Ask Our Doctors – Archive
Our Medical Directors are outstanding physicians that you will find to be very personable and compassionate, who take care to ensure that you have the most cutting-edge fertility treatments at your disposal. This is your outlet to ask your questions to the doctors.
Hi. Dr. Sher,
I’m interested in a consult with you. I’ve had a few IVF cycles and have been told that the PGS of the embryos that make it to Day 5/6 are abnormal. I have been reading about PGS and it appears that that may not always be indicative at the only thing being test is the one strand of the test. What are your thoughts of PGS for older (just turned 43) wannabe moms? Also, I’d be curious as to how you customize treatment. My current clinic as me doing the same protocol and I’m wondering if there is a different protocol that may yield better results? In advance, I appreciate your time!
About a decade ago, I, along with my associate, Levent Keskintepe PhD were the first to introduce full chromosome Preimplantation Genetic Sampling/Screening (PGS) into the IVF clinical realm to try and identify euploid embryos whose cells contained the required 46 chromosomes (23 pairs) necessary to render them potentially “competent” to propagate viable pregnancies. Aneuploid embryos (those that have more or less than a total of 46 chromosomes) are by and large considered to be “incompetent”, far less likely to propagate a viable pregnancy and thus largely unworthy of being transferred to the uterus.
Initially the primary method used for PGS was, comparative genomic hybridization (CGH). The methodology was not without certain problems. A few years ago, new and improved technology known as next generation gene sequencing (NGS) emerged. This has since all but replaced other methodologies. Gene sequencing determines the precise order of nucleotides within a DNA molecule. It includes any method or technology that is used to determine the order of the four bases—adenine, guanine, cytosine, and thymine—in a strand of DNA.
The widely held belief is that the ideal time to biopsy embryos for PGS is when they reach the most advanced stage of preimplantation development (the blastocyst stage) by 5-6 days post-fertilization. At this point several cells are microsurgically removed from the embryo’s outer cellular layer (trophectoderm-TE), processed and subjected to PGS analysis. The blastocysts are ultra-rapidly frozen (vitrified) and held for future dispensation in a subsequent frozen embryo transfer (FET) cycle, once test results are known.
Access to several cells through TE biopsy provides more DNA for reliable analysis that can be attained through the testing of a single cell removed from a day-2-3 cleaved embryo. It is this plus the belief that the hypercellular blastocyst is far less likely to be damaged through such microsurgical intervention that would be the case with a 4-10 cell, day-3 cleaved embryo that has led to the preferred timing for biopsy to be on day 5-6 blastocysts..
When PGS testing was first introduced, initial results were most-encouraging. Embryo implantation rates of >50% and birth rates of 50-60% when up to two euploid blastocysts were transferred, were being reported. In addition, the reported incidence of miscarriages and chromosomal birth defects was likewise greatly reduced. In fact, we were so encouraged that most of us predicted that a time would come where full embryo karyotyping through PGS would become a routine part of IVF. But alas…..we were soon to be disappointed when following the widespread introduction of PGS testing success rates started dropping. This was especially the case when PGS was performed on embryos derived from the eggs of older women and women with severely diminished ovarian reserve (DOR). With further investigation it began to dawn upon us that:
a)Chromosomal numerical integrity, while being the most important determinant of embryo “competency” was likely not the only factor that impacted embryo “competency”. Indeed advancing age was revealed to increase the incidence of embryo aneuploidy, independent of embryo karyotype and this is probably linked to non-chromosomal, genetic and metabolomic factors that might also be age-related.
b)Independent of embryo competency, there are many variables, that can and also do determine IVF outcome and these are often outside the control of the embryology/genetic laboratory. They include selection and implementation of individualized protocols for controlled ovarian stimulation (COS), endometrial factors that determine embryo implantation (e.g. anatomical an immunologic implantation dysfunction), technical skill of the physician performing embryo transfer etc.
c)Not all PGS-aneuploid embryos are “incompetent”. Some are mosaic (see elsewhere) and these are often capable of “autocorrecting” upon being transferred to the uterus, and propagating healthy babies.
Example A: Under optimal conditions embryo “competency” is determined by age and the protocol used for COS. In women <39Y of age roughly 1:2 blastocysts will likely be euploid “competent” and were such an embryo be gently and expertly transferred to a “receptive” uterine environment, the chance of a viable pregnancy should about 55-60%. This means that when ET is performed in such ideal IVF candidates, the chance of it resulting in a live birth should be about 27%-30% per embryo.
Example B: Conversely, when it comes to a woman in her mid-forties, the chance of an embryo being “competent” is probably < 1:8-10. And, the age-adjusted chance of such a Euploid embryo propagating a live birth is (for reasons cited above) theoretically well below 60% (perhaps around 40%-45%). This extrapolates to a baby rate of no more than 4%-5% per blastocyst transferred. Using the above examples: In Example A: Given that about 50% of the eggs (and thus resulting embryos) of young women are euploid and competent, the transfer up to 2 non-PGS tested blastocysts would likely yield the same results as would the transfer of a single PGS-tested euploid blastocyst. It follows that a patient/couple who are capable and willing to engage a twin pregnancy (which would occur in roughly 25% of such cases), might get as good a result by simply transferring two (2) untested blastocysts and in the process avoid the additional cost of PGS. In Example B: Conversely, the chance of a viable pregnancy in a woman in her mid-40’s would likely be 8-10 times greater when a “competent”, PGS-euploid blastocyst is selectively transferred as compared to when a non-PGS tested blastocyst is transferred to the uterus (4% versus 40%). Albeit that PGS-testing of blastocysts derived from fertilization of an older woman’s eggs is less reliable than for younger counterparts, there would be a distinct benefit/advantage in pre-selecting euploid, “competent” blastocysts for transfer in such cases. Since older women often also have DOR and thus produce fewer eggs/embryos, such women should benefit inordinately from the selective “stockpiling” (banking) of PGS-biopsied blastocysts (vitrification) over several cycles of IVF for collective PGS testing and the subsequent selective transfer of only the most “competent” ones to the uterus with FET. In conclusion, it is my considered opinion that PGS-embryo selection only be considered in the following circumstances: 1.Women over the age of 39Y and those who, regardless of age have significant DOR, are running out of eggs and time, and need to “make hay while the sun shines”! 2.Unexplained IVF failure. 3.Certain cases of recurrent pregnancy loss (RPL). 4.Family gender balancing cases 5.Women who have alloimmune implantation dysfunction (IID) with activation of uterine natural killer cells (NKa)…see elsewhere. 6.Where karyotyping reveals one or other partner to have a balanced chromosomal translocation 7.Known or anticipated specific genetic abnormalities When selectively used PGS is an excellent tool to improve implantation potential and IVF outcome (see above). While PGS provides a new and unique method for selecting the ideal embryos to be transferred, it is not a panacea when it comes to identifying “competent embryos”. There are factors other than numerical chromosomal integrity (karyotype) that can and do influence embryo “competency”, profoundly. PGS embryo selection is in my opinion currently over-used. This is especially the case when it comes to younger women with normal ovarian reserve. Unless the dust is allowed to settle such that this remarkable technology is properly applied, it is my belief that it stands the risk of progressively falling into disrepute. 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 “Biological Clock” and how it should Influence the Selection and Design of Ovarian Stimulation Protocols for IVF.
• A Rational Basis for selecting Controlled Ovarian Stimulation (COS) protocols in women with Diminished Ovarian Reserve (DOR)
•Diagnosing and Treating Infertility due to Diminished Ovarian Reserve (DOR)
•Ovarian Stimulation in Women Who have Diminished Ovarian Reserve (DOR): Introducing the Agonist/Antagonist Conversion protocol
•Controlled Ovarian Stimulation (COS) in Older women and Women who have Diminished Ovarian Reserve (DOR): A Rational Basis for Selecting a Stimulation Protocol
•Optimizing Response to Ovarian Stimulation in Women with Compromised Ovarian Response to Ovarian Stimulation: A Personal Approach.
•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?
•IVF: How Many Attempts should be considered before Stopping?
•, Premature Birth and 2nd Trimester Recurrent Pregnancy Loss (RPL)
•Blastocyst Embryo Transfers done 5-6 Days Following Fertilization are Fast Replacing Earlier day 2-3 Transfers of Cleaved Embryos.
•Frozen Embryo Transfer (FET) versus “Fresh” ET: How to Make the Decision
•Frozen Embryo Transfer (FET): A Rational Approach to Hormonal Preparation and How new Methodology is Impacting IVF.
•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
•IVF: Selecting the Best Quality Embryos to Transfer
•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
•IVF: The first Choice for Infertile Women 40 to 43 Years of Age!
•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.
•The Role of Nutritional Supplements in Preparing for IVF
•Advancing Age of the Woman and IVF: How Old is too old?
•IVF pregnancies: Why They Carry a Greater Risk?
•Is there a link between the use of Fertility Drugs and of Ovarian Cancer?
•Are Injectable Fertility Drugs Safe?
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.
What is your view on G-CSF injections for unexplained miscarriage of euploid embryos?
I have normal NKa, cytokine ratio, immunophenotype, autoimmune antibodies and clotting factors
However I have miscarried two chromosomally normal embryos (10w and 5w respectively)
There is currently a large scale NHS RCT in the UK researching the impact of G-CSF for unexplained RM – results are yet to be published, however anecdotally many women have reported success.
What is your view on G-CSF injections for unexplained miscarriage?
Many thanks
Katy
I do not believe that there is any reliable proof of benefit. As far as the relabilty and validity of the immune t5ests deone inn your case are concerned, please see below:
Testing for Immunologic Implantation Immunologic Dysfunction (IID): Who Should be Tested, Where Should Testing be Done and How should results be interpreted?
Geoffrey Sher MD
I have been struck by the fact that patients suspected of having an immunologic implantation dysfunction, frequently are all too often recommended to undergo the wrong testing, often performed in the wrong laboratories and/ or that the results reported are misinterpreted. This cause a great deal of unnecessary confusion and leads to over-treatment of some and detrimental withholding of required treatment of others.
•Who Should Undergo IID testing:?
When it comes to who should be evaluated, the following conditions should in always raise a suspicion of an underlying IID, and trigger prompt testing:
•A diagnosis of endometriosis or the existence of symptoms suggestive of endometriosis (heavy/painful menstruation and pain with ovulation or with deep penetration during intercourse) I would however emphasize that a definitive diagnosis of endometriosis requires visualization of the lesions at laparoscopy or laparotomy )
•A personal or family history of autoimmune disease such as hyper/hypothyroidism (as those with elevated or depressed TSH blood levels, regardless of thyroid hormonal dysfunction), Lupus erythematosus, Rheumatoid arthritis, dermatomyositis, scleroderma etc.)
•“Unexplained” infertility
•Recurrent pregnancy loss
•A history of having miscarried a conceptus that, upon testing of products of conception, was found to be euploid (have a normal numerical chromosomal configuration.
•Unexplained IVF failure
• “Unexplained” intrauterine growth retardation due to placental insufficiency or late pregnancy loss of a chromosomally normal baby
•What Parameters should be tested?
In my opinion, too many Reproductive Immunologists unnecessarily unload a barrage of costly IID tests on unsuspecting patients. In most cases the initial test should be for NK cell activation, and only if this is positive, is it necessary to expand the testing.
The parameters that require measurement include:
oFor Autoimmune Implantation Dysfunction: Autoimmune implantation dysfunction, most commonly presents with presumed “infertility” due to such early pregnancy losses that the woman did not even know she was pregnant in the first place. Sometimes there as an early miscarriage. Tests required are: a) blood levels of all IgA, IgG and IgM-related antiphospholipid antibodies (APA’s) directed against six or seven specific phospholipids, b) both antithyroid antibodies (antithyroid and antimicrosomal antibodies), c) a comprehensive reproductive immunophenotype (RIP) and, c) most importantly, assessment of Natural Killer (NK) cell activity (rather than concentration) by measuring by their killing, using the K-562 target cell test and/or uterine cytokine measurement. As far as the ideal environment for performing such tests, it is important to recognize that currently there are only about 5 or 6, Reproductive Immunology Reference Laboratories in the U.S capable of reliably analyzing the required elements with a sufficient degree of sensitivity and specificity (in my opinion).
oFor Alloimmune implantation Dysfunction: While alloimmune Implantation usually presents with a history of unexplained (usually repeated) miscarriages or secondary infertility (where the woman conceived initially and thereupon was either unable to conceive started having repeated miscarriages it can also present as “presumed” primary infertility. Alloimmune dysfunction is diagnosed by testing the blood of both the male and female partners for matching DQ alpha genes and NK/CTL activation. It is important to note that any DQ alpha match (partial or complete) will only result in IID when there is concomitant NK/CTL activation (see elsewhere on this blog).
•How should results be interpreted?
Central to making a diagnosis of an immunologic implantation dysfunction is the appropriate interpretation of natural killer cell activity (NKa) .In this regard, one of the commonest and most serious errors, is to regard the blood concentration of natural killer cells as being significant. Rather it is the activity (toxicity) of NK cells that matters as mentioned. Then there is the interpretation of reported results. The most important consideration is the percentage of target cells “killed” in the “native state”. In most cases a level of >10% killing should be regarded with suspicion and >12% overtly abnormal. In my opinion, trying to interpret the effect of adding IVIG or Intralipid to the sample in order assess whether and to what degree the use of these products would have a therapeutic benefit is seriously flawed and of little benefit. Clinically relevant NK cell deactivation can only be significantly effected in vivo and takes more than a week following infusion to occur. Thus what happens in the laboratory by adding these products to the sample prior to K-562 target cell testing is in my opinion likely irrelevant.
There exists a pervasive but blatant misconception on the part of many, that the addition of IL/IVIG can have an immediate down-regulatory effect on NK cell activity. This has established a demand that Reproductive Immunology Reference Laboratories report on NK cell activity before and following exposure to IVIG and/or IL. However, the fact is that activated “functional” NK cells (NKa) cannot be deactivated in the laboratory. Effective down-regulation of activated NK cells can only be adequately accomplished if their activated “progenitor/parental” NK cells are first down-regulated. Thereupon once these down-regulated “precursor” NK cells are exposed to progesterone, they will begin spawning normal and functional NK cells, which takes about 10-14 days. It follows that to assess for a therapeutic response to IVIG/IL therapy would require that the patient first be treated (10-14 days prior to embryo transfer) and thereupon, about 2 weeks later, be retested. While at 1st glance this might seem to be a reasonable approach, in reality it would be of little clinical benefit because even if blood were to be drawn 10 -14 days after IL/IVIG treatment it would require an additional 10 days to receive results from the laboratory, by which time it would be far too late to be of practical advantage.
Neither IVIG nor IL is capable of significantly suppressing already activated “functional NK cells”. For this to happen, the IL/IVIG would have to down-regulate progenitor (parent) NK cell” activity. Thus, it should be infused 10-14 several prior to ovulation or progesterone administration so that the down-regulated “progenitor/precursor” NK cells” can propagate a sufficient number of normally regulated “functional NK cell” to be present at the implantation site 7 days later.
Geoff Sher
Dear Dr Sher,
My follicle sizes are (2 x 1.9), (2.2 x 1.5), (2.4 x 2), (1.5x .9)& (2.2 x 2.1) my protocol is lupron flare
I have to do trigger shot tonight. I am scared that those over 2. Flociles are over cooked. I wonder what do you think? What is the best size for folicles?
Regards
Mojdeh
I wish I could tell you with confidence, but a few do seem a little large, in my opinion.
Geoff Sher
Hello Dr, I have had PCOS for over 3yrs now. I wa put on clomid from day 2 to day 6. On day 10 and 11, i was given fostinom to increase the growth of my follicles. On day 13, i had a follicle of 21mm and so i was given hcg trigger on the same day. I was told to take400mg of cyclogest pessariries vaginally from day 16.
I took a beta test on day 29 and it was negative. My doctor told me to continue with the cyclogest for another week. Been having cramps all through this period, I noticed brown discharge on Day 35, on day 36, hubby and I were baby dancing but we had to stop because i felt a very sharp pain in my lower abdomin,noticed a little spotting but only after i dipped my finger into my vagina. today is day 37 and i see some brownish blood but with no clots. I am also still experiencing cramps. So i am confused, is this a period i am getting or could it be implantation bleeding?
Although not certain, I suspect that you are about to have a period!
Geoff Sher
Hello,
This is my first IVF cycle and we did a FET due to risk of OHSS. The FET resulted in a chemical. We transferred 2 embryos, 3BB and 3CC. I think these were day 6 blasts. We have 1 more frozen a 4BC day 7 blast. We are thinking whether to spend money transferring this one or start a fresh cycle?
Our embryologist advised to start a fresh cycle, but the Doctor is suggesting that there is a chance that this one could stick so we should transfer It first and then if it doesn’t make a pregnancy then start a fresh cycle. We are confused about which road to go down.
I agree with your doctor. If you have a viable expanded blastocyst frozen, that should be transferred.
Geoff Sher