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(NEW) IVF: Approach to Selecting the Best Embryos for Transfer to the Uterus.


by Dr. Geoffrey Sher on January 2, 2018

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 ploidy 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, molecular or immunologic impediments to implantation” is the most likely to propagate a viable pregnancy.

Embryo transfer (ET) is undoubtedly one of the most important variables that determine 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 that upon being transferred to a receptive uterine environment are capable of propagating a normal pregnancy (i.e. “competent embryos”). The following methods currently in use for differentiating between “competent” and “incompetent” embryos all to a lesser or greater degree lack both sensitivity and specificity in evaluating “embryo quality/”competence”:

  • Microscopic Embryo Grading which evaluates and grades embryos based upon their structural appearance (morphology).
  • Prolonged embryo culture to the Blastocyst stage, an approach aimed at culling the poorer quality embryos. Thus embryos that survive to the blastocysts stage are the ones that are most likely to be ‘competent”. This provides a much greater likelihood of embryo “competency” as compared to microscopic grading.
  • Preimplantation Genetic Screening (PGS) permits identification and the transfer of embryos that have a full quota of 23 pairs of chromosomes have the greatest likelihood of being “competent”.

MICROSCOPIC GRADING OF DAY-3 EMBRYOS: Several such grading systems are presently in use. By and large, they all try to assess embryo “competency” by quantifying the number of cells (blastomeres) present, their symmetry and the number of embryo fragments (“fragmentation”) observed. Embryos that divide too slowly as well as those that divide too rapidly, as well as those that have irregular sized blastomeres and/or prominent evidence of fragmentation are the ones that are most likely to be “incompetent”. So it is that day-3 embryos that have 5-9 blastomeres which are symmetrical in form and exhibit minimal fragmentation…tend to be the ones more likely to be “competent”. Notwithstanding the above, it is always important to recognize that even the best looking, cleaved embryos are often “incompetent” and that regardless of microscopic embryo grade, the woman’s age profoundly impacts embryo “competency”. For example, at age <35at age <35y, roughly 50-60% of morphologically sound embryos are competent whereas by the time the woman reaches 43 years of age, <10% of her embryos are likely to be “competent”.

BLASTOCYST ASSESSMENT: Embryos that reach the expanded blastocyst stage by day 5-6 post-fertilization are the ones that are most likely to be “competent”. But once again, as with day-3 cleaved embryos, advancing age also profoundly impacts the embryo “competency”. In the past, IVF specialists tended to argue in favor of transferring early cleaved embryos to the uterus the natural “natural uterine environment” than to incubate them for 2-3 more days so as to allow them to reach the blastocyst stage. However, recent research has shown this to be an erroneous belief. In fact, with very few exceptions, embryos that fail to progress to the blastocyst stage in culture are chromosomally/genetically abnormal and even if they had been transferred earlier, would not have been capable of propagating a healthy pregnancy anyway. Since, regardless of the woman’s age, most cleaved embryos will fail to develop into blastocysts because they  are “incompetent”, it follows that extending embryo culture to day 5 or 6 and allowing many “incompetent” to be culled in the process, helps select of the best-quality embryos, allowing for fewer to be transferred without compromising outcome in any way.  And the transfer of fewer embryos also reduces the incidence of multiple pregnancies.

PREIMPLANTATION GENETIC SCREENING (PGS). This involves the performance of a biopsy of the outer cellular layer (trophectoderm) of day 5-6 blastocysts followed by full karyotyping (counting of all chromosomes). Embryos with a full quota of 46 (23 pairs) chromosomes (i.e. euploid) are the ones most likely (but not inevitably so) to be “competent, while those with an irregular chromosome quota (aneuploid) are the ones that are most likely to be “incompetent”. However, some aneuploid blastocysts will also contain euploid blastomeres. Such embryos are termed “mosaic” and they have the ability post-implantation, to “autocorrect” in the uterus and subsequently propagate viable, healthy babies.  It is presently not possible to reliably differentiate between incompetent, aneuploid and mosaic embryos in the laboratory. This is why embryos with single chromosomal aneuploidies should not be discarded and should be considered eligible for transfer. Moreover, PGS testing is also not 100% accurate. Errors occur in 5-8% of tests. For these reasons it is my opinion that PGS while a valuable tool, should be used selectively in IVF. In my practice, I largely reserve recommending PGS to older patients and those with diminished ovarian reserve who because of age have reduced embryo “competency” or because they are running out of time only produce few eggs at a time. I also advise using PGS in cases of recurrent pregnancy loss, unexplained repeated IVF failure and when there are strongly suspected underlying chromosomal/genetic abnormalities.

About Staggered -IVF (St-IVF: St-IVF is the process of separating an IVF cycle into two (or more) segments so as to allow for the PGS-identification of “competent” embryos (i.e. those capable of propagating healthy babies) and thereupon selecting such embryos for transfer in a future cycle. Phase 1 Involves the egg retrieval, fertilization and growing embryos to the blastocyst stage whereupon they are biopsied for PGS analysis. All blastocysts are then cryobanked by ultra-rapid freezing (vitrification) while awaiting availability of the karyotype report from the genetic laboratory…about 1-2 weeks later. Thereupon, plans are made for hormonal preparation and the Staggered (St)-FET with ≤ 2 warmed (thawed), euploid, “competent’ embryos/blastocysts (i.e. Phase 2).

  • Embryo Banking: Older women and women with diminished ovarian reserve, who are often running out of time on the biological clock can bank or stockpile their PGS-normal blastocysts (over several cycles, if need be) for subsequent dispensation. This allows them to “make hay while the sun still shines”, thereby affording them a palatable alternative to using donated eggs.

Staggered –IVF (St-IVF)  has the potential to vastly improve IVF outcome per embryo transferred (baby-rate per embryo) eliminate aneuploidy-related miscarriages/ birth defects and has heralded a new era, where it only requires the transfer one (1) “competent” blastocyst to propagate a single healthy baby.

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  • Priscilla okojie - January 16, 2018 reply

    Please doc what are the chances of a success in an IVF circle when a woman has endomentriosis.

    Dr. Geoffrey Sher

    Dr. Geoffrey Sher - January 16, 2018 reply

    Priscilla,

    That is an impossible question to address here! However, please cosider the following:

    Endometriosis is a condition that occurs when the uterine lining (endometrium) grows not only in the interior of the uterus but in other areas, such as the fallopian tubes, ovaries and the bowel. Endometriosis is a complex condition where, the lack or relative absence of an overt anatomical barrier to fertility often belies the true extent of reproductive problem(s).
    All too often the view is expounded that the severity of endometriosis-related infertility is inevitably directly proportionate to the anatomical severity of the disease itself, thereby implying that endometriosis causes infertility primarily by virtue of creating anatomical barriers to fertilization. This over-simplistic and erroneous view is often used to support the performance of many unnecessary surgeries for the removal of small innocuous endometriotic lesions, on the basis of such “treatment” evoking an improvement in subsequent fertility.
    It is indisputable that even the mildest form of endometriosis can compromise fertility. It is equally true that, mild to moderate endometriosis is by no means a cause of absolute “sterility”.
    Rather, when compared with normally ovulating women of a similar age who do not have endometriosis, women with mild to moderate endometriosis are about four to six times less likely to have a successful pregnancy.
    Endometriosis often goes unnoticed for many years. Such patients are frequently, erroneously labeled as having “unexplained infertility”, until the diagnosis is finally clinched through direct visualization of the lesions at the time of laparoscopy or laparoscopy. Not surprisingly, many patients with so called “unexplained” infertility, if followed for a number of years, will ultimately reveal endometriosis.

    Women who have endometriosis are much more likely to be infertile. There are several reasons for this:

    • First-Ovulation Dysfunction: In about 25 – 30% of cases, endometriosis is associated with ovulation dysfunction. Treatment requires controlled ovarian stimulation (COS). The problem is that the toxic pelvic environment markedly reduces the likelihood that anything other than IVF will enhance pregnancy potential.
    • Second- Toxic Pelvic environment that compromises Fertilization Endometriosis is associated with the presence of toxins in peritoneal secretions while it is tempting to assert that normally ovulating women with mild to moderate endometriosis would have no difficulty in conceiving if their anatomical disease is addressed surgically or that endometriosis-related infertility is confined to cases with more severe anatomical disease…nothing could be further from the truth. The natural conception rate for healthy ovulating women in their early 30’s (who are free of endometriosis) is about 15% per month of trying and 70% per year of actively attempting to conceive. Conversely, the conception rate for women of a comparable age who have mild or moderate pelvic endometriosis (absent or limited anatomical disease) is about 5-6% per month and 40% after 3 years of trying. As sperm and egg(s) travel towards the fallopian tubes they are exposed to these toxins which compromise the fertilization process. In fact it has been estimated that there is a 5-6 fold reduction in fertilization potential because of these toxins which cannot be eradicated. Frankly, it really does not matter whether an attempt is made to remove endometriosis deposits surgically as this will not improve pregnancy potential. The reason is that for every deposit observed, there are numerous others that are in the process of developing and are not visible to the naked eye and whether visible or not, such translucent deposits still produce toxins. This also explains why surgery to remove visible endometriosis deposits, controlled ovarian stimulation with or without intrauterine insemination will usually not improve pregnancy potential. Only IVF, through removing eggs before they are exposed to the toxic pelvic environment, fertilizing them in-vitro and then transferring the embryos to the uterus represents the only way to enhance pregnancy potential.
    • Third-Pelvic adhesions and Scarring: In its most severe form, endometriosis is associated with scarring and adhesions in the pelvis, resulting in damage to, obstruction or fixation of the fallopian tubes to surrounding structures, thereby preventing the union of sperm and eggs.
    • Fourth-Ovarian Endometriomas, Advanced endometriosis is often associated with ovarian cysts (endometriomas/chocolate cysts) that are filled with altered blood and can be large and multiple. When these are sizable (>1cm) they can activate surrounding ovarian connective tissue causing production of excessive male hormones (androgens) such as testosterone and androstenedione. Excessive ovarian androgens can compromise egg development in the affected ovary (ies) resulting in an increased likelihood of numerical chromosomal abnormalities (aneuploidy) and reduced egg/embryo competency”. In my opinion large ovarian endometriomas need to be removed surgically or rough sclerotherapy before embarking on IVF.
    • Fifth- Immunologic Implantation Dysfunction (IID). Endometriosis, regardless of its severity is associated with immunologic implantation dysfunction linked to activation of uterine natural killer cells (NKa) and cytotoxic uterine lymphocytes (CTL) in about 30 of cases. This is diagnosed by testing the woman’s blood for NKa using the K-562 target cell test or by endometrial biopsy for cytokine analysis, and, for CTL by doing a blood immunophenotype. These NKa attack the invading trophoblast cells (developing “root system” of the embryo/early conceptus) as soon as it tries to gain attachment to the uterine wall. In most cases, this results in death of the embryo even before the pregnancy is diagnosed and sometimes, in a chemical pregnancy or even an early miscarriage. . As such, many women with endometriosis, rather than being infertile, in the strict sense of the word, often actually experience repeated undetected “mini-miscarriages”.

    Advanced Endometriosis: In its most advanced stage, anatomical disfiguration is causally linked to the infertility. In such cases, inspection at laparoscopy or laparoscopy will usually reveal severe pelvic adhesions, scarring and “chocolate cysts”. However, the quality of life of patients with advanced endometriosis is usually so severely compromised by pain and discomfort, that having a baby is often low on the priority list. Accordingly, such patients are usually often more interested in relatively radical medical and surgical treatment options (might preclude a subsequent pregnancy), such as removal of ovaries, fallopian pubis and even the uterus, as a means of alleviating suffering.

    Moderately Severe Endometriosis. These patients have a modest amount of scarring/ adhesions and endometriotic deposits which are usually detected on the ovaries, fallopian tubes, bladder surface and low in the pelvis, behind the uterus. In such cases, the fallopian tubes are usually opened and functional.

    Mild Endometriosis: These patients who at laparoscopy or laparotomy are found to have no significant distortion of pelvic anatomy are often erroneously labeled as having “unexplained” infertility. To hold that the there can only infertility can only be attributed to endometriosis if significant anatomical disease can be identified, is to ignore the fact that, biochemical, hormonal and immunological factors profoundly impact fertility. Failure to recognize this salient fact continues to play havoc with the hopes and dreams of many infertile endometriosis patients.

    TREATMENT:
    The following basic concepts apply to management of endometriosis-related infertility:

    1. Controlled Ovulation stimulation (COS) with/without intrauterine insemination (IUI): Toxins in the peritoneal secretions of women with endometriosis exert a negative effect on fertilization potential regardless of how sperm reaches the fallopian tubes. This helps explain why COS with or without IUI will usually not improve the chances of pregnancy (over no treatment at all) in women with endometriosis. IVF is the only way by which to bypass this problem.
    2. Laparoscopy or Laparotomy Surgery aimed at restoring the anatomical integrity of the fallopian tubes does not counter the negative influence of toxic peritoneal factors that inherently reduce the chances of conception in women with endometriosis four to six fold. Nor does it address the immunologic implantation dysfunction (IID) commonly associated with this condition. Pelvic surgery is relatively contraindicated for the treatment of infertility associated with endometriosis, when the woman is more than 35 years of age. With the pre-menopause approaching, such women do not have the time to waste on such less efficacious alternatives. In contrast, younger women who have time on their side might consider surgery as a viable option. Approximately 30 -40 percent of women under 35 years of age with endometriosis will conceive with in two to three years following corrective pelvic surgery.
    3. Sclerotherapy for ovarian endometriomas (“chocolate” cysts). About 15 years ago I introduced “sclerotherapy”, a relatively non-invasive, safe and effective outpatient method to permanently eliminate endometriomas without surgery being required. Sclerotherapy for ovarian endometriomas involves needle aspiration of the liquid content of the endometriotic cyst, followed by the injection of 5% tetracycline into the cyst cavity. Treatment results in disappearance of the lesion within 6-8 weeks, in more than 75% of cases so treated. Ovarian sclerotherapy can be performed under local anesthesia or under general anesthesia. It has the advantage of being an ambulatory office- based procedure, at low cost, with a low incidence of significant post-procedural pain or complications and the avoidance of the need for laparoscopy or laparotomy
    4. The role of selective immunotherapy More than half of women who have endometriosis harbor antiphospholipid antibodies (APA) that can compromise development of the embryo’s root system (trophoblast). In addition and far more serious, is the fact that in about one third of cases endometriosis, regardless of its severity is associated with NKa and cytotoxic uterine lymphocytes (CTL) which can seriously jeopardize implantation. This immunologic implantation dysfunction (IID) is diagnosed by testing the woman’s blood for APA, for NKa (using the K-562 target cell test or by endometrial biopsy for cytokine activity) and, for CTL (by a blood immunophenotype). Activated NK cells attack the invading trophoblast cells (developing “root system” of the embryo/early conceptus) as soon as it tries to gain attachment to the uterine wall. In most cases, this results in rejection of the embryo even before the pregnancy is diagnosed and sometimes, in a chemical pregnancy or an early miscarriage. . As such, many women with endometriosis, rather than being infertile, in the strict sense of the word, often actually experience repeated undetected “mini-miscarriages”.

    Women who harbor APA’s often experience improved IVF birth rates when heparinoids (Clexane/Lovenox) are administered from the onset of ovarian stimulation with gonadotropins until the 10th week of pregnancy. NKa is treated with a combination of Intralipid (IL) and steroid therapy: Intralipid (IL) is a solution of small lipid droplets suspended in water. When administered intravenously, IL provides essential fatty acids, linoleic acid (LA), an omega-6 fatty acid, alpha-linolenic acid (ALA), an omega-3 fatty acid.IL is made up of 20% soybean oil/fatty acids (comprising linoleic acid, oleic acid, palmitic acid, linolenic acid and stearic acid) , 1.2% egg yolk phospholipids (1.2%), glycerin (2.25%) and water (76.5%).IL exerts a modulating effect on certain immune cellular mechanisms largely by down-regulating NKa.

    The therapeutic effect of IL/steroid therapy is likely due to an ability to suppress pro-inflammatory cellular (Type-1) cytokines such as interferon gamma and TNF-alpha. IL/steroids down-regulates NKa within 2-3 weeks of treatment the vast majority of women experiencing immunologic implantation dysfunction. In this regard IL is just as effective as Intravenous Gamma globulin (IVIg) but at a fraction of the cost and with a far lower incidence of side-effects. Its effect lasts for 4-9 weeks when administered in early pregnancy.
    5. The role of IVF: The toxic pelvic environment caused by endometriosis, profoundly reduces natural fertilization potential. As a result normally ovulating infertile women with endometriosis and patent Fallopian tubes are much less likely to conceive naturally, or by using fertility agents alone (with or without intrauterine (IUI) insemination. The only effective way to bypass this adverse pelvic environment is through IVF. I am not suggesting here that all women who have endometriosis require IVF! Rather, I am saying that in cases where the condition is further compromised by an IID associated with NKa and/or for older women(over 35y) who have diminished ovarian reserve (DOR) where time is of the essence, it is my opinion that IVF is the treatment of choice.

    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:
    • 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!
    • Treating Out-of-State and Out-of-Country Patients at Sher-IVF in Las Vegas
    • Should IVF Treatment Cycles be provided uninterrupted or be Conducted in 7-12 Pre-scheduled “Batches” per Year
    • A personalized, stepwise approach to IVF
    • How Many Embryos should be transferred: A Critical Decision in IVF.
    • Endometriosis and Immunologic Implantation Dysfunction (IID) and IVF
    • Endometriosis and Infertility: Why IVF Rather than IUI or Surgery Should be the Treatment of Choice.
    • Endometriosis and Infertility: The Influence of Age and Severity on Treatment Options
    • Early -Endometriosis-related Infertility: Ovulation Induction (with or without Intrauterine Insemination) and Reproductive Surgery Versus IVF
    • Treating Ovarian Endometriomas with Sclerotherapy.
    • Effect of Advanced Endometriosis with Endometriotic cysts (Endometriomas) on IVF Outcome & Treatment Options.
    • Deciding Between Intrauterine Insemination (IUI) and In Vitro Fertilization (IVF).
    • Intrauterine Insemination (IUI): Who Needs it & who Does Not: Pro’s &
    • Induction of Ovulation With Clomiphene Citrate: Mode of Action, Indications, Benefits, Limitations and Contraindications for its ue
    • Clomiphene Induction of Ovulation: Its Use and Misuse!

    If you are interested in my advice or medical 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.
    Also, my 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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