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Staggered IVF with PGS – Selection  of “Competent” Embryos Greatly Enhances the Utility & Efficiency of IVF

by Dr. Geoffrey Sher on September 28, 2017

Staggered-IVF involves the use of Preimplantation Genetic Screening of advanced embryos (blastocysts) to identify those that are euploid (“competent”) and thereupon  the subsequent transfer to the uterus of embryos identified as being chromosomally “competent” in later cycle(s) of hormone replacement.

In human reproduction, the establishment of an ideal seed/soil relationship is pivotal, since both embryo “competence” and uterine receptivity are indispensable to the development of a healthy baby.  It is, however undeniable that reproductive failure (i.e. failed implantation, miscarriages and major birth anomalies) are far more likely to be due to embryo “incompetence” (70-75%) than to a lack of uterine receptivity (25-30%).

Even in young women, an advanced embryo (blastocyst) that “looks good” under a microscope will at best, will have a 30% chance of implanting successfully and this statistic becomes progressively attenuated with advancing age such that by 40 years of age the chance would at best be 15% and at 45 years, only  4-5%.

There is a profound lack of correlation between the microscopic appearance (grading) of an embryo and its subsequent ability to propagate a viable pregnancy (“competency”). It is mostly (but not exclusively) the embryo’s chromosomal configuration that will determine its “competence.” The number of chromosomes in a cell is referred to as its ploidy. A cell with a normal number of chromosomes is referred to as euploid while one with an irregular chromosome number is aneuploid.

It appears that the ploidy of the mature egg (rather than the sperm) that largely determines the post-fertilization chromosome configuration of the embryo and thus its “competence” to propagate a viable pregnancy.

We and others have reported on the fact that it is primarily the numerical chromosomal make-up (karyotype) of the egg, (rather than the sperm) which is the main determinant of an embryo’s chromosomal integrity and its “competence”. An egg with an abnormal karyotype (aneuploid) cannot propagate a “competent” embryo while one with all its chromosomes intact (euploid) is highly likely to do so. The fact is that most human eggs are aneuploid. In fact, even in young women >50% of all mature eggs (MII) are likely to be aneuploid and thus incapable of propagating “competent” embryos. And, egg aneuploidy increases progressively with advancing age such that by the mid-forties the incidence of egg aneuploidy is > 90%.

The transfer of 1-2 euploid, (“competent”) embryos to a receptive uterine environment has better than a 50% chance of resulting in pregnancy. Since the vast majority of IVF failures and early miscarriages are attributable to embryo aneuploidy, it follows that transferring euploid, “competent” embryos, can significantly reduce this risk.

Staggered in Vitro Fertilization (St-IVF): As stated above, St-IVF involves using PGS testing of advanced embryos (blastocyst) to identify those that are euploid (“competent”). Since PGS requires several days to perform, it precludes transferring fresh embryos to the uterus. Instead they need to be cryobanked (vitrified) and stored for subsequent transfer in a later cycle.  Thus a St- IVF cycle involves 2 stages: The first involves ovarian stimulation, egg retrieval, fertilization of the eggs and subsequent blastocyst biopsy 5-6 days later, to remove a few cells for karyotyping. This is followed by ultra-rapidly freezing (vitrifying) and storing them.  The second stage (embryo transfer of euploid embryos) is performed later. It involves hormonal preparation of the recipient’s uterus, thawing/warming of one or two pre-vitrified euploid blastocysts and then transferring these to the uterus.

St-IVF improves the efficiency of the IVF process by:

  • Markedly improving the birth rate per embryo transferred
  • Avoiding the need to transfer several embryos at a time thereby reducing the likelihood of high order multiple pregnancies (triplets or greater) and
  • Reducing the incidence aneuploidy-related miscarriages and birth defects such as Down and Edwards’s syndromes.
  • Making it possible for older women and those who have diminished ovarian reserve, to stockpile PGS-normal embryos over a number of cycles (Embryo Banking), test them and then selectively transfer one or two PGS-“competent” embryos in a subsequent cycle for a much improved pregnancy rate per embryo transferred and a significant reduction in the risk of miscarriage.

A few words of caution: While PGS with full embryo karyotyping indeed represents a major break-through in the IVF arena, is not a panacea.  First, even euploid embryos will in about 20% of cases, not be fully “competent”. Confounding genetic and metabolic factors that are not detectable through karyotyping, as well as variations in technical skill and laboratory errors can all compromise outcome. In addition, not all PGS-aneuploid embryos are incompetent. In some cases embryo aneuploidy may be initiated following fertilization of a euploid egg with a euploid sperm when mitotic cell replication goes wrong. In such cases some (but not all) of the embryo’s cells may be aneuploid). This is referred to as “mosaicism” which in most cases autocorrects during subsequent development. The problem lies in the fact that it is currently not possible to reliably differentiate between egg-related (meiotic) aneuploidy and mitotic aneuploidy mosaicism. Finally, a totally “competent” embryo might fail to develop due to anatomical (uterine lining thickness) and immunologic implantation dysfunction rather than aneuploidy. This all serves to explain why only about half of euploid embryos/blastocysts transferred will propagate viable pregnancies.

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  • jackie maia - April 8, 2018 reply

    HI Dr Sher. I messaged you a while back about embryo grade, success and pgs status. I will be choosing which embryo to transfer soon. I will be choosing between grades c and b euploid embryos from fresh donor eggs. Should I make my choice based on embryo grade? I will have frozen embryos pgs normal from 2 different donors: Donor #1 very young but out of 10 fresh eggs produced one euploid grade 3cc embryo. 2/2 positives but do not know if they are ongoing pg. Donor #2 is in process but looks very promising on day 3. She is close to 30 and has 2 children and one proven cycle out of one transfer. I will bet that Donr #2 will have normal grade b embryos to choose from. How big of a difference once pgs normal is there in success between a grade b and grade c embryo? ty doctor!!! jackie

    Dr. Geoffrey Sher

    Dr. Geoffrey Sher - April 8, 2018 reply

    I don’t think it matters which euploid blastocysts you choose. In my opinion, their prior grade as cleaved embryos is trumped by them making it to blastocyst by day 6 and being euploid by PGS.

    Good luck!

    Geoff Sher

    jackie maia - April 8, 2018 reply

    Thank you, Dr! I trust your expertise! :)))

    Dr. Geoffrey Sher

    Dr. Geoffrey Sher - April 9, 2018 reply

    You are welcome!

    Geoff Sher

  • G M - December 30, 2017 reply

    Hello Dr Sher, I’m 46 yrs , tried ivf first time with donor egg and pgs done , this was best quality embryo at 5 days blastocyst, euploid but my first cycle failed , uterine line was good more than 9 cm , i had one polyp removed 2 months back , the polyps position was close to cervix .what is the reason of my failure of my first ivf ?I have endometriosis for long .My uterus is in retroverted position.we are devastated . Please suggest us . We had another 4 euploid blastocyst left.Do you think I should try another cycle or think ofgestational carrier ? why this first ivf cycle with donor egss failed ?

    Dr. Geoffrey Sher

    Dr. Geoffrey Sher - December 30, 2017 reply

    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).
    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.

    • The IVF Journey: The importance of “Planning the Trip” Before Taking the Ride”
    • 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
    • Use of GnRH Antagonists (Ganirelix/Cetrotide/Orgalutron) in IVF-Ovarian Stimulation Protocols.
    • 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.
    • Human Growth Hormone Administration in IVF: Does it Enhances Egg/Embryo Quality and Outcome?
    • The BCP: Does Launching a Cycle of Controlled Ovarian Stimulation (COS). Coming off the BCP Compromise Response?
    • Blastocyst Embryo Transfers should be the Standard of Care in IVF
    • IVF: How Many Attempts should be considered before Stopping?
    • “Unexplained” Infertility: Often a matter of the Diagnosis Being Overlooked!
    • 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
    • Treating Out-of-State and Out-of-Country Patients at Sher-IVF in Las Vegas:
    • 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

    If you are interested in seeking my advice or services, I urge you to contact my concierge, Julie Dahan ASAP to set up a Skype or an in-person consultation with me. You can also contact Julie by phone or via email at 702-533-2691/ Julied@sherivf.com You can also apply online at http://www.SherIVF.com .

    *FYI
    The 4th edition of my newest book ,”In Vitro Fertilization, the ART of Making Babies” is available as a down-load through http://www.Amazon.com or from most bookstores and public libraries.

    Geoffrey Sher MD

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