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Why the Standard Practices for Embryo Transfers are Rapidly Shifting

by Dr. Geoffrey Sher on June 4, 2016

Embryo transfer (ET) is undoubtedly a rate limiting factor when it comes to IVF outcome. In fact, in my opinion, it is the single most important procedural step in IVF. Optimal performance of ET takes practice, confidence, dexterity, timing, gentility and skill. Out of all of the hands-on procedures involved in the IVF process, embryo transfer is by far the most difficult to teach. In fact, any women may fail to conceive simply because the practicing physician did not (or could not) perform this procedure optimally.

The issue of whether it is better to transfer early (day 2-3 post fertilization) cleaved embryos rather than (day 5-6) blastocysts continues to be a controversy among practitioners in the field. Here I wish to focus on the reasons why I favor transferring blastocysts.

Not too long ago, it was believed that the sooner an embryo was transferred into the “natural environment” of the uterus, the greater would be the chance of it implanting and propagating a viable pregnancy. Thus most IVF physicians advocated day 2 or day 3 embryo transfers preferentially. About 20 years ago, we began to realize that there was no validity to the belief that an embryo would develop better and have a greater chance of propagating a baby by being inside the uterus earlier than it would by being allowed to first develop into a blastocyst in an incubator. About a decade later, it was realized that cleaved embryos that fail to develop into blastocysts are with few exceptions numerically chromosomally “incompetent” (aneuploid) such that had they been transferred earlier, they almost certainly would not have developed into blastocysts and would not have propagated a pregnancy anyway. Now most of us practicing in this field believe it to be preferential to selectively transfer blastocysts rather than earlier cleaved embryos. Don’t get me wrong! I am not saying that there is never a place for doing earlier pre-blastocyst transfers. Patients that only have one or two cleaved embryos available might as well transfer them early.

The recent popularization of full preimplantation genetic sampling (PGS) using methods such as comparative genomic hybridization (CGH), next generation gene sequencing (NGS) and SNP array, now allow us to identify those blastocysts that are the most “competent”. Selective transfer of such embryos improves the implantation rate per embryo by a factor of 2-3.

It is important to bear in mind that morphologically good looking day 3 embryos/blastocysts that are determined microscopically to be of a “high grade” , are by no means always numerically chromosomally “competent” euploid , and the likelihood of such embryos being “competent” diminishes progressively with advancing age of the woman. Only through the performance of full PGS can his age-related discrepancy be reduced.

While it would be acceptable to me to transfer 2 PGS-untested blastocysts to women under 39 years, and to transfer 3 to older women, I would not recommend transferring more than 2 PGS-normal embryos at any age.

The following are arguments in favor of performing blastocysts transfers:

  • By waiting to day 5-6 many unworthy, aneuploid and “incompetent” embryos can be culled out, thereby allowing for the transfer of fewer embryos and minimizing the risk of high order multiple pregnancies.
  • Diagnostic Advantages:
    • Failure of the expected number of cleaved embryos to advance to the blastocyst stage of development in culture, raises the suspicion of underlying inherent embryo “incompetence”, which is usually (but not exclusively) egg-related rather than due to a sperm factor. While age of the woman is the most important factor involved, it can also be due to the wrong protocol of ovarian stimulation being used).
    • It facilitates the performance of PGS to identify and then selectively transfer only most “competent” (euploid) blastocysts. In such cases, provided there is no underlying uterine implantation dysfunction implantation and pregnancy rate is enhanced significantly.

Of course, for the treating physician it is far less stressful not have to have to confront a patient with her having no surviving embryos to transfer. The avoidance of this has in my opinion, in the past, been one of the main reasons why IVF practitioners have elected to transfer cleaved embryos rather than blastocysts. But such a policy is usually not in the in the patients’ best interest. In my opinion, it is far better to advise the patient to do a blastocyst transfer since that is almost always in their best interest.

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  • Thamar - November 26, 2016 reply

    Dr Sher! I can’t find where I previously posted a question! Do you think pgs testing on day 3 embryos that make it to blast puts me at a disadvantage? My clinic tested mine on day 3 and discarded abnormals day 5 froze my normals. All made to day 5 no attrition.

    Dr. Geoffrey Sher

    Dr. Geoffrey Sher - November 26, 2016 reply

    No! In fact it might even be better. Very few genetics labs are testing day 3 embryos any longer.

    Geoff Sher

  • Emma Keogh - November 14, 2016 reply

    Dear Dr Sher
    I have been pregnant 5 times. First pregnancy 2010 ended at 8 weeks, tested positive for anticardiolipin antibodies. Had my daughter naturally in 2012 having taken prog, aspirin, clexane and steroids to 12 weeks. She had a small birth defect (universal Choanal atresia that was repaired at 2 years of age). I had her at 37. My ovarian reserve dropped and by 39 it was 5. I did TSI and got pregnant straight away with a small dose of gonal F. Ended at 10 weeks, did not have tissue tested. Did TSI very soon again, and at 40 had another miscarriage at 10 weeks (tested down syndrome) – I had even taken 25mg eltroxin for thyroid antibodies. . I then embarked on IVF (long protocol) with PGS, I had 2 day 5 blasts. One was normal, one was inconclusive. The embryo was retested and it was normal. I took the meds until 12 weeks and I also had intralipds 7 days before transfer and positive pregnancy test stage. My pregnancy was fine until 21 weeks when we found our boy had right sided CDH, he also developed hydrops at 24 weeks. He was born at 34 weeks 2 days and lived for 7 hours. We are obviously devastated. I of course want answers. Is there any course of action you would recommend taking?

    Dr. Geoffrey Sher

    Dr. Geoffrey Sher - November 14, 2016 reply

    Clearly, we need to talk! This is too complex for a limited response here.

    Please call or email Julie Dahan, my patient concierge. She will guide you on how to set up an in-person or Skype consultation with me. You can reach Julie at on her cell phone or via email at any time:
    Julie Dahan
    • Email: Julied@sherivf.com
    • Phone: 702-533-2691
     800-780-7437

    Geoff Sher

    I also suggest that you access the 4th edition of my book ,”In Vitro Fertilization, the ART of Making Babies”. It is available as a down-load through http://www.Amazon.com or from most bookstores and public libraries.

  • Sarah - September 6, 2016 reply

    Hi Dr. Sher,
    I’m about to come back to your clinic for a stimulation protocol to hopefully bank some embryos for potential gestational carrier as well as to do a FET of my day 6 blastocyst from my last cycle. I’ve never had a day 6 blastocyst before (they were all day 5 in the past). I’m seeing conflicting research online as to whether there is a difference in pregnancy success rates between day 5 and day 6 blastocysts. I’m a little nervous putting in a day 6 I guess and just wondering if you know if there is any research to support it makes a difference using a day 5 or 6 blastocyst? Thank you!

    Dr. Geoffrey Sher

    Dr. Geoffrey Sher - September 6, 2016 reply

    Both day 5 & day 6 blastocysts produce babies…although day 5 embryos have got an edge when it comes to success.

    Geoff sher

  • Francesca - August 23, 2016 reply

    I have had two miscarriages in the last 6 months. One of a PGS normal top grade embryo and one of abnormal identical twins (they had trisomy 15) the embryo for which was not screened as it was our sole blastocyst. I have recently tested and frozen a day 6 poorer quality hatched blastocyst (good quality TE but poor quality inner cell mass) which surprisingly came back from NGS PGS as euploid. Aside from the increased risk it will not thaw due to its poorer quality, should the visual assessment affect my chances of a live birth? My clinic has never biopsied a day 6 blastocyst of this lower quality, but as I have low egg numbers, this was my only survivor. They cannot therefore advise as to chances. Do you have any knowledge/experience of this?
    Kind regards

    Dr. Geoffrey Sher

    Dr. Geoffrey Sher - August 24, 2016 reply

    Hi Francesca,

    I am afraid that without much more information I cannot answer your question authoritatively. However, based upon your history alone, I suspect that you could have an implantation dysfunction.

    Whenever a patient fails to achieve a viable pregnancy following embryo transfer (ET), the first question asked is why! Was it simply due to, bad luck?, How likely is the failure to recur in future attempts and what can be done differently, to avoid it happening next time?.
    It is an indisputable fact that any IVF procedure is at least as likely to fail as it is to succeed. Thus when it comes to outcome, luck is an undeniable factor. Notwithstanding, it is incumbent upon the treating physician to carefully consider and address the causes of IVF failure before proceeding to another attempt:
    1. Age: The chance of a woman under 35Y of age having a baby per embryo transfer is about 35-40%. From there it declines progressively to under 5% by the time she reaches her mid-forties. This is largely due to declining chromosomal integrity of the eggs with advancing age…”a wear and tear effect” on eggs that are in the ovaries from birth.
    2. Embryo Quality/”competency (capable of propagating a viable pregnancy)”. As stated, the woman’s age plays a big role in determining egg/embryo quality/”competency”. This having been said, aside from age the protocol used for controlled ovarian stimulation (COS) is the next most important factor. It is especially important when it comes to older women, and women with diminished ovarian reserve (DOR) where it becomes essential to be aggressive, and to customize and individualize the ovarian stimulation protocol.
    We used to believe that the uterine environment is more beneficial to embryo development than is the incubator/petri dish and that accordingly, the earlier on in development that embryos are transferred to the uterus, the better. To achieve this goal, we used to select embryos for transfer based upon their day two or microscopic appearance (“grade”). But we have since learned that the further an embryo has advanced in its development, the more likely it is to be “competent” and that embryos failing to reach the expanded blastocyst stage within 5-6 days of being fertilized are almost invariably “incompetent” and are unworthy of being transferred. Moreover, the introduction into clinical practice about a decade ago, (by Levent Keskintepe PhD and myself) of Preimplantation Genetic Sampling (PGS), which assesses for the presence of all the embryos chromosomes (complete chromosomal karyotyping), provides another tool by which to select the most “competent” embryos for transfer. This methodology has selective benefit when it comes to older women, women with DOR, cases of unexplained repeated IVF failure and women who experience recurrent pregnancy loss (RPL).
    3. The number of the embryos transferred: Most patients believe that the more embryos transferred the greater the chance of success. To some extent this might be true, but if the problem lies with the use of a suboptimal COS protocol, transferring more embryos at a time won’t improve the chance of success. Nor will the transfer of a greater number of embryos solve an underlying embryo implantation dysfunction (anatomical molecular or immunologic).Moreover, the transfer of multiple embryos, should they implant, can and all too often does result in triplets or greater (high order multiples) which increases the incidence of maternal pregnancy-induced complications and of premature delivery with its serious risks to the newborn. It is for this reason that I rarely recommend the transfer of more than 2 embryos at a time and am moving in the direction of advising single embryo transfers …especially when it comes to transferring embryos derived through the fertilization of eggs from young women.
    4. Implantation Dysfunction (ID): Implantation dysfunction is a very common (often overlooked) cause of “unexplained” IVF failure. This is especially the case in young ovulating women who have normal ovarian reserve and have fertile partners. Failure to identify, typify, and address such issues is, in my opinion, an unfortunate and relatively common cause of repeated IVF failure in such women. Common sense dictates that if ultrasound guided embryo transfer is performed competently and yet repeated IVF attempts fail to propagate a viable pregnancy, implantation dysfunction must be seriously considered. Yet ID is probably the most overlooked factor. The most common causes of implantation dysfunction are:
    a. A“ thin uterine lining”
    b. A uterus with surface lesions in the cavity (polyps, fibroids, scar tissue)
    c. Immunologic implantation dysfunction (IID)
    d. Endocrine/molecular endometrial receptivity issues
    Certain causes of infertility are repetitive and thus cannot readily be reversed. Examples include advanced age of the woman; severe male infertility; immunologic infertility associated with alloimmune implantation dysfunction (especially if it is a “complete DQ alpha genetic match between partners plus uterine natural killer cell activation (NKa).
    My answer to patients who ask me when is the time to stop undergoing IVF is ….Aside from the weight of the financial burden, the time to stop is when in spite of thorough and comprehensive evaluation, there is no remediable and treatable explanation for repeated failure.

    I strongly recommend that you visit http://www.DrGeoffreySherIVF.com. Then go to my Blog and access the “search bar”. Type in the titles of any/all of the articles listed below, one by one. “Click” and you will immediately be taken to those you select. Please also take the time to post any questions or comments with the full expectation that I will (as always) respond promptly.
    • Controlled Ovarian Stimulation (COS) for IVF: Selecting the ideal protocol
    • IVF: Factors Affecting Egg/Embryo “competency” during Controlled Ovarian Stimulation(COS)
    • The Fundamental Requirements For Achieving Optimal IVF Success
    • Ovarian Stimulation for IVF using GnRH Antagonists: Comparing the Agonist/Antagonist Conversion Protocol.(A/ACP) With the“Conventional” Antagonist Aproach
    • Ovarian Stimulation in Women Who have Diminished Ovarian Reserve (DOR): Introducing the Agonist/Antagonist Conversion protocol
    • Anti Mullerian Hormone (AMH) Measurement to Assess Ovarian Reserve and Design the Optimal Protocol for Controlled Ovarian Stimulation (COS) in IVF.
    • IVF Failure and Implantation Dysfunction:
    • The Role of Immunologic Implantation Dysfunction (IID) & Infertility (IID):PART 1-Background
    • Immunologic Implantation Dysfunction (IID) & Infertility (IID):PART 2- Making a Diagnosis
    • Immunologic Dysfunction (IID) & Infertility (IID):PART 3-Treatment
    • Thyroid autoantibodies and Immunologic Implantation Dysfunction (IID)
    • Immunologic Implantation Dysfunction: Importance of Meticulous Evaluation and Strategic Management:(Case Report
    • Intralipid and IVIG therapy: Understanding the Basis for its use in the Treatment of Immunologic Implantation Dysfunction (IID)
    • Intralipid (IL) Administration in IVF: It’s Composition; How it Works; Administration; Side-effects; Reactions and Precautions
    • Natural Killer Cell Activation (NKa) and Immunologic Implantation Dysfunction in IVF: The Controversy!
    • Endometrial Thickness, Uterine Pathology and Immunologic Factors
    • Vaginally Administered Viagra is Often a Highly Effective Treatment to Help Thicken a Thin Uterine Lining
    • Traveling for IVF from Out of State/Country–
    • A personalized, stepwise approach to IVF
    • How Many Embryos should be transferred: A Critical Decision in IVF.
    • The Role of Nutritional Supplements in Preparing for IVF

    Please call or email Julie Dahan, my patient concierge. She will guide you on how to set up an in-person or Skype consultation with me. You can reach Julie at on her cell phone or via email at any time:
    Julie Dahan
    • Email: Julied@sherivf.com
    • Phone: 702-533-2691
     800-780-7437

    Geoff Sher

    I also suggest that you access the 4th edition of my book ,”In Vitro Fertilization, the ART of Making Babies”. It is available as a down-load through http://www.Amazon.com or from most bookstores and public libraries.

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