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IVF: Selecting the Best Quality Embryos to Transfer

by Dr. Geoffrey Sher on December 5, 2016

The numerical chromosomal configuration of a cell is referred to as its karyotype or ploidy. A cell with an irregular chromosome number is referred to as aneuploid while one with a normal karyotype, as euploid. It is predominantly (but not exclusively) the chromosomal configuration of the embryo that determines its subsequent ability, upon reaching a receptive uterine environment, to propagate a normal pregnancy, also referred to as its “competence.” A “euploid” (competent) embryo transferred to a receptive uterine environment (free of anatomical, or immunologic impediments to implantation is highly likely to propagate a “viable pregnancy “

Embryo transfer (ET) is undoubtedly one of the most important variables that determines IVF outcome. The procedure itself requires gentle placement of one or more embryo(s) near the roof of the uterine cavity under direct ultrasound guidance. Central to successful IVF outcome is the selection of high quality embryos for transfer to a receptive uterine environment, ones that are the most capable of propagating a normal pregnancy (i.e. “competent embryos”). The following methods for differentiating between “competent” and “incompetent” embryos have been in use:

  1. Graduated Embryo Scoring (GES): With Graduated Embryo Scoring (GES) each embryo is separately examined through a series of microscopic assessments over a period of 72 hours following fertilization. The maximum allotted GES score is 100. Research has shown that in women <39Y, the transfer of cleaved embryos with a GES score of > 70 and are transferred to the uterus on day 3 post-fertilization, each have a 25%-30% likelihood of implanting successfully as compared to 15-20% when the GES score is <70. Comparative implantation rates are lower for older women decline to under 10% per embryo by the time the egg provider reaches 43 years of age.
  1. Blastocyst Transfer: The presumption has always been that it is better to transfer healthy embryos into the uterus earlier rather than later. Recent research has clearly shown this to be an erroneous belief. In fact, with few exceptions, embryos that that fail to progress to the blastocyst stage in culture are almost always chromosomally abnormal and would not propagate a healthy pregnancy anyway, even if they were to be transferred earlier. Since only about 30% of embryos progress to blastocysts by day 5-6 post-fertilization, there is a clear advantage in allowing embryos to grow to blastocysts in order to cull out many of the abnormal ones. Simply stated, the major benefit from extending embryo culture to day 5-6 is a natural selection of the best-quality embryos. This means high pregnancy rates can be achieved through the transfer of fewer embryos than usual, thus reducing the risk of high-order multiple pregnancies. It is
  1. The Embryo Marker Expression Test (EMET): By measuring the concentration of a genetic marker known as sHLA-G (soluble human leukocyte antigen-G), which is released into the media in which early embryos are growing after fertilization, it is possible to identify those embryos more likely to produce a pregnancy. This so called. Embryo Marker Expression Test (EMET) is performed 46 hours after the egg retrieval to identify EMET-positive, or “more likely to be competent” embryos. Levent Keskintepe PhD and I determined, based upon the performance of EMET in more than 1,000 women undergoing IVF, that the transfer of even a single EMET, positive (EMET+)-testing embryo into anatomically and immunologically receptive uteri of women under 39y resulted in better than a 40% likelihood of a viable pregnancy. In women 39y-43y the comparable viable pregnancy rate when HLA-G + embryos were transferred was about 25-30%..
  1. Preimplantation Genetic (PGS) Using Next Generation Gene Sequencing.

Prior to PGS, the lack of a reliable method by which to accurately assess embryo “competence” often prompted even the most well intended IVF practitioner to transfer several embryos at a time in an attempt to optimize the likelihood of a pregnancy resulting. The widespread adoption of such practice, resulted in a virtual explosion in the incidence of high order multiple births (triplets or greater). The high costs associated with addressing short term and long term, obstetric, neonatal, and social complications resulting from such high order multiple pregnancies, is/was one of the main reasons why many health insurance providers in the U.S.A. were reluctant to voluntarily cover IVF services.

The introduction of PGS into the clinical IVF arena by Levent Keskintepe and myself about 10 years ago, for the first time provided access to a method by which to relatively reliably differentiate between “competent” and “incompetent” embryos. This advance has led to:

  • A lowering of the incentive to transfer multiple embryos with a commensurate reduction in the incidence of multiple pregnancies. ,
  • Markedly improved IVF success rates: In the fact the transfer of even a single PGS-normal blastocyst to a receptive uterus yields about a 45-60% pregnancy rate.
  • Lowering of the miscarriage rate down to <10% and
  • Minimizing the chance of a chromosomal birth defects such as Down syndrome.

Many IVF programs that offer PGS embryo selection, require that all participating patients consent to all aneuploid embryos () be disposed of. However, there is now growing evidence to suggest that following embryo transfer, some aneuploid embryos will in the process of ongoing development, convert to the euploid state (i.e. “autocorrection”) and then go on to develop into chromosomally normal offspring. So clearly, by summarily discarding all aneuploid embryos as a matter of routine we are sometimes destroying some embryos that might otherwise have “autocorrected” and gone on to develop into normal offspring.

The basis for such embryo “autocorrection” lies in the fact that some embryos found through PGS-karyotyping to harbor one or more aneuploid cells (blastomeres) will often also harbor chromosomally normal (euploid) cells (blastomeres). The coexistence of both aneuploid and euploid cells coexisting in the same embryo is referred to as “mosaicism.” As stated, some mosaic embryos will In the process of subsequent cell replication convert to the normal euploid state (i.e. autocorrect).

It is against this background, that an ever increasing number of IVF practitioners, rather than summarily discard PGS-identified aneuploid embryos are now choosing to cryobanking (freeze-store) certain of them, to leave open the possibility of ultimately transferring them to the uterus.

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  • Liz - February 17, 2017 reply

    What are your thoughts on endometrial scratching to aid implantation and improve IVF success rates? Do you see a benefit to this or more negatives? I am leaning toward the latter based on your #2 remark above.

    Dr. Geoffrey Sher

    Dr. Geoffrey Sher - February 17, 2017 reply

    The use of the “scratch” technique is admittedly becoming more widespread but I personally see no benefit to it at all.

    Geoff Sher

    Liz - February 20, 2017 reply

    Hi Dr. Sher,

    Thank you for your thoughts on the endo scratch.

    My history: I’m 33 years old and my husband is 32 years old. We’ve been diagnosed with unexplained/mild male factor infertility. Been trying to conceive 2+ years. Normal FSH (ranging 6.14-7.63) and AMH levels (ranging from 3.76-4.18). My TSH was slightly elevated so I have been taking 50mg of Synthroid for the past 9 months which has kept my level around 2.5. No history of endometriosis or PCOS. My husband has normal testosterone levels (530), normal count (ranging 17-53 mil/ml, mostly in the 30-40 range), slightly low to average motility (ranging from 20-65% with most being in the 40’s) and low strict morphology (ranging 6%-12%).

    We went thru 4 rounds of clomid alone. Then an additional 4 rounds of clomid paired with IUI. All unsuccessful. Follicle growth and lining always presented well.

    Our first IVF round was Antagonist protocol. I had 20 follicles retrieved, 19 mature, 15 fertilized, only one made it to Day 7 (6BB). Our embroyologist noted that the sperm looked good but that my eggs looked granular/fragmented. I should also note that I started on 15o IU of Gonal F/Menopur but after 3 days changed to 75 IU because of what appeared to be a strong stimulation. We triggered with Lupron to avoid OHSS. My estrogen spiked to 3600 so we cancelled the fresh transfer and did a subsequent FET w/ the 6BB which failed.

    I’m about to begin IVF#2 and we have changed the protocol to a MD Lupron. I will be starting at 75 IU of Gonal F/Menopur. My doctor feels switching up the meds and dosage will produce a better outcome and perhaps better quality eggs/embryos.

    I would really value your opinion on this new protocol. Do you think the initial protocol could have affected my egg quality? Everything I’ve read about MD Lupron protocol is geared toward those with diminished ovarian reserve, low responders or advanced reproductive age which none apply to me.

    Thank you in advance your time and dedication to helping others. It’s truly honorable.

    Dr. Geoffrey Sher

    Dr. Geoffrey Sher - February 20, 2017 reply

    The reason you had a Lupron trigger was for fear of developing OHSS. I am personally opposed to this method of trigger (see below). I also thi9nk that the protocol used on you for ovarian stimulation needs to be critically reviewed and possibly revised.

    Traditionally egg retrievals are timed for about 36 hours after a 10,000U hCG “trigger”. The hCG hormone thereupon remains in the system for up to a week. When patients who overstimulate following ovarian stimulation experience prolonged exposure to hCG the risk of developing severe ovarian hyperstimulation syndrome with its incumbent life-endangering complications escalates. Attempts to mitigate this risk have included:
    a) withholding the hCG trigger altogether thereby preventing luteinization of follicle granulosa cells and preventing the production of vasoactive substances (e.g. VEGF) which when overproduced escalate the risk/severity of OHSS,
    b) prematurely administering the hCG trigger to arrest further follicular growth and escalation in blood estradiol levels,
    c) reducing the dosage of hCG by half, to 5,000U in the hope of limiting/restricting the luteinization process and,
    d) supplanting the “hCG trigger’ by an “Agonist (e.g. Lupron) trigger” that causes promotes meiotic egg maturation buy causing a surge in the release of pituitary LH.
    All of the options above do indeed reduce the risk of developing OHSS. “a)” completely prevents egg maturation from occurring and thus virtually precludes the harvesting of “competent” eggs, while “b), c), and d)”all adversely affect egg “competency” to a lesser or greater degree, thereby compromising both embryo quality and IVF outcome.
    Use of the “Lupron trigger” bears further mention: Since its recent introduction, this approach has really gained popularity and caught on in a big way. In truth, there can be little argument that it markedly reduces the incidence, severity and risk of complications associated with severe ovarian hyperstimulation. However use of the “Lupron trigger” often comes at the expense of egg/embryo quality as well as IVF outcome. Thus, the question arises as to whether this approach is advisable, and if not, what the best alternative to its use would be. The reason why the “Lupron trigger” is in my opinion ill-advised, is that in cases of ovarian hyperstimulation, where there are numerous follicles with eggs that need to undergo meiosis following the “trigger”, the magnitude of the LH surge, induced by a “Lupron GnRHa trigger” is often insufficient. This can result in suboptimal egg maturation (meiosis), leading to the generation of an inordinate number of immature/dysmature eggs as well as in an increase in the number of large follicles that fail to yield eggs at all (“so called “empty follicles). This is why I do not employ the “Lupron trigger” approach in my practice, preferring instead to use the long pituitary down-regulation, along with “prolonged coasting” in women who are deemed to be at risk for developing OHSS. My position is further supported by a recent publication showing that for this very reason, the use of a GnRHa-induced “trigger is not helpful.
    Prolonged Coasting, my preferred choice!: My approach is consistently to have my patients who are at risk of developing OHSS, launch their ovarian stimulation, coming off a monophasic birth control pill (BCP). The last few days on the BCP is accompanied by the addition of Lupron. Thereupon the BCP is stopped and Lupron therapy is continued. After 3-7 days menstruation usually ensues, at which point the dosage of Lupron is reduced and low dosage FSHr (Follistim/Gonal-F/Puregon) -dominant ovarian stimulation is commenced. Lupron and gonadotropins are then continued together. This approach is referred to as the “Long Pituitary Down-regulation protocol” Use of the BCP is intended to lower LH and thereby reduce stromal activation (hyperthecosis) in the hope of controlling ovarian androgen (mainly testosterone) release (too much ovarian testosterone is harmful to egg development). Seventy five (75) units of LH/hCG (Luveris/Menopur) is added from the 3rd day of gonadotropin stimulation. Starting on the 7th day of ovarian stimulation with gonadotropins, I start watching daily for the # and size of follicles developing and for the rise in blood [E2]. If there are > 25 follicles, the patient becomes a candidate for “prolonged coasting” I keep stimulating with gonadotropins (regardless of the [E2]) until: a) 50% of all follicles reach 14mm and b) the [E2] reaches 2500pg/ml. At that point, gonadotropin stimulation is discontinued abruptly while daily Lupron injections continue. Thereupon I follow the daily blood [E2] without doing further US examinations. The [E2] will almost invariably continue to rise. I carefully plot the rise in [E2] (regardless of how high it goes). Usually, within 1-3 days it will plateau and then start to decline. As soon as the [E2] drops below 2500pg/ml (and not before then), I administer the 10,000U hCGu (Novarel/Pregnyl/Profasi) “trigger” or 500mcg of hCGr (Ovidrel) and then schedule an egg retrieval for 36h later. ICSI is a MUST because “coasted” eggs usually have few or no surrounding cumulus cells and eggs without a cumulus layer will not readily fertilize on their own. All fertilized eggs are cultured to the blastocyst (up to 6 days) whereupon I transfer up to two into the uterus, or vitrify all expanded blastocysts for subsequent dispensation at the directive of the patient. In some cases the embryos are biopsied for PGS testing prior to being cryostored. Subsequent frozen embryo transfers are conducted as per the wishes of the patients.

    It is important to point out that the success of this “prolonged coasting” approach depends on precise timing of the initiation and the conclusion of “prolonged coasting”. If you start too early, follicle growth will stop and the cycle will be lost. If you start too late, you will encounter too many post-mature/cystic follicles (>22mm) that usually harbor abnormally developed eggs.

    Use of the above approach avoids unnecessary cycle cancellation, severe OHSS, and optimizes egg/embryo quality. The worst you will encounter is mild to moderate OHSS and this too is uncommon.

    The use of an agonist or GNRH trigger while reducing the risk of severe OHSS developing comes at the expense of egg/embryo quality and could compromise IVF outcome.

    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.
    • Anti Mullerian Hormone (AMH) Measurement to Assess Ovarian Reserve and Design the Optimal Protocol for Controlled Ovarian Stimulation (COS) in IVF.
    • Taking A Fresh Look at Ovarian Hyperstimulation Syndrome (OHSS), its Presentation, Prevention and Management
    • Preventing Severe Ovarian Hyperstimulation Syndrome (OHSS) with “Prolonged Coasting”
    • Understanding Polycystic Ovarian Syndrome (PCOS) and the Need to Customize Ovarian Stimulation Protocols.
    • “Triggering” Egg Maturation in IVF: Comparing urine-derived hCG, Recombinant DNA-hCG and GnRH-agonist:
    • Intrauterine Insemination (IUI): Who Needs it & who Does Not: Pro’s & Con’s!
    • IUI-Reflecting upon its Use and Misuse : Time for a Serious “Reality Check”.
    • Micro-IVF: Often Preferable to Ovarian Stimulation with or Without IUI
    • The Role of Gender Selection in 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.

    Liz - February 21, 2017

    Thank you for the detailed response and recommending articles to read. I will definitely look at those over the coming days.

    I had no idea a Lupron trigger could have negative affects on egg/embryo quality. Lesson learned there.

    It seems like your LP Down Regulation protocol is more similar to a MD Lupron protocol. Have you had any experience with the MD Lupron protocol? And if so, do you feel it has less of a negative impact on the quality of eggs/embryos?

    Lastly, taking into account my age and history, and pending a successful round 2, what would be your recommendation on the number of embryos to transfer? Do the success rates dramatically increase if transferring 2 (vs. 1)?

    Many thanks

    Dr. Geoffrey Sher

    Dr. Geoffrey Sher - February 21, 2017

    I do not in any way endorse the MD Lupron protocol because with Lupron starting at the time that ovarian stimulation begins causes a surge in LH release and that increases ovarian testosterone which if present in large amount can adversely affect egg/embryo quality. The MDL protocol in my opinion is especially harmful when used in older women and those with diminished ovarian reserve (regardless of age).

    As for the b# of embryos that should be transferred. My policy is never to transfer >2 blastocysts.

    In my opinion, the protocol used for ovarian stimulation, against the backdrop of age, and ovarian reserve are the drivers of egg quality and egg quality is the most important factor affecting embryo “competency”.
    Older women as well as those who (regardless of age) have diminished ovarian reserve (DOR) tend to produce fewer and less “competent” eggs, the main reason for reduced IVF success in such cases. The compromised outcome is largely due to the fact that such women tend to have increased LH biological activity which often results in excessive LH-induced ovarian testosterone production which in turn can have a deleterious effect on egg/embryo “competency”.
    Certain ovarian stimulation regimes either promote excessive LH production (e.g. short agonist/Lupron- “flare” protocols, clomiphene and Letrozole), augment LH/hCG delivered through additional administration (e.g. high dosage menotropins such as Menopur), or fail to protect against body’s own/self-produced LH (e.g. late antagonist protocols where drugs such as Ganirelix/Cetrotide/Orgalutron that are first administered 6-7 days after ovarian stimulation has commenced).
    I try to avoid using such protocols/regimes (especially) in older women and those with DOR, favoring instead the use of a modified, long pituitary down-regulation protocol (the agonist/antagonist conversion protocol-A/ACP) augmented by adding supplementary human growth hormone (HGH). I further recommend Staggered IVF with embryo banking of PGS (next generation gene sequencing/NGS)-normal blastocysts in such cases. This type of approach will in my opinion, optimize the chance of a viable pregnancy per embryo transfer procedure and provide an opportunity to capitalize on whatever residual ovarian reserve and egg quality still exists, allowing the chance to “make hay while the sun still shines”.
    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
    • Anti Mullerian Hormone (AMH) Measurement to Assess Ovarian Reserve and Design the Optimal Protocol for Controlled Ovarian Stimulation (COS) in IVF.
    • The “Biological Clock” and how it should Influence the Selection and Design of Ovarian Stimulation Protocols for IVF.
    • Diagnosing and Treating Infertility due to Diminished Ovarian Reserve (DOR)
    • Controlled Ovarian Stimulation (COS) in Older women and Women who have Diminished Ovarian Reserve (DOR): A Rational Basis for Selecting a Stimulation Protocol
    • 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?
    • Staggered IVF: An Excellent Option When. Advancing Age and Diminished Ovarian Reserve (DOR) Reduces IVF Success Rate
    • Embryo Banking/Stockpiling: Slows the “Biological Clock” and offers a Selective Alternative to IVF-Egg Donation.
    • Preimplantation Genetic Testing (PGS) in IVF: It Should be Used Selectively and NOT be Routine.
    • Preimplantation Genetic Sampling (PGS) Using: Next Generation Gene Sequencing (NGS): Method of Choice.
    • PGS in IVF: Are Some Chromosomally abnormal Embryos Capable of Resulting in Normal Babies and Being Wrongly Discarded?
    • PGS and Assessment of Egg/Embryo “competency”: How Method, Timing and Methodology Could Affect Reliability
    • Implications of “Empty Follicle Syndrome and “Premature Luteinization”
    • Premature Luteinization (“the premature LH surge): Why it happens and how it can be prevented.

    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.

    Geoff Sher

    Liz - February 24, 2017

    Thank you for the detailed explanation. You talk a lot about LH and ovarian testosterone levels and their possible negative impact. What levels do you recommend staying under during stimulation? My IVF round as mentioned above had the following LH levels from day 4 thru day 10 of stimulation (2.02, .87, 2.9, 1.45, .5-trigger day).

    You also mentioned that it can be counter productive to have too many follicles greater than 22mm due to abnormal eggs. I had 19 mature that were estimated at the following sizes day of trigger (24, 23, 4-22, 2-21, 20, 3-19, 3-18, 2-17, 3-16, 2-15, 14). Was I triggered too late?

    Dr. Geoffrey Sher

    Dr. Geoffrey Sher - February 24, 2017

    Blood levels of LH are not reflective of actual LH-induced ovarian testosterone because: a) LH is released in a pulsatile fashion and before absolute levels rise in the blood, the valleys between the peaks must first fill in and b) blood levels don’t always equate with biological activity . The biological activity of LH increases with age and DOR.. Thus the simple answer is that in such women, while level of of LH may be higher, you cannot become totally complacent when they are lower.

    AS far as the follicle sizes you report here, without much more additional information such as, age, the induced hormonal changes, the protocol used for stimulation as well as its implementation, I cannot respond authoritatively.

    Sorry!

    Geoff Sher

    Liz - March 5, 2017 reply

    Hi Dr. Sher,

    I have a few more questions as I really value your opinion.

    Is your favored Long pituitary down regulation protocol the same as Lupron Down/Luteal Lupron protocol?

    Also, are there any supplements/vitamins you recommend to support egg quality?

    What are your thoughts on melatonin supplements? Are the ok to take if you have hyperthyroidism?

    Thank you.

    Dr. Geoffrey Sher

    Dr. Geoffrey Sher - March 5, 2017

    The answer to your question is by and large yes, it is the same as a luteal phase DR protocol but I launch off a BCP and in special circumstances, I do a modification…the Agonist/Antagonist Conversion protocol (A/ACP)…see below.

    Also, Hyperthyroidism is often an autoimmune condition and as such can be associated with an immunologic implantation dysfunction (IID)…see below.

    Finally, please see below regarding nutritional supplements in IVF. Melatonin should be fine, but whether it helps…no one knows.

    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

    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.

  • Nazneen - January 16, 2017 reply

    Good day. I am 28 year old with Grade 4 endometriosis and both my tubes are not patent. I have had 2 rounds of IVF.
    IVF1 – 1 day 5 blastocyst, resulted in a biochemical pregnancy (fresh cycle)
    IVF 2 – 2 day 5 blastocyst implanted – BFN
    I have 1 frozen day 6 blastocyst left. during this round I will be given clexane, Atosiban and intralipids. ( I was not given intralipids or clexane in my previous attempts). My question is, iare there good odds of a successful pregnancy with a Day 6 Blastocyst? Is there anything I can do to make this round successful as this is my last chance due to financial constraints. Any advice will be much appreciated.

    Dr. Geoffrey Sher

    Dr. Geoffrey Sher - January 16, 2017 reply

    Yes! Their are good odds with a day 6 blastocyst transfer. Not as good as with Day-5 but close.

    More important is to consider the following:

    The considerable emotional, physical and financial burden associated with infertility treatment in general and with IVF in specific, demand that factors known to affect outcome be identified and regulated prior to initiating treatment.

    Just as a successful garden needs a ”good” seed properly planted in fertile soil to produce healthy plants, successful embryo implantation requires a good seed (genetically “normal” embryo) and fertile soil (receptive uterine lining) to make a healthy baby. I have long used this “Seed/Soil Relationship” analogy to help clarify the critical nature of the interaction between embryo and endometrium in the successful propagation of pregnancy..

    There have in the last decade been numerous reports suggesting that certain drugs/supplements (e.g. GCSF) and endometrial receptivity testing/preparation might dramatically improve implantation. As yet, none of these have been proven to be effective. This article addresses the influence of the most relevant and important factors that are known to affect .endometrial receptivity and discusses approaches to treatment:

    1. Endometrial thickness
    In 1989, I first demonstrated that in both normal and “hormonally stimulated” cycles, preovulatory endometrial thickness as assessed by ultrasound examination, is partially predictive of embryo implantation (pregnancy) potential following IVF. Ideally the endometrium should measure at least 8.0mm in thickness, (but preferably >9mm).

    A “poor” endometrial lining is most commonly due to: 1) inflammation of the uterine lining (endometritis) that usually occurs as a result of endometritis (inflammation of the uterine lining that can follow a septic delivery, partial retention of the placenta following delivery, abortion or miscarriage, 2) severe adenomyosis (gross invasion of the uterine muscle by endometrial glandular tissue), 3) multiple fibroid tumors of the uterine wall) 4) prenatal exposure to the synthetic hormone, diethylstilbestrol (DES) and, 5) following >3, consecutive, back to back cycles of clomiphene citrate ovulation induction.

    Treatment with vaginal Sildenafil (Viagra): Hitherto, attempts to augment endometrial growth in women with poor endometrial linings by bolstering circulating estrogen blood levels (through the administration of increased doses of fertility drugs, aspirin administration and with supplementary estrogen therapy) have yielded disappointing results.

    In the mid-90’s I first reported on the finding that thee vaginal administration of Viagra for several days prior to the “hCG trigger “ or progesterone administration enhances uterine blood flow and estrogen delivery to the uterine lining and so improves endometrial thickening. Then In October 2002, I reported on the administration of vaginal Viagra to 105 women with repeated IVF failure due to persistently thin endometrial linings. All of the women had experienced at least two (2) prior IVF failures attributed to intractably thin uterine linings. About 70% of these women responded to treatment with Viagra suppositories with a marked improvement in endometrial thickness and 45% of these women achieved live IVF- births following a single cycle of treatment with Viagra. Nine percent (9%) miscarried. None of the women who had failed to achieve an improvement in endometrial thickness following Viagra therapy, subsequently and who underwent embryo transfers achieved viable pregnancies.

    2.Uterine Pathology:
    It has long been suspected that anatomical defects of the uterus might result in infertility.
    While myomas (fibroids) embedded deep in the uterine wall, are unlikely to cause infertility, an association between their presence and infertility has been observed in cases where they distort the uterine cavity, or protrude as submucous polyps through the endometrial lining. It would appear that even small submucous myomas have the potential to prejudice implantation.

    Far too many infertile women found to have a partial or complete septum in the uterus are subjected to surgical excision of the septum with a promise that this will enhance subsequent implantation. This is an erroneous belief. Contrary to popular belief, the presence of a septum that partially or completely partitions the uterine cavity, while being responsible (in some cases) for late miscarriages and premature onset of labor, does NOT cause failed implantation.

    It is likely that most surface lesions in the uterine cavity, whether due to an endometrial, placental or fibroid polyp (no matter how small), or intrauterine adhesions, have the potential to interfere with implantation by producing a local “inflammatory”- type response, not too dissimilar in nature from that which is caused by a foreign body such as a intrauterine contraceptive device. Unfortunately, a dye X-Ray test (hysterosalpingogram/HSG) will often miss many smaller such lesions. The only reliable methods for diagnosing even the smallest of such lesions, is through the performance of a hysterosongram (HSN),a hysteroscopy or an MRI.

    Hysterosonogram (syn. Saline ultrasound): This procedure involves the trans-cervical injection of a physiological saline solution via a catheter, into the uterine cavity. The fluid distended cavity is then examined by vaginal ultrasound for any irregularities that might point to surface lesions such as polyps, fibroid tumors, scarring, or a uterine septum. If performed correctly, the HSN is highly effective in recognizing even the smallest surface lesions that protrude into the uterine cavity. It is less expensive, less traumatic, and diagnostically, equally reliable as hysteroscopy. The only disadvantage lies in the fact that if a lesion is detected, it may require the subsequent performance of hysteroscopic surgical approach to treating the problem..

    Hysteroscopy: Diagnostic hysteroscopy is an office procedure that is performed under intravenous sedation, general or local anesthesia, with minimal discomfort to the patient. The procedure involves the insertion of a thin, lighted, telescope like instrument known as a hysteroscope through the vagina and cervix into the uterus in order to fully examine the uterine cavity. The uterus is first distended with carbon dioxide gas, which is passed through a sleeve adjacent to the hysteroscope. As is the case with FUS, diagnostic hysteroscopy facilitates examination of the inside of the uterus under direct vision for defects that might interfere with implantation.

    We have observed that approximately 8% of candidates for IVF have intrauterine lesions that require attention prior to undergoing IVF in order to optimize the chances of a successful outcome. We strongly recommend that all patients who have such lesions undergo surgery (D&C and/or hysteroscopic resection) to correct the pathology prior to undergoing IVF. Depending on the severity and nature of the pathology, therapeutic hysteroscopy may require general anesthesia. If so, it should be performed in an outpatient surgical facility or in a conventional operating room.

    3. Immunologic factors
    The implantation process begins six or seven days after fertilization of the egg. At this time, specialized embryonic cells (i.e., the trophoblast), which later becomes the placenta; begin growing into the uterine lining. When the trophoblast and the uterine lining meet, they, along with Immune cells in the lining, become involved in a “cross talk” through mutual exchange of hormone-like substances called cytokines. Because of this complex immunologic interplay, the uterus is able to foster the embryo’s successful growth. Thus, from the very earliest stage of implantation the trophoblast establishes a foundation for the future nutritional, hormonal and respiratory interchange between mother and baby. In this manner, the interactive process of implantation is not only central to survival in early pregnancy but also to the quality of life after birth.

    Considering its importance, it is not surprising that failure of proper function of this immunologic interaction during implantation has been implicated as a cause of recurrent miscarriage, late pregnancy fetal loss, IVF failure, and infertility. A partial list of immunologic factors that may be involved in these situations includes anti-phospholipid antibodies (APA), antithyroid antibodies (ATA), and most importantly activation of uterine natural killer cells (NKa). Presently, these immunologic markers in the blood can be only adequately measured by a handful of highly specialized reproductive immunology laboratories in the United States. I personally use Reproductive Immunology Associates in Van Nuys, CA or Reprosource in Boston, MA.

    The Central role of Natural Killer cells: After ovulation and during early pregnancy, NK cells comprise more than 70% of the immune cell population of the uterine lining. NK cells produce a variety of local hormones known cytokines. Uncontrolled, excessive release of certain cytokines (i.e. TH-1 cytokines) is highly toxic to the trophoblast (“root system”) of the embryo” leading to their programmed death (apoptosis) and, subsequently to failed or compromised/dysfunctional implantation. In the following situations NK cells become activated, and start to produce an excess of TH-1 cytokines:

    • Autoimmune Implantation Dysfunction: This is most commonly seen in association with a personal or family history of autoimmune diseases such as ith conditions such as Rheumatoid arthritis, hypothyroidism endometriosis and Lupus Erythematosus, Scleroderma, Dermatomyositis etc. It is also encountered in one third of women who have endometriosis (regardless of its severity), and in cases of “unexplained infertility” as well as with recurrent pregnancy loss (RPL).
    • Alloimmune implantation dysfunction where the male and female partners share specific genetic (DQ-alpha and/or HLA) similarities This is commonly seen in cases of RPL and in cases of secondary infertility

    Activated NK cells (NKa) can be detected through the K-562 target cell blood test and (more recently) through uterine biopsy for TH-1 cytokine activity. Treatment involves selective use of Intralipid (IL) or immunoglobulin (IVIG) therapy combined with oral steroids, initiated more 10-14 days prior to embryo transfer and in most cases of alloimmune implantation dysfunction, the transfer of a single blastocyst at a time.

    If you wish to discuss your case with me, feel free to 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.

  • Lee - December 30, 2016 reply

    Dear Dr Sher,

    Thank you for your great article on this topic. I am currently facing a similar issue: after four IVF cycles, I only have one mosaic day 7 embryo, which has big deletion on the long arm of chromosomes 5. I am debating if I want to transfer this. I am 40 already, and I am pursuing my second child. Could you give me some advice on this? Very very appreciate your time and help!

    Dr. Geoffrey Sher

    Dr. Geoffrey Sher - December 30, 2016 reply

    Hi Lee,

    You could transfer the embryo but please be awar]e that day-7 embryos do not yield reasonable results.

    Geoff Sher

    Lee - December 30, 2016 reply

    Again thank you for your reply. When you say “not reasonable results”, do you mean the pgs results are nor representative? Which direction would the actual embryo situation go, more likely to be incompetent or more likely to be competent than what the pgs result shows?

    Dr. Geoffrey Sher

    Dr. Geoffrey Sher - December 30, 2016 reply

    No! I am giving an opinion on the viability on day-7 embryos…regardless of PGS grading.

    Geoff Sher

    Lee - December 30, 2016 reply

    I went back to check the details of the embryo: it was a day 7 Hatching Blastocyst grade 523. My first successful pregnancy was with a slow growth embryo too (I transferred a morula and an early blast embryo but not know which one became my healthy boy). With my history, would I tend to produce slow growth embryos? This time the mosaic embryo is a girl however. Thank you again!

    Dr. Geoffrey Sher

    Dr. Geoffrey Sher - December 30, 2016 reply

    Good luck Lee!

    And Happy New Year!

    Geoff Sher

  • Tamar - December 8, 2016 reply

    Thanks so much for your response! I read an article in fertility and sterility “Cleavage-stage biopsy significantly impairs human embryonic implantation potential while blastocyst biopsy does not: a randomized and paired clinical trial”. That concerned me. That I’m being set up for failure due to the biopsy being done on day 3. This study seemed pretty valid being randomized. Patients that did cleavage biopsies had lower rates of implantation. Also me having such a high fertilization rate and getting to day 5 15/17 – 5 of those coming back pgs normal from day 3 biopsies. I was afraid maybe I’d have more normals if we had waited

    Dr. Geoffrey Sher

    Dr. Geoffrey Sher - December 8, 2016 reply

    Good luck!

    Geoff Sher

  • Ahmad - December 8, 2016 reply

    Generally after how many should I go for Pregnancy test after IVF blastocyst.

    Dr. Geoffrey Sher

    Dr. Geoffrey Sher - December 8, 2016 reply

    Generally 9 and 11 days post-transfer.

    Geoff Sher

  • Tamar - December 8, 2016 reply

    Your opinion on day 3 pgs biopsy with freeze on day 5. I have a high fertilization rate (usually lose 1) and all make it to blast on day 5-6. But my clinic has been doing a cleavage biopsy every time. Am I being set up for failure? I’m 41 and have a high rate of normals and high fertilization rate. But they are doing day 3 biopsies and discarding abnormals on day 5. But they ALL usually make it to day 5. They use IVIGEN now Igenomix that uses cgh pgs I’m pretty sure. Thanks!

    Dr. Geoffrey Sher

    Dr. Geoffrey Sher - December 8, 2016 reply

    Respectfully, something does not sound quite right here. I would ask them to do blastocyst biopsies.

    Geoff Sher

    Tamar - December 8, 2016 reply

    So you think that the normals could be not normal, and some of the “abnormals” would of been normal if tested day 5? They were testing as if I was going to do a fresh transfer of a normal on day 5 therefore day 3 testing. I guess I wanted to know your opinion on day 3 pgs testing and its validity.

    Dr. Geoffrey Sher

    Dr. Geoffrey Sher - December 8, 2016 reply

    Human embryo development occurs through a process that encompasses reprogramming, sequential cleavage divisions and mitotic chromosome segregation and embryonic genome activation. Chromosomal abnormalities may arise during germ cell and/or pre-implantation embryo development, and represents a major cause of early pregnancy loss. About a decade ago, I and an associate, Levent Keskintepe Ph.D were the first to introduce full embryo karyotyping (identification of all 46 chromosomes) through preimplantation genetic sampling (PGS) as a method by which to selectively transfer only euploid embryos (i.e. those that have a full component of chromosomes) to the uterus. We subsequently reported on a 2-3 fold improvement in implantation and birth rates as well as a significant reduction in early pregnancy loss, following IVF. Since then PGS has grown dramatically in popularity such that it is now widely used throughout the world.
    Most IVF programs that offer PGS services, require that all participating patients consent to all their aneuploid embryos (i.e. those with an irregular quota of chromosomes) be disposed of. However, there is now growing evidence to suggest that following embryo transfer, some aneuploid embryos will in the process of ongoing development, convert to the euploid state (i.e. “autocorrection”) and then go on to develop into chromosomally normal offspring. In fact, I am personally aware of several such cases occurring within our IVF network. So clearly , summarily discarding all aneuploid embryos as a matter of routine we are sometimes destroying some embryos that might otherwise have “autocorrected” and gone on to develop into normal offspring.
    Thus by discarding aneuploid embryos the possibility exists that we could be denying some women the opportunity of having a baby. This creates a major ethical and moral dilemma for those of us that provide the option of PGS to our patients. On the one hand, we strive “to avoid knowingly doing harm” (the Hippocratic Oath) and as such would prefer to avoid or minimize the risk of miscarriage and/or chromosomal birth defects and on the other hand we would not wish to deny patients with aneuploid embryos, the opportunity to have a baby.
    The basis for such embryo “autocorrection” lies in the fact that some embryos found through PGS-karyotyping to harbor one or more aneuploid cells (blastomeres) will often also harbor chromosomally normal (euploid) cells (blastomeres). The coexistence of both aneuploid and euploid cells coexisting in the same embryo is referred to as “mosaicism.” As stated, some mosaic embryos will In the process of subsequent cell replication convert to the normal euploid state (i.e. autocorrect)
    It is against this background, that an ever increasing number of IVF practitioners, rather than summarily discard PGS-identified aneuploid embryos are now choosing to cryobanking (freeze-store) certain of them, to leave open the possibility of ultimately transferring them to the uterus. In order to best understand the complexity of the factors involved in such decision making, it is essential to understand the causes of embryo aneuploidy of which there are two varieties:
    1. Meiotic aneuploidy” results from aberrations in chromosomal numerical configuration that originate in either the egg (most commonly) and/or in sperm, during preconceptual maturational division (meiosis). Since meiosis occurs in the pre-fertilized egg or in and sperm, it follows that when aneuploidy occurs due to defective meiosis, all subsequent cells in the developing embryo/blastocyst/conceptus inevitably will be aneuploid, precluding subsequent “autocorrection”. Meiotic aneuploidy will thus invariably be perpetuated in all the cells of the embryo as they replicate. It is a permanent phenomenon and is irreversible. All embryos so affected are thus fatally damaged. Most will fail to implant and those that do implant will either be lost in early pregnancy or develop into chromosomally defective offspring (e.g. Down syndrome, Edward syndrome, Turner syndrome).
    2. “Mitotic aneuploidy” occurs when following fertilization and subsequent cell replication (cleavage), some cells (blastomeres) of a meiotically euploid early embryo mutate and become aneuploid. This is referred to as mosaicism. Thereupon, with continued subsequent cell replication (mitosis) the chromosomal make-up (karyotype) of the embryo might either comprise of predominantly aneuploid cells or euploid cells. The subsequent viability or competency of the conceptus will thereupon depend on whether euploid or aneuploid cells predominate. If in such mosaic embryos aneuploid cells predominate, the embryo will be “incompetent”). If (as is frequently the case) euploid cells prevail, the mosaic embryo will be “competent” and capable of propagating a normal conceptus.
    Since some mitotically aneuploid (“mosaic”) embryos can, and indeed do “autocorrect’ while meiotically aneuploid embryos cannot, it follows that an ability to differentiate between these two varieties of aneuploidy would be of considerable clinical value. And would provide a strong argument in favor of preserving certain aneuploid embryos for future dispensation.
    Aneuploidy, involves the addition (trisomy) or subtraction (monosomy) of one chromosome in a given pair. As previously stated, some aneuploidies are meiotic in origin while others are mitotic “mosaics”. Certain aneuploidies involve only a single, chromosome pair (simple aneuploidy) while others involve more than a single pair (i.e. complex aneuploidy). Aside from monosomy involving absence of the y-sex chromosome (i.e. XO) which can resulting in a live birth (Turner syndrome) all monosomies involving autosomes (non-sex chromosomes) are lethal and will not result in viable offspring). Some autosomal meiotic aneuploidies, especially trisomies 13, 18, 21, can progress to viable, but severely chromosomally defective babies. All other meiotic autosomal trisomies will almost invariably, either not attach to the uterine lining or upon attachment, will soon be rejected. All forms of meiotic aneuploidy are irreversible while mitotic aneuploidy (“mosaicism) often autocorrects in the uterus. Most complex aneuploidies are meiotic in origin and will almost invariably fail to propagate viable pregnancies.
    There is presently no microscopic or genetic test that can reliable differentiate between meiotic and mitotic aneuploidy. Notwithstanding this, the fact that some “mosaic” embryos can autocorrect in the uterus, makes a strong argument in favor of transferring aneuploid of embryos in the hope that the one(s) transferred might be “mosaic” and might propagate viable healthy pregnancies. On the other hand, it is the fear that embryo aneuploidy might result in a chromosomally abnormal baby that has led many IVF physicians to strongly oppose the transfer of any aneuploid embryos to the uterus.
    While certain meiotic aneuploid trisomies (e.g. trisomies 13, 18, & 21) can and sometimes do result in chromosomally defective babies, no other meiotic autosomal trisomies can do so. Thus the transfer of trisomic embryos in the hope that one or more might be mosaic, should exclude the use of embryos with trisomies 13, 18 or 21. Conversely, no autosomal monosomic embryos are believed to be capable of resulting in viable pregnancies, thereby making the transfer of autosomally monosomic embryos, in the hope that they are “mosaic”, a far less risky proposition. Needless to say, if such action is being contemplated, it is absolutely essential to make full disclosure to the patient (s) , and to insure the completion of a detailed informed consent agreement which would include a commitment by the patient (s) to undergo prenatal genetic testing aimed at excluding a chromosomal defect in the developing baby and/or a willingness to terminate the pregnancy should a serious birth defect be diagnosed.

    I hope this helps.

    Geoff Sher

    Tamar - December 8, 2016 reply

    So you don’t think that my embryos that were biopsied on day 3 and frozen on day 5 that came back normal have the same chance as if they were biopsied on day 5?

    Dr. Geoffrey Sher

    Dr. Geoffrey Sher - December 8, 2016 reply

    Probably!

    Geoff Sher

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