INKLINGS Personalized medicine or ‘‘one size fits all’’? It is not too much of a stretch to assert that the ‘‘holy grail’’ of assisted reproductive technology (ART) has been the selection and transfer of a single embryo that will result in a successful and healthy pregnancy. Due in large measure to improvements both in stimulation strategies and laboratory technique, the efficiency of implantation following in vitro fertilization (IVF)/embryo transfer has improved dramatically over the last few decades. As pregnancy rates have improved, multi-fetal pregnancies have risen to the fore as the dominant risk of ART. The worldwide promulgation of national, legislative and voluntary professional guidelines limiting the number of embryos transferred has resulted in a marked reduction in the rates of higher-order multiple gestations, but thus far has had a minimal impact on the incidence of twin gestations (1). The conventional approach to embryo selection has relied predominantly on morphologic criteria and more recently the acquisition of kinetic data on early embryonic development via time-lapse imaging. When deciding whether to transfer a single embryo (eSET) versus any number of embryos in excess of one, patient-specific factors are also taken into account, specifically including the patient's chronological age and past treatment history. Using morphologic criteria, it has been demonstrated in a young IVF population that a strategy of eSET followed, if the first transfer is unsuccessful, by subsequent transfer of a single thawed embryo can yield similar pregnancy rates to the transfer of two fresh embryos (dET), while eliminating the risk of dizygotic twins (2). Over the past decade and a half, modifications in culture media have allowed prolonged in vitro culture and relatively efficient progression of cleavage stage embryos to blastocysts, thus affording an additional approach to embryonic self-selection and, for many ‘‘good prognosis’’ patients, improved per embryo implantation rates. Notwithstanding the possible association of prolonged tissue culture and blastocyst transfer with certain risks, including increased rates of monozygotic twinning and slightly increased rates of adverse neonatal outcomes (3), blastocyst culture and transfer has become a prevalent strategy in ART with demonstrably high implantation rates in eligible populations. Of note, despite the incorporation of blastocyst selection into widespread clinical practice, eSET still comprises a minor proportion of embryo transfers nationwide. According to the 2011 Society for Assisted Reproductive Technology Registry, 30.8% of ART cycles in the United States resulted in twin births in women younger than 35 years. There has recently been a reinvigorated interest in the potential role of preimplantation genetic screening (PGS) as an approach to maximizing per-transfer pregnancy and live birth rates, and potentially increasing the proportion of eSET cycles at IVF clinics. The resurgent enthusiasm for PGS results from a combination of factors including refinements in molecular diagnosis (trophectoderm biopsy with 24 chromosome screening [CCS]) and improvements in the efficiency of blastocyst cryopreservation through vitrification, permitting subsequent transfer of a euploid embryo(s) in an unstimulated 922
cycle. Although long term follow-up of children resulting from a combination of blastocyst culture, trophectoderm biopsy, vitrification and thaw/transfer is obviously lacking, preliminary experience has thus far been reassuring and there are potential benefits in terms of implantation rates, reduced risk of miscarriage and the prospect of an increased rate of singleton deliveries (should the technique shift practice patterns to higher rates of eSET in IVF clinics). One can plausibly argue that the increased use of PGS could indeed prove beneficial for some specific patient cohorts: women with recurrent aneuploid pregnancy losses, good responders with repetitive IVF failures and donor oocyte recipients. These benefits would be nullified unless the dominant approach becomes eSET, as the incidence of dizygotic twins would presumably rise to unacceptable levels should multiple euploid blastocysts be transferred. The more provocative question is whether a strategy of routine blastocyst biopsy and PGS via CCS should dominate the practice of ART or indeed become the standard of care. Even putting aside the lack of long term safety data, there are clearly significant concerns with such a proposal. Given that euploidy rates among biopsied blastocysts in good prognosis patients younger than 34 years of age appear to be in the vicinity of 70% (4), PGS might improve the already high eSET success rate (selected on the basis of morphology alone) for these patients by as much as 25%; however, this enhancement would be achieved through a clearly more invasive and significantly more costly procedure, especially in the setting of cryopreserved supernumerary blastocysts where the option of subsequent thawed/eSET cycles without biopsy exists. One could argue that the target population should in fact ideally be older and poorer prognosis patients, i.e., those in whom transfer of two or more embryos is common clinical practice; this concept will be to a significant degree limited by logistical considerations, however. Older patients, as well as women with diminished ovarian reserve in general, typically attain fewer oocytes and embryos; if one assumes mean blastulation rates of approximately 50% in experienced laboratories with perhaps a third of all embryos developing into fair-togood quality blastocysts, plus a loss rate of roughly 5%– 10% following thaw, embryonic attrition rates will loom large as a significant practical issue for patients with relatively few fertilized oocytes. In centers exclusively performing blastocyst transfers with or without PGS, this inevitably leads to a subset of clinically challenging patients who (often repetitively) fail to undergo embryo transfer despite having cleavage stage embryos on day 3. The argument that embryos that fail to develop into acceptable quality blastocysts in vitro could not have implanted had they been transferred at an earlier stage (i.e., day 3) is unprovable and furthermore implausible unless one posits that the average ART laboratory (or even the most refined laboratory) has essentially attained clinical perfection and is at least on a par with in vivo physiology. Establishment of routine blastocyst culture with PGS as a clinic's standard operating procedure would therefore be a clinical trade-off: one would achieve fewer ‘‘futile transfers’’ VOL. 101 NO. 4 / APRIL 2014
Fertility and Sterility® (i.e., a higher clinic-specific success rate per transfer) at the cost of an increased risk of ‘‘futile cycles’’ and ‘‘futile retrievals.’’ The impact that this practice will have on the national reporting of IVF success rates (e.g., should the denominator in the success rate be 3 if three oocyte retrievals are required to achieve a single embryo transfer procedure) has been previously discussed in this journal (5). More importantly, a significant number of poorer prognosis patients, including those with diminished ovarian reserve, poor fertilization rates and/or poor embryo development may be deprived of their best chance for success with autologous oocytes, and some of these patients will be precipitously directed toward treatment with donor oocytes. Indeed, such clinically challenging patients comprise a significant proportion of the total population presenting for evaluation and treatment at many tertiary referral IVF centers. As with other disease states, the goal of therapy for infertility should be the optimal management of the individual patient: a ‘‘one size fits all’’ approach would inevitably risk depriving some patients of effective treatment. Blastocyst biopsy and CCS is an important addition to the assisted reproductive technology armamentarium and will likely be of value for a subset, and at some centers perhaps even a significant proportion, of their IVF patients. It is likely that this technology is finally, at least for a selected group of patients, ‘‘ready for primetime’’. Leading proponents of the expanded application of CCS in ART readily admit that studies published thus far have not included poor responders or patients with poor embryo quality; it is therefore all the more important that IVF practitioners understand the limitations of the available data as they begin to incorporate these strategies into their patterns of practice.
VOL. 101 NO. 4 / APRIL 2014
Owen K. Davis, M.D. Zev Rosenwaks, M.D. The Ronald O. Perelman and Claudia Cohen Center for Reproductive Medicine, Weill Cornell Medical College, New York, New York http://dx.doi.org/10.1016/j.fertnstert.2014.02.030 You can discuss this article with its authors and with other ASRM members at http://fertstertforum.com/daviso-personalized-medicine/ Use your smartphone to scan this QR code and connect to the discussion forum for this article now.* * Download a free QR code scanner by searching for “QR scanner” in your smartphone’s app store or app marketplace.
REFERENCES 1. 2.
3.
4.
5.
Davis OK. Elective single-embryo transfer- has its time arrived? N Engl J Med 2004;351:2440–1. € T, Jablonowska B, Pinborg A, Strandell A, et al. Thurin A, Hausken J, Hillensjo Elective single-embryo transfer versus double-embryo transfer in in vitro fertilization. N Engl J Med 2004;351:2392–402. Practice Committee of the American Society for Reproductive Medicine, Practice Committee Society for Assisted Reproductive Technology. Blastocyst culture and transfer in clinical-assisted reproduction: a committee opinion. Fertil Steril 2013;99:667–72. Franasiak JM, Forman EJ, Hong KH, et al. The nature of aneuploidy with increasing age of the female partner: a review of 15,169 consecutive trophectoderm biopsies evaluated with comprehensive chromosomal screening. Fertil Steril 2014;101:656–63.e1. Cedars MI. National reporting of in vitro fertilization success rates: how do we get patients useful information? Fertil Steril 2013;100:1210.
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cycle. Although long term follow-up of children resulting from a combination of blastocyst culture, trophectoderm biopsy, vitrification and thaw/transfer is obviously lacking, preliminary experience has thus far been reassuring and there are potential benefits in terms of implantation rates, reduced risk of miscarriage and the prospect of an increased rate of singleton deliveries (should the technique shift practice patterns to higher rates of eSET in IVF clinics). One can plausibly argue that the increased use of PGS could indeed prove beneficial for some specific patient cohorts: women with recurrent aneuploid pregnancy losses, good responders with repetitive IVF failures and donor oocyte recipients. These benefits would be nullified unless the dominant approach becomes eSET, as the incidence of dizygotic twins would presumably rise to unacceptable levels should multiple euploid blastocysts be transferred. The more provocative question is whether a strategy of routine blastocyst biopsy and PGS via CCS should dominate the practice of ART or indeed become the standard of care. Even putting aside the lack of long term safety data, there are clearly significant concerns with such a proposal. Given that euploidy rates among biopsied blastocysts in good prognosis patients younger than 34 years of age appear to be in the vicinity of 70% (4), PGS might improve the already high eSET success rate (selected on the basis of morphology alone) for these patients by as much as 25%; however, this enhancement would be achieved through a clearly more invasive and significantly more costly procedure, especially in the setting of cryopreserved supernumerary blastocysts where the option of subsequent thawed/eSET cycles without biopsy exists. One could argue that the target population should in fact ideally be older and poorer prognosis patients, i.e., those in whom transfer of two or more embryos is common clinical practice; this concept will be to a significant degree limited by logistical considerations, however. Older patients, as well as women with diminished ovarian reserve in general, typically attain fewer oocytes and embryos; if one assumes mean blastulation rates of approximately 50% in experienced laboratories with perhaps a third of all embryos developing into fair-togood quality blastocysts, plus a loss rate of roughly 5%– 10% following thaw, embryonic attrition rates will loom large as a significant practical issue for patients with relatively few fertilized oocytes. In centers exclusively performing blastocyst transfers with or without PGS, this inevitably leads to a subset of clinically challenging patients who (often repetitively) fail to undergo embryo transfer despite having cleavage stage embryos on day 3. The argument that embryos that fail to develop into acceptable quality blastocysts in vitro could not have implanted had they been transferred at an earlier stage (i.e., day 3) is unprovable and furthermore implausible unless one posits that the average ART laboratory (or even the most refined laboratory) has essentially attained clinical perfection and is at least on a par with in vivo physiology. Establishment of routine blastocyst culture with PGS as a clinic's standard operating procedure would therefore be a clinical trade-off: one would achieve fewer ‘‘futile transfers’’ VOL. 101 NO. 4 / APRIL 2014
Fertility and Sterility® (i.e., a higher clinic-specific success rate per transfer) at the cost of an increased risk of ‘‘futile cycles’’ and ‘‘futile retrievals.’’ The impact that this practice will have on the national reporting of IVF success rates (e.g., should the denominator in the success rate be 3 if three oocyte retrievals are required to achieve a single embryo transfer procedure) has been previously discussed in this journal (5). More importantly, a significant number of poorer prognosis patients, including those with diminished ovarian reserve, poor fertilization rates and/or poor embryo development may be deprived of their best chance for success with autologous oocytes, and some of these patients will be precipitously directed toward treatment with donor oocytes. Indeed, such clinically challenging patients comprise a significant proportion of the total population presenting for evaluation and treatment at many tertiary referral IVF centers. As with other disease states, the goal of therapy for infertility should be the optimal management of the individual patient: a ‘‘one size fits all’’ approach would inevitably risk depriving some patients of effective treatment. Blastocyst biopsy and CCS is an important addition to the assisted reproductive technology armamentarium and will likely be of value for a subset, and at some centers perhaps even a significant proportion, of their IVF patients. It is likely that this technology is finally, at least for a selected group of patients, ‘‘ready for primetime’’. Leading proponents of the expanded application of CCS in ART readily admit that studies published thus far have not included poor responders or patients with poor embryo quality; it is therefore all the more important that IVF practitioners understand the limitations of the available data as they begin to incorporate these strategies into their patterns of practice.
VOL. 101 NO. 4 / APRIL 2014
Owen K. Davis, M.D. Zev Rosenwaks, M.D. The Ronald O. Perelman and Claudia Cohen Center for Reproductive Medicine, Weill Cornell Medical College, New York, New York http://dx.doi.org/10.1016/j.fertnstert.2014.02.030 You can discuss this article with its authors and with other ASRM members at http://fertstertforum.com/daviso-personalized-medicine/ Use your smartphone to scan this QR code and connect to the discussion forum for this article now.* * Download a free QR code scanner by searching for “QR scanner” in your smartphone’s app store or app marketplace.
REFERENCES 1. 2.
3.
4.
5.
Davis OK. Elective single-embryo transfer- has its time arrived? N Engl J Med 2004;351:2440–1. € T, Jablonowska B, Pinborg A, Strandell A, et al. Thurin A, Hausken J, Hillensjo Elective single-embryo transfer versus double-embryo transfer in in vitro fertilization. N Engl J Med 2004;351:2392–402. Practice Committee of the American Society for Reproductive Medicine, Practice Committee Society for Assisted Reproductive Technology. Blastocyst culture and transfer in clinical-assisted reproduction: a committee opinion. Fertil Steril 2013;99:667–72. Franasiak JM, Forman EJ, Hong KH, et al. The nature of aneuploidy with increasing age of the female partner: a review of 15,169 consecutive trophectoderm biopsies evaluated with comprehensive chromosomal screening. Fertil Steril 2014;101:656–63.e1. Cedars MI. National reporting of in vitro fertilization success rates: how do we get patients useful information? Fertil Steril 2013;100:1210.
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