but rather on optimizing patient outcomes.Implementation of CCS in normal responders positively

affects outcomes and for the first time empowers practicaleSET without compromising clinical outcomes. This proce-dure will positively affect many patients. Some cautionshould remain. The data in low responders and in womenwith recurrent loss are insufficient to draw definitiveconclusions.

CCS will not eliminate all clinical failures. Many otherchallenging problems remain to be resolved. Still, these areexciting times as embryonic aneuploidy screening movesclinical care ever closer to that ‘‘holy grail’’ of one embryo–one healthy baby.

Richard T. Scott Jr., M.D.a

Jason M. Franasiak, M.D.b

Eric J. Forman, M.D.aa Reproductive Medicine Associates of New Jersey; and

b Robert Wood Johnson Medical School, Rutgers University,Basking Ridge, New Jersey

http://dx.doi.org/10.1016/j.fertnstert.2014.06.022

You can discuss this article with its authors and with otherASRM members at

http://fertstertforum.com/scottr-comprehensive-chromosome-screening-synchronous-blastocyst-transfer/

to scan this QR codeand connect to thediscussion forum forthis article now.*

* Download a free QR code scanner by searching for “QRscanner” in your smartphone’s app store or app marketplace.

REFERENCES

1. Scott RT Jr, Upham KM, Forman EJ, Hong KH, Scott KL, Taylor D, et al. Blas-

tocyst biopsy with comprehensive chromosome screening and fresh embryotransfer significantly increases in vitro fertilization implantation and deliveryrates: a randomized controlled trial. Fertil Steril 2013;100:697–703.

2. Forman EJ, Hong KH, Ferry KM, Tao X, Taylor D, Levy B, et al. In vitro fertiliza-tion with single euploid blastocyst transfer: a randomized controlled trial. Fer-til Steril 2013;100:100–7.

3. Yang Z, Liu J, Collins GS, Salem SA, Liu X, Lyle SS, et al. Selection of single blas-tocysts for fresh transfer via standard morphology assessment alone and witharray CGH for good prognosis IVF patients: results from a randomized pilotstudy. Mol Cytogenet 2012;5:24.

4. Shapiro BS, Daneshmand ST, Garner FC, Aguirre M, Ross R. Contrasting pat-terns in in vitro fertilization pregnancy rates among fresh autologous, freshoocyte donor, and cryopreserved cycles with the use of day 5 or day 6 blasto-cysts may reflect differences in embryo-endometrium synchrony. Fertil Steril2008;89:20–6.

661