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 am 45 years old and due to have 2 x day 2 embryos implanted in 2 days time. Donor eggs from 22 year old woman with 1 child) and partners sperm.
The clinic told us yesterday they planned day 2 transfer and recommended 2 embryos transferred.
We are a bit worried now. The transfer is due 45 hours from now. My partner gave sperm 5 hours ago.
Our worries are:
1. 2 days is earlier then we expected and there is a lot of confusing information out there.
2. should we be choosing 1 or 2 embryo transfer.
With thanks
Susan
Our worries are:
1. 2 days is earlier then we expected and there is a lot of confusing information out there.
A: Some programs still transfer on day 2-3. It works, but in my opinion transferring on day 5-6 as blastocysts is preferable. Embryos that fail to make it that far are almost always abnormal, anyway. vSo transferring them earlier would not have helped.
2. should we be choosing 1 or 2 embryo transfer.
A: Personally I would go with 2.
Good luck!
Geoff Sher
Dear Dr Sher
I am just going through my 7th miscarriage after a frozen embryo transfer. I have high Nk cells, especially TNF-a. I also tested positive for anti nuclear antibodies, Factor V leiden, MTHFR and protein S deficiency. I also have a small septum which my doctor doesn’t think is a problem. For my last treatment, I had 2 intralipid infusions, was on 40ml clexane, 20mg prednisolone, calcium, progesterone, inositol and folate and vitamins. I also made sure to eat as healthy as possible with lots of omega 3 intake. Still I miscarried. 2 good quality blastocysts were transferred, so I don’t think the embryos were the problem. With all this immunotherapy, still my body rejects the embryos. Do you have any advice pls?
You could have an alloimmune cause for your immunologic issue . This needs to be evaluated.
When it comes to reproduction, humans are the poorest performers of all mammals. In fact we are so inefficient that up to 75% of fertilized eggs do not produce live births, and up to 30% of pregnancies end up being lost within 10 weeks of conception (in the first trimester). RPL is defined as two (2) or more failed pregnancies. Less than 5% of women will experience two (2) consecutive miscarriages, and only 1% experience three or more.
Pregnancy loss can be classified by the stage of pregnancy when the loss occurs:
•Early pregnancy loss (first trimester)
•Late pregnancy loss (after the first trimester)
•Occult “hidden” and not clinically recognized, (chemical) pregnancy loss (occurs prior to ultrasound confirmation of pregnancy)
•Early pregnancy losses usually occur sporadically (are not repetitive).
In more than 70% of cases the loss is due to embryo aneuploidy (where there are more or less than the normal quota of 46 chromosomes). Conversely, repeated losses (RPL), with isolated exceptions where the cause is structural (e.g., unbalanced translocations), are seldom attributable to numerical chromosomal abnormalities (aneuploidy). In fact, the vast majority of cases of RPL are attributable to non-chromosomal causes such as anatomical uterine abnormalities or Immunologic Implantation Dysfunction (IID).
Since most sporadic early pregnancy losses are induced by chromosomal factors and thus are non-repetitive, having had a single miscarriage the likelihood of a second one occurring is no greater than average. However, once having had two losses the chance of a third one occurring is double (35-40%) and after having had three losses the chance of a fourth miscarriage increases to about 60%. The reason for this is that the more miscarriages a woman has, the greater is the likelihood of this being due to a non-chromosomal (repetitive) cause such as IID. It follows that if numerical chromosomal analysis (karyotyping) of embryonic/fetal products derived from a miscarriage tests karyotypically normal, then by a process of elimination, there would be a strong likelihood of a miscarriage repeating in subsequent pregnancies and one would not have to wait for the disaster to recur before taking action. This is precisely why we strongly advocate that all miscarriage specimens be karyotyped.
There is however one caveat to be taken into consideration. That is that the laboratory performing the karyotyping might unwittingly be testing the mother’s cells rather than that of the conceptus. That is why it is not possible to confidently exclude aneuploidy in cases where karyotyping of products suggests a “chromosomally normal” (euploid) female.
Late pregnancy losses (occurring after completion of the 1st trimester/12th week) occur far less frequently (1%) than early pregnancy losses. They are most commonly due to anatomical abnormalities of the uterus and/or cervix. Weakness of the neck of the cervix rendering it able to act as an effective valve that retains the pregnancy (i.e., cervical incompetence) is in fact one of the commonest causes of late pregnancy loss. So also are developmental (congenital) abnormalities of the uterus (e.g., a uterine septum) and uterine fibroid tumors. In some cases intrauterine growth retardation, premature separation of the placenta (placental abruption), premature rupture of the membranes and premature labor can also causes of late pregnancy loss.
Much progress has been made in understanding the mechanisms involved in RPL. There are two broad categories:
1.Problems involving the uterine environment in which a normal embryo is prohibited from properly implanting and developing. Possible causes include:
•Inadequate thickening of the uterine lining
•Irregularity in the contour of the uterine cavity (polyps, fibroid tumors in the uterine wall, intra-uterine scarring and adenomyosis)
•Hormonal imbalances (progesterone deficiency or luteal phase defects). This most commonly results in occult RPL.
•Deficient blood flow to the uterine lining (thin uterine lining).
•Immunologic implantation dysfunction (IID). A major cause of RPL. Plays a role in 75% of cases where chromosomally normal preimplantation embryos fail to implant.
•Interference of blood supply to the developing conceptus can occur due to a hereditary clotting disorder known as Thrombophilia.
2.Genetic and/or structural chromosomal abnormality of the embryo.Genetic abnormalities are rare causes of RPL. Structural chromosomal abnormalities are slightly more common but are also occur infrequently (1%). These are referred to as unbalanced translocation and they result from part of one chromosome detaching and then fusing with another chromosome. Additionally, a number of studies suggest the existence of paternal (sperm derived) effect on human embryo quality and pregnancy outcome that are not reflected as a chromosomal abnormality. Damaged sperm DNA can have a negative impact on fetal development and present clinically as occult or early clinical miscarriage. The Sperm Chromatin Structure Assay (SCSA) which measures the same endpoints are newer and possibly improved methods for evaluating.
IMMUNOLOGIC IMPLANTATION DYSFUNCTION
Autoimmune IID: Here an immunologic reaction is produced by the individual to his/her body’s own cellular components. The most common antibodies that form in such situations are APA and antithyroid antibodies (ATA).
But it is only when specialized immune cells in the uterine lining, known as cytotoxic lymphocytes (CTL) and natural killer (NK) cells, become activated and start to release an excessive/disproportionate amount of TH-1 cytokines that attack the root system of the embryo, that implantation potential is jeopardized. Diagnosis of such activation requires highly specialized blood test for cytokine activity that can only be performed by a handful of reproductive immunology reference laboratories in the United States.
Alloimmune IID, i.e., where antibodies are formed against antigens derived from another member of the same species, is believed to be a relatively common immunologic cause of recurrent pregnancy loss.
Autoimmune IID is often genetically transmitted. Thus it should not be surprising to learn that it is more likely to exist in women who have a family (or personal) history of primary autoimmune diseases such as lupus erythematosus (LE), scleroderma or autoimmune hypothyroidism (Hashimoto’s disease), autoimmune hyperthyroidism (Grave’s disease), rheumatoid arthritis, etc. Reactionary (secondary) autoimmunity can occur in conjunction with any medical condition associated with widespread tissue damage. One such gynecologic condition is endometriosis. Since autoimmune IID is usually associated with activated NK and T-cells from the outset, it usually results in such very early destruction of the embryo’s root system that the patient does not even recognize that she is pregnant. Accordingly the condition usually presents as “unexplained infertility” or “unexplained IVF failure” rather than as a miscarriage.
Alloimmune IID, on the other hand, usually starts off presenting as unexplained miscarriages (often manifesting as RPL). Over time as NK/T cell activation builds and eventually becomes permanently established the patient often goes from RPL to “infertility” due to failed implantation. RPL is more commonly the consequence of alloimmune rather than autoimmune implantation dysfunction.
However, regardless, of whether miscarriage is due to autoimmune or alloimmune implantation dysfunction the final blow to the pregnancy is the result of activated NK cells and CTL in the uterine lining that damage the developing embryo’s “root system” (trophoblast) so that it can no longer sustain the growing conceptus. This having been said, it is important to note that autoimmune IID is readily amenable to reversal through timely, appropriately administered, selective immunotherapy, and alloimmune IID is not. It is much more difficult to treat successfully, even with the use of immunotherapy. In fact, in some cases the only solution will be to revert to selective immunotherapy plus using donor sperm (provided there is no “match” between the donor’s DQa profile and that of the female recipient) or alternatively to resort to gestational surrogacy.
DIAGNOSING THE CAUSE OF RPL
In the past, women who miscarried were not evaluated thoroughly until they had lost several pregnancies in a row. This was because sporadic miscarriages are most commonly the result of embryo numerical chromosomal irregularities (aneuploidy) and thus not treatable. However, a consecutive series of miscarriages points to a repetitive cause that is non-chromosomal and is potentially remediable. Since RPL is most commonly due to a uterine pathology or immunologic causes that are potentially treatable, it follows that early chromosomal evaluation of products of conception could point to a potentially treatable situation. Thus I strongly recommend that such testing be done in most cases of miscarriage. Doing so will avoid a great deal of unnecessary heartache for many patients.
Establishing the correct diagnosis is the first step toward determining effective treatment for couples with RPL. It results from a problem within the pregnancy itself or within the uterine environment where the pregnancy implants and grows. Diagnostic tests useful in identifying individuals at greater risk for a problem within the pregnancy itself include:
•Karyotyping (chromosome analysis) both prospective parents
•Assessment of the karyotype of products of conception derived from previous miscarriage specimens
•Ultrasound examination of the uterine cavity after sterile water is injected or sonohysterogram, fluid ultrasound, etc.)
•Hysterosalpingogram (dye X-ray test)
•Hysteroscopic evaluation of the uterine cavity
•Full hormonal evaluation (estrogen, progesterone, adrenal steroid hormones, thyroid hormones, FSH/LH, etc.)
•Immunologic testing to include:
a)Antiphospholipid antibody (APA) panel
b)Antinuclear antibody (ANA) panel
c)Antithyroid antibody panel (i.e., antithyroglobulin and antimicrosomal antibodies)
d)Reproductive immunophenotype
e)Natural killer cell activity (NKa) assay (i.e., K562 target cell test)
f)Alloimmune testing of both the male and female partners
TREATMENT OF RPL
Treatment for Anatomic Abnormalities of the Uterus: This involves restoration through removal of local lesions such as fibroids, scar tissue, and endometrial polyps or timely insertion of a cervical cerclage (a stitch placed around the neck of the weakened cervix) or the excision of a uterine septum when indicated.
Treatment of Thin Uterine Lining: A thin uterine lining has been shown to correlate with compromised pregnancy outcome. Often this will be associated with reduced blood flow to the endometrium. Such decreased blood flow to the uterus can be improved through treatment with sildenafil and possibly aspirin.
Sildenafil (Viagra) Therapy. Viagra has been used successfully to increase uterine blood flow. However, to be effective it must be administered starting as soon as the period stops up until the day of ovulation and it must be administered vaginally (not orally). Viagra in the form of vaginal suppositories given in the dosage of 25 mg four times a day has been shown to increase uterine blood flow as well as thickness of the uterine lining. To date, we have seen significant improvement of the thickness of the uterine lining in about 70% of women treated. Successful pregnancy resulted in 42% of women who responded to the Viagra. It should be remembered that most of these women had previously experienced repeated IVF failures.
Use of Aspirin: This is an anti-prostaglandin that improves blood flow to the endometrium. It is administered at a dosage of 81 mg orally, daily from the beginning of the cycle until ovulation.
Treating Immunologic Implantation Dysfunction with Selective Immunotherapy: Modalities such as IL/IVIg, heparinoids (Lovenox/Clexane), and corticosteroids (dexamethasone, prednisone, prednisolone) can be used in select cases depending on autoimmune or alloimmune dysfunction.
The Use of IVF in the Treatment of RPL
In the following circumstances, IVF is the preferred option:
1.When in addition to a history of RPL, another standard indication for IVF (e.g., tubal factor, endometriosis, and male factor infertility) is superimposed.
2.In cases where selective immunotherapy is needed to treat an immunologic implantation dysfunction.
The reason for IVF being a preferred approach in such cases is that in order to be effective, the immunotherapy needs to be initiated well before spontaneous or induced ovulation. Given the fact that the anticipated birthrate per cycle of COS with or without IUI is at best about 15%, it follows that short of IVF, to have even a reasonable chance of a live birth, most women with immunologic causes of RPL would need to undergo immunotherapy repeatedly, over consecutive cycles. Conversely, with IVF, the chance of a successful outcome in a single cycle of treatment is several times greater and, because of the attenuated and concentrated time period required for treatment, IVF is far safer and thus represents a more practicable alternative
Since embryo aneuploidy is a common cause of miscarriage, the use of preimplantation genetic diagnosis (PGD), with tests such as CGH, can provide a valuable diagnostic and therapeutic advantage in cases of RPL. PGD requires IVF to provide access to embryos for testing.
There are a few cases of intractable alloimmune dysfunction due to absolute DQ alpha matching where Gestational Surrogacy or use of donor sperm could represent the only viable recourse, other than abandoning treatment altogether and/or resorting to adoption. Other non-immunologic factors such as an intractably thin uterine lining or severe uterine pathology might also warrant that last resort consideration be given to gestational surrogacy.
The good news is that if a couple with RPL is open to all of the diagnostic and treatment options referred to above, a live birthrate of 70%–80% is ultimately achievable.
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
•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.
•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
•Treating Out-of-State and Out-of-Country Patients at Sher-IVF in Las Vegas:
•Traveling for IVF from Out of State/Country–
•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.
Thanks a lot for your response. So what do you think would be the treatment to my alloimmune dysfunction. My doctor has suggested using neupogen? What are your thoughts regarding this?
hi Am 27 years old now, trying to conceive for 2 years now since 2014. Have been diagonased with PCOS. Rest all test are normal. Hysteroscopy was also done and came out fine.
IVF 1 was on Sep 2014. 6 embryos 5 day Blastocyst , did PGD , 4 AA – 2, 4AB – 2, remaing BA -2
Oct 2014 – FET 1 – one embryo – Negative
Jan 2015 FET 2 – 2 embryo – Postive .. pregant with twins..We thought,we almost had it. but 26 weeks premature delivery with no symptoms.
babies passed away after 5 days.
Went to Dr after 4 months. Dr said some placenta remains did D&C
Waited a month
FET 3 – Nov 2015 – Negative
FET 4 – Jan 2016 – Negative
Dr felt lowquality embryo, so did 2 IVF
IVf 2 – march 2016 – 4 emrbyos – 5AA -1 ,4AA -2, 4BB -1
FET 1 – April 2016 – Negative -HCG was 5 , then 15 then 25 then dropped to 17 .. medications stopped ..
Dr recomended Hysteroscopy to check, all came good he said after test.
FET 2 – With blood thinners after transfer and progestrone was recommended ,
canncelled 1 cycle as wall thinkness was only 5.next time it was 8 when dr said and transfered 2 days after checking wall thickness was 7
estrace pills,progestone injection and vaginal after transfer.
1 HCG was positive they said with 73 ,2 days after it dropped to 48, dr has asked to stop medication today sep 21.
Really heart broken
Any advice and suggestions on what else we can do further.
There is so much here: The possible effect of the protocols used for ovarian stimulation and uterine preparation for FET; The possibility that retained products (placental tissue) might have become infected and adversely affected the receptivity of the uterine lining; The possibility of an underlying immunologic implantation dysfunction (IID). It is not possible to discuss all this at this forum. We really do need to talk.
Whenever a patient fails to achieve a viable pregnancy following embryo transfer (ET), the first question asked is why! Was it simply due to, bad luck?, How likely is the failure to recur in future attempts and what can be done differently, to avoid it happening next time?.
It is an indisputable fact that any IVF procedure is at least as likely to fail as it is to succeed. Thus when it comes to outcome, luck is an undeniable factor. Notwithstanding, it is incumbent upon the treating physician to carefully consider and address the causes of IVF failure before proceeding to another attempt:
1.Age: The chance of a woman under 35Y of age having a baby per embryo transfer is about 35-40%. From there it declines progressively to under 5% by the time she reaches her mid-forties. This is largely due to declining chromosomal integrity of the eggs with advancing age…”a wear and tear effect” on eggs that are in the ovaries from birth.
2.Embryo Quality/”competency (capable of propagating a viable pregnancy)”. As stated, the woman’s age plays a big role in determining egg/embryo quality/”competency”. This having been said, aside from age the protocol used for controlled ovarian stimulation (COS) is the next most important factor. It is especially important when it comes to older women, and women with diminished ovarian reserve (DOR) where it becomes essential to be aggressive, and to customize and individualize the ovarian stimulation protocol.
We used to believe that the uterine environment is more beneficial to embryo development than is the incubator/petri dish and that accordingly, the earlier on in development that embryos are transferred to the uterus, the better. To achieve this goal, we used to select embryos for transfer based upon their day two or microscopic appearance (“grade”). But we have since learned that the further an embryo has advanced in its development, the more likely it is to be “competent” and that embryos failing to reach the expanded blastocyst stage within 5-6 days of being fertilized are almost invariably “incompetent” and are unworthy of being transferred. Moreover, the introduction into clinical practice about a decade ago, (by Levent Keskintepe PhD and myself) of Preimplantation Genetic Sampling (PGS), which assesses for the presence of all the embryos chromosomes (complete chromosomal karyotyping), provides another tool by which to select the most “competent” embryos for transfer. This methodology has selective benefit when it comes to older women, women with DOR, cases of unexplained repeated IVF failure and women who experience recurrent pregnancy loss (RPL).
3.The number of the embryos transferred: Most patients believe that the more embryos transferred the greater the chance of success. To some extent this might be true, but if the problem lies with the use of a suboptimal COS protocol, transferring more embryos at a time won’t improve the chance of success. Nor will the transfer of a greater number of embryos solve an underlying embryo implantation dysfunction (anatomical molecular or immunologic).Moreover, the transfer of multiple embryos, should they implant, can and all too often does result in triplets or greater (high order multiples) which increases the incidence of maternal pregnancy-induced complications and of premature delivery with its serious risks to the newborn. It is for this reason that I rarely recommend the transfer of more than 2 embryos at a time and am moving in the direction of advising single embryo transfers …especially when it comes to transferring embryos derived through the fertilization of eggs from young women.
4.Implantation Dysfunction (ID): Implantation dysfunction is a very common (often overlooked) cause of “unexplained” IVF failure. This is especially the case in young ovulating women who have normal ovarian reserve and have fertile partners. Failure to identify, typify, and address such issues is, in my opinion, an unfortunate and relatively common cause of repeated IVF failure in such women. Common sense dictates that if ultrasound guided embryo transfer is performed competently and yet repeated IVF attempts fail to propagate a viable pregnancy, implantation dysfunction must be seriously considered. Yet ID is probably the most overlooked factor. The most common causes of implantation dysfunction are:
a.A“ thin uterine lining”
b.A uterus with surface lesions in the cavity (polyps, fibroids, scar tissue)
c.Immunologic implantation dysfunction (IID)
d.Endocrine/molecular endometrial receptivity issues
Certain causes of infertility are repetitive and thus cannot readily be reversed. Examples include advanced age of the woman; severe male infertility; immunologic infertility associated with alloimmune implantation dysfunction (especially if it is a “complete DQ alpha genetic match between partners plus uterine natural killer cell activation (NKa).
I strongly recommend that you visit http://www.DrGeoffreySherIVF.com. Then go to my Blog and access the “search bar”. Type in the titles of any/all of the articles listed below, one by one. “Click” and you will immediately be taken to those you select. Please also take the time to post any questions or comments with the full expectation that I will (as always) respond promptly.
•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
•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.
•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
•Traveling for IVF from Out of State/Country–
•A personalized, stepwise approach to 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.
The mid-trimester loss might have been the result of cervical incompetence. It was not likely due to poor embryo quality…in my opinion. You may need a cervical cerclage at 12-15 weeks to prevent tis from happening again…with the next pregnancy. Discuss with your OB/GYN.
Something else might be going on with regard to your subsequent early losses.Whenever a patient fails to achieve a viable pregnancy following embryo transfer (ET), the first question asked is why! Was it simply due to, bad luck?, How likely is the failure to recur in future attempts and what can be done differently, to avoid it happening next time?.
It is an indisputable fact that any IVF procedure is at least as likely to fail as it is to succeed. Thus when it comes to outcome, luck is an undeniable factor. Notwithstanding, it is incumbent upon the treating physician to carefully consider and address the causes of IVF failure before proceeding to another attempt:
1.Age: The chance of a woman under 35Y of age having a baby per embryo transfer is about 35-40%. From there it declines progressively to under 5% by the time she reaches her mid-forties. This is largely due to declining chromosomal integrity of the eggs with advancing age…”a wear and tear effect” on eggs that are in the ovaries from birth.
2.Embryo Quality/”competency (capable of propagating a viable pregnancy)”. As stated, the woman’s age plays a big role in determining egg/embryo quality/”competency”. This having been said, aside from age the protocol used for controlled ovarian stimulation (COS) is the next most important factor. It is especially important when it comes to older women, and women with diminished ovarian reserve (DOR) where it becomes essential to be aggressive, and to customize and individualize the ovarian stimulation protocol.
We used to believe that the uterine environment is more beneficial to embryo development than is the incubator/petri dish and that accordingly, the earlier on in development that embryos are transferred to the uterus, the better. To achieve this goal, we used to select embryos for transfer based upon their day two or microscopic appearance (“grade”). But we have since learned that the further an embryo has advanced in its development, the more likely it is to be “competent” and that embryos failing to reach the expanded blastocyst stage within 5-6 days of being fertilized are almost invariably “incompetent” and are unworthy of being transferred. Moreover, the introduction into clinical practice about a decade ago, (by Levent Keskintepe PhD and myself) of Preimplantation Genetic Sampling (PGS), which assesses for the presence of all the embryos chromosomes (complete chromosomal karyotyping), provides another tool by which to select the most “competent” embryos for transfer. This methodology has selective benefit when it comes to older women, women with DOR, cases of unexplained repeated IVF failure and women who experience recurrent pregnancy loss (RPL).
3.The number of the embryos transferred: Most patients believe that the more embryos transferred the greater the chance of success. To some extent this might be true, but if the problem lies with the use of a suboptimal COS protocol, transferring more embryos at a time won’t improve the chance of success. Nor will the transfer of a greater number of embryos solve an underlying embryo implantation dysfunction (anatomical molecular or immunologic).Moreover, the transfer of multiple embryos, should they implant, can and all too often does result in triplets or greater (high order multiples) which increases the incidence of maternal pregnancy-induced complications and of premature delivery with its serious risks to the newborn. It is for this reason that I rarely recommend the transfer of more than 2 embryos at a time and am moving in the direction of advising single embryo transfers …especially when it comes to transferring embryos derived through the fertilization of eggs from young women.
4.Implantation Dysfunction (ID): Implantation dysfunction is a very common (often overlooked) cause of “unexplained” IVF failure. This is especially the case in young ovulating women who have normal ovarian reserve and have fertile partners. Failure to identify, typify, and address such issues is, in my opinion, an unfortunate and relatively common cause of repeated IVF failure in such women. Common sense dictates that if ultrasound guided embryo transfer is performed competently and yet repeated IVF attempts fail to propagate a viable pregnancy, implantation dysfunction must be seriously considered. Yet ID is probably the most overlooked factor. The most common causes of implantation dysfunction are:
a.A“ thin uterine lining”
b.A uterus with surface lesions in the cavity (polyps, fibroids, scar tissue)
c.Immunologic implantation dysfunction (IID)
d.Endocrine/molecular endometrial receptivity issues
Certain causes of infertility are repetitive and thus cannot readily be reversed. Examples include advanced age of the woman; severe male infertility; immunologic infertility associated with alloimmune implantation dysfunction (especially if it is a “complete DQ alpha genetic match between partners plus uterine natural killer cell activation (NKa).
I strongly recommend that you visit http://www.DrGeoffreySherIVF.com. Then go to my Blog and access the “search bar”. Type in the titles of any/all of the articles listed below, one by one. “Click” and you will immediately be taken to those you select. Please also take the time to post any questions or comments with the full expectation that I will (as always) respond promptly.
•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
•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.
•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
•Treating Out-of-State and Out-of-Country Patients at Sher-IVF in Las Vegas:
•Traveling for IVF from Out of State/Country–
•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.
Hello,
I had an egg collection yesterday. 2 retrieved. None fertilized. We have 1 frozen embryo. Is it wise to transfer this embryo now or do my chances of success dramatically improve by doing a whole new FET cycle later.
I would transfer the frozen blastocyst now as the next step.
Geoff Sher
Hello, I’m doing a FET again and really having trouble deciding on whether or not to put one or two day 5 blasts ( NOT cgh tested) back in. What have you done, what was your reasoning and what was the outcome?
The decision on how many embryos to transfer confronts most IVF physicians and their IVF patients. It is driven by a goal that both share in common, namely that of optimizing the chance of IVF treatment resulting in pregnancy. Clearly, the more embryos transferred, the greater the likelihood of success. However, there is overwhelming evidence to show that the more embryos transferred to the mother’s uterus, the greater the risk of a multiple pregnancy resulting and the higher the multiple, the higher the risk to both mother and babies. Pregnancy complications such as miscarriage, pre-eclampsia, late pregnancy bleeding, an increased incidence of cesarean section, post-delivery hemorrhage etc., are all much more prevalent, placing the mother at risk. Preterm delivery is also much more likely to occur and the earlier the baby is born, the less equipped it is to cope with extrauterine existence, placing it at great risk of complications such as respiratory distress, impaired neurologic and visual development and necrotizing enterocolitis …..to name but a few . While such complications do occur with a twin pregnancy, their incidence and severity increases exponentially with high order multiples (triplets or greater). In fact, in such cases the likelihood that at least one of the babies not surviving the ravages of premature delivery or being left severely developmentally impaired is about 50:50.
Since the higher the number of embryos transferred the greater the chance of a multiple pregnancy, it is incumbent on the treating physician to minimize the number he/she delivers into the uterine cavity with IVF. When deciding on the number of embryos to transfer, the patient’s chance for success (her prognosis) needs to be considered. The younger the woman, the better the microscopic quality of the embryos (their grade), the stage of development of the embryos (cleaved or blastocyst) , the chromosomal integrity of available embryos as assessed by preimplantation genetic sampling (PGS); and the number of supernumerary embryos left over for cryopreservation (freezing) and storage, are factors that should all be taken into consideration. In general, it is recommended that fewer embryos that have reached the blastocyst stage (day 5-6 after fertilization) be transferred than if the transfer were to be done earlier at the cleavage stage (day 2-3 after fertilization). This is because, the further an embryo has advanced in development the greater the likelihood that it will propagate a viable pregnancy.
Consider the fact that when comparing singleton with twin and triplet pregnancies:
Twins have 3-times, and triplets, a 6-times greater perinatal mortality rate.
Twins have 6-times, and triplets, an 11-times greater likelihood of developing cerebral palsy.
Twins are 50% and triplets 80% more likely to be born prematurely.
Mothers of twins are 3-times, and mothers of triplets, 7-times more likely to experience serious pregnancy-induced complications.
The anguish of losing one or more of your children at birth or watching them endure a life-long disability is a situation no parent would wish to face, yet it is a frequent consequence of multiple births. Why then do so many IVF practitioners still insist on transferring multiple embryos at a time? The following are the main reasons for this:
Most infertile patients simply do not perceive any great risk associated with multiple gestations, especially when it comes to twins. In fact most, consider multiple pregnancy to be a “bonus”…a favorable outcome. Faced with the high emotional and financial cost associated with IVF treatment, most couples prefer to complete their families in one attempt so as to “maximize the use of their resources.” In fact, when asked, almost 90% of couples undergoing IVF in the United States are desirous of having twins. Some are even interested or covet having high order multiples (triplets or beyond). Education is urgently needed to make IVF candidates fully aware of the risks associated with multiple gestations.
The inability to differentiate between embryos that will propagate a healthy pregnancy (i.e. “competent” embryos) and those that will not (“incompetent” embryos): Most IVF patients erroneously believe that a “pretty”, embryo (one given a high grade because it fulfils the microscopic criteria of “good quality”) should invariably make a baby. This is simply not the case. Consider the fact that such a microscopically “good quality” embryo from a 30-year-old has about an 8-times greater chance of resulting in a normal birth than would an identical looking embryo of a 45 year old! This confronts IVF practitioners with a “damned if you do, damned if you don’t” situation; driven by patient pressure to achieve a pregnancy and by competing market forces, they still too often choose to transfer multiple embryos, often with disastrous results. It is generally true that declining egg/embryo “competency”with advancing age justifies transferring more embryos in older women – especially in those over 40 years of age – but this still needs to be carefully measured against the risk of multiple gestations.Not only is multiple gestation the most common complication of infertility treatment, it has also become the most costly in terms of its social impact. If all of the factors associated with multiple gestations are considered, including the costs of antenatal maternal hospitalization, neonatal intensive care for premature infants, as well as the costs of chronic medical care, rehabilitation and special education, the projected annual cost of IVF-associated multiple gestations in the United States is approximately $1.5 billion as compared to about $550 million for all the other IVF cycles performed.
On the positive side is the fact that the last decade has seen a slight but significant decline in the IVF twin pregnancy rate from about 25% to about 22%, as well as a decline in the incidence of triplets from 5% to about 3%. Still, IVF multiple birth rates are about ten times higher than those associated with natural conception. Clearly, multiple pregnancy (especially high-order multiples) represents a complex problem that can no longer be justified as an acceptable outcome following IVF treatment.
Most in the IVF field are in agreement that it is probably best not to transfer more than 2 embryos at a time in younger women. The reason is that embryos derived from the eggs of a young woman (under 35 years) are much more likely to lead to a pregnancy than are those derived from older women. That is why most IVF programs in the United States therefore recommend transferring up to 2 embryos at a time in such cases. For women over 40, many still transfer 3 or even 4 embryos. For those between 35 and 40 years of age, 2-3.
What About Single Embryo Transfers: Advances in IVF technology have brought the noble goal of transferring a single embryo at a time without reducing the chance of a successful IVF, well within reach. Numerous studies have demonstrated that the cumulative birth rate after single embryo transfer (SET), followed by subsequent transfers of individually thawed left-over embryos, is as effective in achieving pregnancy as implanting multiple embryos at one time. And by this approach the risk of multiple births can be virtually eliminated. Moreover, using the SET approach, more than 80% of women under 40 years of age will deliver babies within first four single embryo transfers. At the same time, SET’s would likely cut the cost of health care per IVF baby by about $50,000 per live-birth.
A recent study found that, compared with singleton deliveries, the costs for twins, triplets and higher-order deliveries are approximately four, 11 and 18 times greater, respectively – mostly due to maternal and neonatal complications.
When we use the term “competent” embryo, we mean one which, upon being transferred to a “receptive” or “hospitable” uterus, will in most cases propagate a viable gestation. By far the single most important determinant of embryo “competency” is its karyotype (the number of chromosomes present). Aneuploid embryos (those with too many or too few chromosomes) are uniformly “incompetent” while “euploid” embryos (those with the correct number) are by and large “competent.” An incompetent embryo will not result in a normal pregnancy. In most cases it will either fail to implant or will miscarry early on. It follows that the ability to efficiently identify competent embryos for selective individual transfer would likely represent a “game changer” in the IVF arena.
In the past, the ability to select competent embryos for transfer has been thwarted by:
a. Lack of reliability of microscopic morphologic (appearance) embryo grading.
b. The inability of traditional pre-implantation genetic diagnosis/sampling (PGD/s) and chromosomal evaluation (karyotyping) by conventional Fluorescence In-Situ Hybridization (FISH) to be able to access all of the embryo’s chromosomes.
Let’s take a look at the merit and reliability of several current methods used to select the best embryo(s) for transfer:
•Microscopic Embryo Grading: Currently, most IVF centers culture embryos in groups and then perform a single microscopic evaluation (at 2, 3 or 5-6 days) prior to embryo transfer of one or more to the uterus. This approach is limited in scope and in its ability to reliably discriminate between “competent” and “incompetent” embryos, since chromosomally abnormal embryos are often identical in appearance to those that are normal. Embryos should be at 2 to 4 cells at 48 hours after egg retrieval and about 6-9 cells by 72 hours. The cells in an embryo are also referred to as “blastomeres.” Ideally the blastomeres should be of even size, and there should be less than 20% fragmentation, or blebbing. This is where portions of the embryo’s cells have broken off and are found lying free as debris inside its substance .Most IVF clinics “grade” each embryo using one of many scoring systems. Unfortunately, there is no agreement at all as to which system to use. But regardless of the microscopic grading system used, one thing is certain…they all lack reliability because they cannot evaluate the chromosomal integrity of the embryo.
•Blastocyst Embryo Transfer: A blastocyst is an embryo which has developed to the point of having 2 different cell components and a fluid cavity. Human embryos, in culture in an IVF lab, or developing naturally in the female body, usually reach the blastocyst stage by day 5 or 6 after fertilization. Many “incompetent” embryos are culled out as the embryo progresses to the blastocyst stage. Thus, those embryos that make it to blastocyst are far more likely than their day 2-3 counterparts to be competent. Embryos that do not reach blastocyst are in about 90% of cases chromosomally abnormal (aneuploid) and would not have been worthy of transfer earlier on anyway. Routinely taking embryos to blastocyst is thus a good idea since, if they do not make it, they are incompetent anyway.By waiting five or six days post fertilization to select and transfer only blastocysts to the uterus, we can improve the likelihood that those being transferred are the “competent” ones.
•Preimplantation Genetic Sampling (PGS) using Next Generation Gene Sampling (NGS) : This very promising method for embryo selection represents a real breakthrough in the IVF arena. NGS allows for identification of all 23 pairs of the chromosomes, providing a reliable method for differentiating between “competent” and “incompetent” embryos. Even without CGH embryo selection, “one embryo/one healthy baby” is now even more attainable. However, the introduction of CGH has made embryo selection much more scientific, virtually removing the incentive to transfer multiple embryos at a time. One of the perceived disadvantages of CGH embryo selection is the cost of such testing. However, while the performance of egg/embryo PGS does increase the cost per cycle of IVF, it actually lowers the “cost per IVF baby”. Since NGS testing requires several days to complete, the use of this technology usually requires that advanced embryos (blastocysts) be frozen and stored (cryostored) in a subsequent cycle. The separation of an IVF cycle into two separate phases to achieve this objective is referred to as Staggered-IVF (St-IVF). Cryostoring blastocysts allows sufficient time for the CGH testing to be completed.
•Embryo Vitrification (Ultra-rapid Freezing): Until about a decade ago, cryopreservation of human embryos had been somewhat problematic because it caused ice crystals to form inside the embryo, damaging or destroying it. The recent introduction of ultra-rapid freezing or vitrification (read the article on vitrification here) has changed all that. With vitrification, embryos are so rapidly frozen that no ice forms, yielding a post-thaw embryo survival rate of about 90%. Impressively, birth rates following the transfer of thawed, pre-vitrified embryos hardly differ from those using fresh embryos.
The Hippocratic Oath, states that the cardinal rule of medicine is “primum non nocera” (“foremost do no harm”). Since multiple pregnancy is the most serious complication of Assisted Reproductive Medicine, and IVF has been responsible for a virtual explosion in the incidence of twins and higher order multiples, those of us that practice medicine in this arena have a solemn responsibility to educate our patients and then to restrict the number of embryos we transfer at one time. Central to achieving this goal is to optimize the ability to select the most “competent” embryos for transfer.
Good luck!
Geoff Sher
800-780-7437