Letter to the editor regarding ‘Euploid single embryo transfer: The new IVF paradigm’

TO THE EDITOR:

Because the whole premise of their argument is mistaken, it is remarkable that the headline of Forman and Scott’s recent article “Euploid Single-Embryo Transfer: The New IVF Paradigm” did not even contain a question mark.¹

Here is why: Preimplantation genetic screening (PGS) is a technique to assess embryos for chromosomal abnormalities before transfer. It has been over a decade since it was first proposed to improve in vitro fertilization (IVF) outcomes because aneuploid embryos are a principal cause of failed implantation and miscarriages. A seemingly brilliant idea in clinical practice, however, its use has been disappointing. It not only failed to improve outcomes but, especially in older women, may have adversely affected them.^2,3 And such patients had been considered the best candidates. Major professional organizations have declared PGS ineffective,^4-6 although only after thousands of women had been exposed.

Only a few years later, PGS is “reborn” in an allegedly improved format, utilizing improved techniques and technologies, allowing greatly improved accuracy in aneuploidy diagnosis. Assuming that more accurate diagnoses would convert PGS from ineffective to effective, however, presumes that PGS’s prior failure was primarily caused by diagnostic inaccuracies. This was, however, unlikely the case. Poor patient selection (ie, concentrating on older women) was a much more likely reason.⁷ Younger women, in whom PGS may improve embryo selection, already experience excellent IVF outcomes without the procedure. Not surprisingly, not a single study utilizing the new PGS methodology has been able to demonstrate outcome advantages.⁸ 

Proponents of PGS, including Forman and Scott’s group, have made claims of efficacy but they do not stand up to scrutiny. Interested readers are referred to a recent review.⁸ The new PGS methodology moved embryo biopsy from cleavage (day 3 after fertilization) to blastocyst (days 5/6) stage. To reach embryo transfer and, therefore, a chance of conception, at least 1 embryo has to survive to days 5/6, and be normal (euploid). However, since older patients generally have lower ovarian reserve, such survival is less likely to happen. Consequently, only the best-prognosis patients will have embryos that reach transfer stage.

This would be fine if Forman and Scott (and others) had reported outcome on an “intent to treat” basis (ie, per cycle start). Claims of efficacy for the new PGS have, however, without exception, been made with reference point embryo transfer.^9-11 They, therefore, are highly biased and, if properly adjusted, show no benefits and, likely, reduced pregnancy chances in poorer-prognosis patients.^7,8

Recognizing this fact, Scott et al. “readjusted” their research after trial registration: From a primary goal of improved pregnancy outcomes they moved to a secondary goal of allegedly significant lowering  of twin pregnancy rates.⁹ Yet, unmentioned in their 3 relevant publications,^9-11 Schoolcraft et al. reported an equally high prognosis among patients undergoing IVF after single embryo transfer at blastocyst stage.¹² Observed lowered twin pregnancy rates, therefore, have no relevance to performance of PGS.⁸

Even with a question mark at the end of the headline, Forman and Scott’s suggested article premise, therefore, would be questionable.

Norbert Gleicher, MD

Vitaly A. Kushnir, MD

David H. Barad, MD, MS

New York, New York

REFERENCES

1. Forman EJ, Scott Jr. RT. Euploid single-embryo transfer: The new IVF paradigm. Contemporary OB/GYN. 2014;59(7):18–36.

2. Mastenbroek S, Twisk M, van Echten-Arends J, et al. In vitro fertilization with preimplantation genetic screening. N Engl J Med. 2007;357:9–17.

3. Gleicher N, Weghofer A, Barad D. Premplantation genetic screening: established and ready for prime time? Fertile Steril. 2008;89:780–788.

4. Practice Committees of the Society for Assisted Reproductive Technologies and American Society for Reproductive Medicine: Preimplantation genetic testing: a practice committee opinion. Fertil Steril. 2008;90:S136–S143.

5. Harton G, Braude P, Lashwood A, Schmutzler A, Treger-Synodinos J, Wilton L, Harper JC: European Society for Human Reproduction and Embryology (ESHRE) PGD Consortium. Hum Reprod. 2011;26:14–24.

6. Anderson RA, Pickering S. The current status of preimplantation genetic screening: British fertility society policy and practice guidelines. Hum Fertil. (Camb) 2008;11:71–75.

7. Gleicher N, Barad DH. A review of, and commentary on the ongoing second clinical introduction of preimplantation genetic screening (PGS) to routine IVF practice. J Assist Reprod Genet. 2012;29:1159–1166.

8. Gleicher N, Kushnir VA, Barad DH. Preimplantation genetic screening (PGS) still in search of a clinical application: a systematic review. Reprod Biol Endocrinol. 2014;12:22.

9. Forman EJ, Hong KH, Ferry KM, Tao X, Taylor D, Levy B, Treff NR, Scott RT Jr. In vitro fertilization with single euploid blastocyst transfer: a randomized controlled trial. Fertil Steril. 2013;100:100–107.e1.

10. Scott TR Jr, Upham KM, Forman EJ, et al. Blastocyst biopsy with comprehensive chromosome screening and fresh embryo transfer significantly increases in vitro fertilization implantation and delivery rates: a randomized controlled trial. Fertil Steril. 2013;100:697–703.

11. Forman EJ, Hong KH, Franasiak JM, Scott RT Jr. Obstetrical and neonatal outcomes from BEST Trial: single embryo transfer with aneuploidy screening improves outcomes after in vitro fertilization without compromising delivery rates. Am J Obstet Gynecol. 2014;210:157.e1–6.

12. Gardner DK, Surrey E, Minjarez D, Leitz A, Stevens J, Schoolcraft WB. Single blastocyst transfer: a prospective randomized trial. Fertil Steril. 2004;81:551–555.

NEXT: THE AUTHORS REPLY >>

IN REPLY:

Our cover story in the July 2014 issue of Contemporary OB/GYN proposed a new IVF paradigm utilizing improvements in embryo biopsy and comprehensive chromosome screening (CCS) to select a chromosomally normal (euploid) embryo to enhance single embryo transfer (SET), a technique that improves safety outcomes for babies conceived through IVF. While we welcome legitimate criticism of this proposed paradigm shift, the letter from Gleicher et al. misrepresents several key aspects of the validation studies and clinical implementation of this exciting technology.

Due to the improved safety and accuracy of blastocyst-stage biopsy for genetic analysis,¹ all clinical trials of CCS have randomized patients when their embryos reached the blastocyst stage. Without any evidence, the letter writers claim that this approach harms older patients because only the “best-prognosis patients” reach embryo transfer. While some patients unfortunately do not produce blastocysts, there is not a single study in the published literature demonstrating lower overall delivery rates when patients have their embryos placed in extended culture.² The uterus is not the physiologically normal environment for day-3 embryos, and embryos with reproductive potential routinely develop into blastocysts in high-quality IVF laboratories. In the most recent public reporting of IVF outcomes, there were zero deliveries among the 108 women > 42 years old who were treated at the letter writers’ own clinic, despite transferring an average of 2.8 day-2 or -3 embryos to the uterus. These women could not have fared worse with blastocyst culture and some would have been spared futile transfers and clinical miscarriages.

Furthermore, it has been clearly demonstrated that blastocyst-stage SET results in significantly higher delivery rates than cleavage-stage SET.³ Thus, to be candidates for SET, patients must produce blastocysts. To be candidates for elective SET, they must produce at least 2 blastocysts from which to select one. The Blastocyst Euploid Selective Transfer (BEST) Trial randomized patients with 2 blastocysts.⁴ Despite the writers’ claim to the contrary, an intent-to-treat analysis was properly performed in accordance with CONSORT guidelines.⁵ A flow diagram accounted for every patient, including those whose embryos did not reach the blastocyst stage, which was only 5% of the study population. Some patients produced only 1 blastocyst and had non-elective SET. Many of these patients delivered, although Gleicher et al. in their review arbitrarily subtracted them from the overall delivery rate without having any access to these data.⁶

The BEST trial was registered with ClinicalTrials.gov (NCT01408433), where it clearly states that the study sought to show similar-not necessarily improved-delivery rates with euploid SET. Improved delivery rates after CCS have been demonstrated in a trial in which a similar number of embryos were transferred to each group.⁷ It is dishonest for the letter writers to claim that our primary goal was “readjusted” after trial registration. The published study clearly states that noninferiority of euploid SET to untested 2-ET was the primary goal.⁴ Like many trials, other important secondary outcomes were also reported, including the tremendous difference in twin risk. What Gleicher et al. fail to appreciate is that showing similar delivery rates with SET is indeed a major accomplishment given the well-established increased maternal and neonatal complications arising from twin pregnancies and the financial burden placed on the healthcare system by preterm twin deliveries arising from IVF.⁸

With improvements in IVF laboratories and genetic technologies, it is no longer necessary to routinely transfer multiple embryos and put couples at high risk of twins and high-order multiple gestation. A new safer paradigm has arrived in IVF: There’s no question about it.

Eric J. Forman, MD

Richard T. Scott, Jr, MD

REFERENCES

1. Scott RT, Jr., Upham KM, Forman EJ, Zhao T, Treff NR. Cleavage-stage biopsy significantly impairs human embryonic implantation potential while blastocyst biopsy does not: a randomized and paired clinical trial. Fertil Steril. 2013;100(3):624–630. 

2. Grifo J, Kofinas J, Schoolcraft WB. The practice of in vitro fertilization according to the published literature. Fertil Steril. 2014 [E-pub].

3. Papanikolaou EG, Camus M, Kolibianakis EM, Van Landuyt L, Van Steirteghem A, Devroey P. In vitro fertilization with single blastocyst-stage versus single cleavage-stage embryos. N Engl J Med. 2006;354:1139-46.

4. Forman EJ, Hong KH, Ferry KM, et al. In vitro fertilization with single euploid blastocyst transfer: a randomized controlled trial. Fertil Steril. 2013;100(1):100-107.

5. Schulz KF, Altman DG, Moher D. CONSORT 2010 statement: updated guidelines for reporting parallel group randomized trials. Obstet Gynecol. 2010;115:1063–1070.

6. Gleicher N, Kushnir VA, Barad DH. Preimplantation genetic screening (PGS) still in search of a clinical application: a systematic review. Reprod Biol Endocrinol. 2014;12:22.

7. Scott RT, Jr., Upham KM, Forman EJ, et al. Blastocyst biopsy with comprehensive chromosome screening and fresh embryo transfer significantly increases in vitro fertilization implantation and delivery rates: a randomized controlled trial. Fertil Steril. 2013;100(3):697–703.

8. Bromer JG, Ata B, Seli M, Lockwood CJ, Seli E. Preterm deliveries that result from multiple pregnancies associated with assisted reproductive technologies in the USA: a cost analysis. Curr Opin Obstet Gynecol. 2011;23:168–173.