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.
Hello Dr. Sher,
I went through 3 IVF with beautiful embryos that I sent to PGS on day 5. on the first treatment I was 37 and out of 7 embryos, all came back with a variety of abnormalities. I discarded them On the second and third treatments at age 39, done with a different doctor, I banked and ended up with 8 embryos that were sent to PGS on day 5 as well and all of them came back with abnormalities. I’m devastated and financially hurt, but was told that one of the embryos that i still have frozen that only had a monosomy 19 or 16 –can’t remember, could result in a pregnancy. What do you think? What are my options. I’m now 40 and last time I tested my AMH it was 0.7.
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. “auto correction”) 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, 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.
Thus by discarding all aneuploid embryos we, in so doing, might 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 “auto correction” 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.” Many such 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 “auto correction”. 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 enormous clinical value. Since some mosaic embryos can “autocorrect” and even go on to propagate a viable baby, the ability to confirm that aneuploidy is mitotic (potentially reversible) would provide a strong argument in favor of preserving certain aneuploid embryos for future dispensation. Unfortunately however, there is presently no microscopic or genetic test that can reliable differentiate between meiotic and mitotic aneuploidy.
Aneuploidy, whether meiotic or mitotic in origin involves the addition of one or more chromosomes to a given pair in human embryos. Certain aneuploidies involve only a single, chromosome pair (simple aneuploidy) while others involve more than a single pair (i.e. complex aneuploidy). Evidence suggests that complex aneuploidy, whether meiotic or mitotic in origin is almost always lethal while all forms of meiotic aneuploidy are permanent. Some aneuploidies, especially those that involve addition of a chromosome to any pair (trisomy) will at times progress to clinical pregnancies (e.g. trisomy 15, 18, 21 or when the sex chromosomes are involve). And as stated previously, most aneuploid embryos, should they attach, will miscarry or result in a chromosomally defective offspring.
On the other hand, some aneuploid embryos have one chromosome (in a given pair) missing (i.e. monosomy). Aside from monosomy involving absence of the Y-sex chromosome (i.e. XO) which can resulting in a live birth (Turner syndrome) all other monosomies involving autosomes (non-sex chromosomes) are lethal and will not result in viable offspring.
Since it is presently not possible, without removing more than 1 cell from an embryo (a very traumatic event) to differentiate between meiotic and mitotic aneuploidy, it follows that making a diagnosis of embryo aneuploidy does not allow for identification of mosaic embryos for transfer. This is especially true when it comes to trisomic embryos that can and sometimes do, propagate chromosomal birth defects such as Down syndrome. It is important to bear in mind that the transfer of trisomic embryos (whether due to meiotic or mitotic aneuploidy) can result in miscarriage or a birth defect. This makes any attempt to transfer such embryos to the uterus fraught with risk and in my opinion, ill advised. Conversely, since true meiotic autosomal monosomic embryos cannot propagate viable pregnancies, performing embryo transfer in such cases in the hope that the aneuploidy is mitotic (mosaic) in origin and will spontaneously “ auto correct”, is a rational consideration. Needless to say, such action would require full disclosure, and the execution of a detailed, informed consent agreement which would include an expressed commitment 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.
Since it is meiotic rather than mitotic aneuploidy that is invariably lethal and given that meiotic aneuploidy originates in the egg, it is my belief that the closer to fertilization that embryo biopsy is done for PGS, the more likely it is that any aneuploidy detected, will be meiotic in origin. The longer you wait thereafter, the greater the likelihood that with repeated mitotic division, mutational changes will result in mitotic aneuploidy (mosaicism). This is why I strongly believe embryo biopsies should be performed on day 2-3 post fertilization rather on day 5-6 days (the blastocyst stage).”
Now to your OPTIONS:
First, in my opinion, the most likely explanation for your repeatedly getting aneuploid embryos is possibly related to the protocol used for ovarian stimulation which needs to be carefully reviewed and revised. I would also suggest a modified, robust, long pituitary down-regulation protocol. I would use an agonist/antagonist conversion protocol with human growth hormone (HGH) augmentation and would recommend Staggered IVF with embryo banking of PGS (next generation gene sequencing)-normal blastocysts, to make hay while the sun still shines.
Please visit my new Blog on this very site, find the “search bar” and 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
•Ovarian Stimulation for IVF using GnRH Antagonists: Comparing the Agonist/Antagonist Conversion Protocol.(A/ACP) With the“Conventional” Antagonist Aproach
•IVF: Factors Affecting Egg/Embryo “competency” during Controlled Ovarian Stimulation(COS)
•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)
•The BCP: Does Launching a Cycle of Controlled Ovarian Stimulation (COS). Coming off the BCP Compromise Response?
•Frozen Embryo Transfer (FET): What Does it Involve?
•Embryo Banking/Stockpiling: Slows the “Biological Clock” and offers a Selective Alternative to IVF-Egg Donation.
•Preimplantation Genetic Sampling (PGS) Using: Next Generation Gene Sequencing (NGS): Method of Choice.
•Why did my IVF Fail?
•A personalized, stepwise approach to IVF
•The Role of Nutritional Supplements in Preparing for IVF
I invite you to call 702-699-7437 or 800-780-7437 or go online on this site and set up a one hour Skype consultation with me to discuss your case in detail.
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
Hello Dr. Sher,
I am 38 years old and my husband is the same age. My husband is diagnosed with MFI (count was borderline normal, motility at 30% and morphology 2%). He was referred to a urologist and was diagnosed with low testosterone. He went on Clomid and count improved to normal, and his motility improved to 50%. Morphology remained at 2%. We also experienced low fertilization rate with our first IVF (we did not do ICSI) with just 10 of 28 mature eggs being fertilized. This improved using ICSI on our second IVF cycle where 12 of 13 eggs fertilized. He is continuing to take Clomid and fertility blend for men vitamins and he just started CoQ10. He is also diabetic (type 2), on metformin, and is overweight.
My tests have come back normal aside from a slightly elevated TSH (I am on synthroid and it’s controlled) and a recent slightly high fasting blood glucose test at 109 and am now on metformin. I am also overweight. I have been pregnant twice, once with our first IVF cycle which ended in a termination for trisomy 21 and once with a chemical pregnancy after an FET.
We have also had karyotype testing which came back normal.
My questions are:
1) Is it normal to have a big drop-off in embryo development between day 3-5? During both IVF cycles we had a decent number of embryos on day 3 (7 of 10 fertilized, and 12 of 12 fertilized) but had a significant drop off when reaching blastocyst stage (1 grade 3BB blastocyst during first cycle and three grade 5AA during second cycle – one of which was PGS abnormal). Can anything be done to improve the rate of embryos developing to blast stage? My doctor has said that the rate of drop-off we’ve experienced is to be expected.
2) I’ve asked about getting a sperm DNA fragmentation test, but my doctor says it wouldn’t change how she treats us. Is there anything that can be done for high sperm fragmentation? PICSI?
For both of our IVF cycles I was on an antagonist protocol with Gonal-f, Menopur, and Ganerelix. For our first IVF cycle, I had a 10,000iu HCG trigger and had 33R, 28Mature, 10 fertilized, 1 day-3-transfer and one 3BB blast. The second cycle I had a mixed HCG/lupron trigger with 13 retrieved, 12 fertilized with ICSI, and 3 blastocysts (one was PGS abnormal).
I am not convinced that your husband’s sperm issues are responsible for the failures and I agree with your RE that a sperm chromatin structure assay will not help..
By the way, I strongly doubt that you have intractably abnormal eggs. In my opinion, your arrest in embryo development and poor egg/embryo quality could readily be due the protocol used for ovarian stimulation which in my opinion needs to be reviewed and revised (see below). I think this will go a long way towards improving egg quality and enhancing embryo development to the blastocyst stage as well as the “competency of those eggs and embryos. I would suggest that you seriously consider “Staggered IVF with PGS testing aqnd selective transfer of euploid embryos. And if there is an II, that needs to be addressed prior to ET (see below).
Finally, given that you have had PGS normal embryos transferred with no viable pregnancy resulting suggests an implantation dysfunction. Additionally, an under-active thyroid in women, is very often due to an underlying autoimmune process which is linked to activation of uterine natural killer cells (NKa) which results . These two factors suggest a strong possibility of immunologic implantation dysfunction (IID) as an important cause of your reproductive dysfunction (please read the articles listed below…carefully).
Whenever a patient fails to achieve a pregnancy following embryo transfer (ET), the first question asked is why! Was it simply due to, bad luck?, How likely is the failure to recur in future attempts and what can be done differently, to avoid it happening next time?.
It is an indisputable fact that any IVF procedure is at least as likely to fail as it is to succeed. Thus when it comes to outcome, luck is an undeniable factor. Notwithstanding, it is incumbent upon the treating physician to carefully consider and address the causes of IVF failure before proceeding to another attempt:
1.Age: The chance of a woman under 35Y of age having a baby per embryo transfer is about 35-40%. From there it declines progressively to under 5% by the time she reaches her mid-forties. This is largely due to declining chromosomal integrity of the eggs with advancing age…”a wear and tear effect” on eggs that are in the ovaries from birth.
2.Embryo Quality/”competency (capable of propagating a viable pregnancy)”. As stated, the woman’s age plays a big role in determining egg/embryo quality/”competency”. This having been said, aside from age the protocol used for controlled ovarian stimulation (COS) is the next most important factor. It is especially important when it comes to older women, and women with diminished ovarian reserve (DOR) where it becomes essential to be aggressive, and to customize and individualize the ovarian stimulation protocol.
We used to believe that the uterine environment is more beneficial to embryo development than is the incubator/petri dish and that accordingly, the earlier on in development that embryos are transferred to the uterus, the better. To achieve this goal, we used to select embryos for transfer based upon their day two or microscopic appearance (“grade”). But we have since learned that the further an embryo has advanced in its development, the more likely it is to be “competent” and that embryos failing to reach the expanded blastocyst stage within 5-6 days of being fertilized are almost invariably “incompetent” and are unworthy of being transferred. Moreover, the introduction into clinical practice about a decade ago, (by Levent Keskintepe PhD and myself) of Preimplantation Genetic Sampling (PGS), which assesses for the presence of all the embryos chromosomes (complete chromosomal karyotyping), provides another tool by which to select the most “competent” embryos for transfer. This methodology has selective benefit when it comes to older women, women with DOR, cases of unexplained repeated IVF failure and women who experience recurrent pregnancy loss (RPL).
3.The number of the embryos transferred: Most patients believe that the more embryos transferred the greater the chance of success. To some extent this might be true, but if the problem lies with the use of a suboptimal COS protocol, transferring more embryos at a time won’t improve the chance of success. Nor will the transfer of a greater number of embryos solve an underlying embryo implantation dysfunction (anatomical molecular or immunologic).Moreover, the transfer of multiple embryos, should they implant, can and all too often does result in triplets or greater (high order multiples) which increases the incidence of maternal pregnancy-induced complications and of premature delivery with its serious risks to the newborn. It is for this reason that I rarely recommend the transfer of more than 2 embryos at a time and am moving in the direction of advising single embryo transfers …especially when it comes to transferring embryos derived through the fertilization of eggs from young women.
4.Implantation Dysfunction (ID): Implantation dysfunction is a very common (often overlooked) cause of “unexplained” IVF failure. This is especially the case in young ovulating women who have normal ovarian reserve and have fertile partners. Failure to identify, typify, and address such issues is, in my opinion, an unfortunate and relatively common cause of repeated IVF failure in such women. Common sense dictates that if ultrasound guided embryo transfer is performed competently and yet repeated IVF attempts fail to propagate a viable pregnancy, implantation dysfunction must be seriously considered. Yet ID is probably the most overlooked factor. The most common causes of implantation dysfunction are:
a.A“ thin uterine lining”
b.A uterus with surface lesions in the cavity (polyps, fibroids, scar tissue)
c.Immunologic implantation dysfunction (IID)
d.Endocrine/molecular endometrial receptivity issues
Certain causes of infertility are repetitive and thus cannot readily be reversed. Examples include advanced age of the woman; severe male infertility; immunologic infertility associated with alloimmune implantation dysfunction (especially if it is a “complete DQ alpha genetic match between partners plus uterine natural killer cell activation (NKa).
My answer to patients who ask me when is the time to stop undergoing IVF is ….Aside from the weight of the financial burden, the time to stop is when in spite of thorough and comprehensive evaluation, there is no remediable and treatable explanation for repeated failure.
Please visit my new Blog on this very site, find the “search bar” and 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
•Ovarian Stimulation for IVF using GnRH Antagonists: Comparing the Agonist/Antagonist Conversion Protocol.(A/ACP) With the“Conventional” Antagonist Aproach
•IVF: Factors Affecting Egg/Embryo “competency” during Controlled Ovarian Stimulation(COS)
•Staggered IVF: An Excellent Option When. Advancing Age and Diminished Ovarian Reserve (DOR) Reduces IVF Success Rate
•Preimplantation Genetic Sampling (PGS) Using: Next Generation Gene Sequencing (NGS): Method of Choice.
•IVF Failure and Implantation Dysfunction: The Role of Endometrial Thickness, Uterine Pathology and Immunologic Factors
•Unexplained IVF Failure
•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)
•Traveling for IVF from Out of State/Country–
•A personalized, stepwise approach to IVF
•The Sperm Chromatin Structure Assay (SCSA): A Measure of the Potential of Sperm to Help Propagate a Viable Pregnancy
•IVF for Women Who Have Previously Conceived (Secondary Infertility).
I invite you to call 702-699-7437 or 800-780-7437 or go online on this site and set up a one hour Skype consultation with me to discuss your case in detail.
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
.
Thanku for your previous reply to my message, after PGD selection I got 1 good quality embryo. My doctor said all good with my lining. He also checked and biopsy a tissue from my lining to check if any natural killers are there. All results came good and ok to proceed embryo transfer. Iam 33 now had natural pregnacy but miscarried thrice due to Harmonia imbalance.So then we took an option to go with if with PGD. But still it failed. My question is when I can get pregnant natural. By taking lot of medicines and choosing IVF PGD, how it can fall negative? My blood test results came negative on Saturday but I still did have bleeding.
Age 37, several failed IVFs, Mach embryo biopsy showed out of phase and no Integrin B, treatment is 3 months of Lupron however estrogen remains, added 2 weeks of Femara and estrogen is still 70. Should I change treatment plan or move forward with Mach transfer endometrial biopsy and see if Integrin B is present now.
I do not believe in the reliability of endometrial function tests. In my opinion, these tests give you no more than a “cloudy”a snap shot and no reliable indication on what will happen in the cycle destined for ET. You need however to seriously consider the advice of your own treating RE. However, if it were up to me … yes! I would go ahead with the ET.
Geoff Sher
Dear dr. Sher
On January 26 we transferred two 3 day embryos. It was a donor egg cycleOn February 3, 8dp3dt I got my fist ever positive beta hcg 66. A day after the beta hcg was 174. Today at 11dp3dt the beta hcg result is 558. How long, according to you, do I have to continue checking the beta hcg before I can start realistically hoping that this is a viable pregnancy?
Thank you.
Liljana
Hello Dr. Sher,
I have a question about my progesterone level dropping. I had IVF frozen embryo day five transfer on January 20. I am 5 weeks along. On Monday February 1, I had BHCG 0f 1243 and progesterone of 30.4. I started to feel cramping yesterday Feb. 5 and as of yesterday my BHCG was 7990 and progesterone level dropped to 14. just wondering if this is a for sure sign of miscarrying or do progesterone levels fluctuate that much. I have no spotting just mild cramping.
Thank you
It is not critical but I would discuss with your RE or OB as in my opinion, I would prefer to see the progesterone above 20ng/ml.
Good luck!
Geoff Sher