Cleavage stage biopsy significantly impairs human embryonic implantation potential while blastocyst biopsy does not A randomized and paired clinical trial

A paired randomized trial demonstrated a 39% relative reduction in implantation rates of embryos after cleavage-stage biopsy. In contrast, blastocyst biopsy had no adverse effect.

Richard T. Scott Jr., M.D., Kathleen M. Ferry, B.S., Eric J. Forman, M.D., Tian Zhao, M.S., Nathan R. Treff, Ph.D.

Volume 100, Issue 3, Pages 624-630, September 2013


To determine if cleavage- or blastocyst-stage embryo biopsy affects reproductive competence.

Paired randomized clinical trial.

Academic-assisted reproduction program.

Attempting conception through IVF.

After selecting two embryos for transfer, one was randomized to biopsy and the other to control. Both were transferred within shortly thereafter. The biopsy was submitted for microarray analysis and single-nucleotide polymorphism (SNP) profiling. Buccal DNA obtained from the neonate after delivery had microarray analysis and SNP profile compared with that of the embryonic DNA. A match confirmed that the biopsied embryo implanted and developed to term, whereas a nonmatch indicated that the control embryo had led to the delivery.

Main Outcome Measure(s):
Paired analysis of the delivery rates of the transferred embryos. Either twin delivery or failure to deliver represents equivalent outcomes for the biopsied and control embryos. In contrast, singletons were determined to be from the biopsied or the control embryo.

Blastomere biopsy on day 3 of development resulted in a significant reduction in sustained implantation. Only 30% of biopsied embryos had sustained implantation and ultimately developed into live-born infants versus 50% of unbiopsied controls, a relative reduction of 39%. In contrast, sustained implantation rates were equivalent (51% vs. 54%) for biopsied and control blastocysts.

Cleavage-stage biopsy markedly reduced embryonic reproductive potential. In contrast, trophectoderm biopsy had no measurable impact and may be used safely when embryo biopsy is indicated.

Clinical Trial Registration Number:

  • Vanessa Peinado

    This is a very interesting study design using SNP
    microarray based DNA fingerprinting methods for the follow up of the implanted
    embryos. However, in my opinion, this study does not accurately reproduce the
    regular protocol for most of the CCS cycles at cleavage stage in which embryo
    biopsy is performed on day-3 with blastocyst transfer on day-5 or day-6. Our
    experience with cleavage stage biopsies differs, and maybe this difference is
    based on the day of embryo transfer. In the published study for the cleavage stage
    biopsy group, biopsy and embryo transfer seem to be performed both at cleavage
    stage, and therefore before blastomere compaction, with the risk of
    manipulation on such stage embryos.

  • Eric Forman

    Lauren: Thanks for your kind comments.This study has completely changed our practice. We no longer perform day 3 biopsy under any circumstances. For patients with fewer than four cleavage stage embryos, we believe it is especially important not to expose the embryos to an intervention that may harm their developmental potential. For programs that cannot obtain results in 24 hours, consider the risk of vitrification of blastocysts which is 5% or less vs. the risk of day 3 biopsy which is approximately 40%. The choice is clear.

  • Lauren Johnson

    I congratulate Dr. Scott and colleagues on this intriguing and well-designed study. I am curious to know how your results have changed your practice. How do you counsel patients about cleavage stage biopsy, especially for those patients with fewer than four cleavage stage embryos? Also, for programs that are unable to obtain PGD/PGS results within 24 hours and must cryopreserve blastocysts for transfer in a subsequent cycle, do you have a sense for a cut-off of blast survivability below which cleavage stage biopsy with fresh transfer would be preferred?

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