In the United States, effective treatment of  natural killer cell /cytotoxic lymphocyte (NK/CTL)-activation associated with either alloimmune or autoimmune implantation dysfunction requires the administration of primarily Intralipid (IL) or Intravenous gamma-globulin (IVIg). Such treatment is much more likely to be successful in the case of` autoimmune implantation dysfunction where the NK/CTL activation is present in advance of the uterus being exposed to the embryo. It is not nearly as effective for the treatment of alloimmune implantation dysfunction where a DQ alpha-matching embryo will exert a sustained activation of NK/CTL over several months of gestation.

It is presently not yet possible to recognize sperm-derived (paternal)  DQ alpha incorporated in the embryo. Accordingly, in cases where the paternal DQ alpha genes only match with one of the mother’s DQ alpha’s (i.e., a partial match) there is a one out of two chance that a transferred embryo will inadvertently be a match with at least one of the mother’s DQ alpha genes. Thus IL and IVIg therapy will only prove half as likely to propagate a viable pregnancy in cases of partial DQ alpha matching as it can achieve in the treatment of NK/CTL activation associated with autoimmune implantation dysfunction. Thus we prefer to transfer only one embryo (rather than multiples) at a time in such cases, for fear of there being one DQ alpha matching embryo in the mix and so “muddying the waters” for the non-DQ alpha matching that otherwise might have propagated a healthy baby.

A real problem arises in cases of a complete match, where both paternal DQ alpha genes match with at least one of the mother’s DQ alphas. Here, every embryo will express a paternal DQ alpha gene that matches that of the mother’s. In such cases, IL therapy will rarely work. The reason is that such treatment cannot match the sustained provocation of NK/CTL activity brought about by an ever-present DQ alpha “clash.” In cases of a complete DQ alpha matching (with associated NK/CTL activation), where all the embryos will inevitably carry one or both paternal DQ alpha that match(es) the mother, there is in my opinion little hope of success, even with Intralipid/steroid therapy. In such cases, gestational surrogacy or the use of non-DQ alpha matching donor sperm may offer the only reasonable chance of a successful IVF outcome.

Some patients ask whether using an egg donor might not offer another solution in such cases. The answer is no! The match-up is between the paternal DQ alpha contribution (in the sperm) and the mother’s uterus. It is not between the sperm and the egg.

IL therapy should be administered in combination (with corticosteroids) at an adequate dosage, 7–14 days prior to planned embryo transfer, and with alloimmune implantation  dysfunction it should (ideally) be maintained, at least through the 1st half of pregnancy. The goal is to down-regulate activated NK/CTL and thereby reinstate a healthy TH-1: TH-2 cytokine balance in advance of a “competent” non-DQ alpha matching embryo reaching the uterus. Treatment of autoimmune  implantation  dysfunction requires that IL (with corticosteroids) be administered only twice, once 7–14 days prior to embryo transfer and then one more time when the beta hCG blood level has shown evidence of an appropriate  rise, thereby suggesting that healthy implantation could be in progress. Supplementation with heparinoid is indicated when there is evidence of concomitant antiphospholipid antibodies or certain types of hereditary clotting defects (thrombophilias) such as a homozygous MTHFR mutation.

The Role of PGS (Full Embryo Chromosomal Karyotyping) in the Treatment of Alloimmune Implantation Dysfunction

Intralipid (IL)/Prednisone therapy only addresses the implantation issue, not embryo competency (which resides in the chromosomal integrity of the embryo transferred. Moreover, as previously alluded to, with a partial DQ alpha match/NK cell activation each blastocyst transferred has a 50:50 chance of matching. Consider the fact that the transfer of a single expanded blastocyst to a young woman (who did not have a DQ alpha match) would yield at best about a 35% chance of propagating a healthy pregnancy. Now, if the woman had a partial DQ alpha match with her partner, given that  each of her embryos  embryo would have a 50:50 chance of matching (and there is currently no way to identify the DQ alpha genotype of an embryo) , the chance of a viable pregnancy would be one half of the otherwise anticipated 35% (i.e. about 17%). If on the other hand the woman’s transferred embryo had been tested and found through PGS Next Generation Gene Sequencing – NGS) to have a full component of 46 chromosomes (i.e. euploid) then the chance of a viable pregnancy would be about 32% (half of an otherwise 65% chance had she not had a partial DQ alpha match with her partner.  Now add to this equation the fact that with a partial DQ alpha match it is probably best to transfer only one embryo at a time in order to reduce the risk that the inadvertent delivery of a DQ alpha matching embryo could potentially cause activation of local uterine NK cell activation that might prejudice the implantation of all embryos being transferred.

The Role of Embryo Banking in Cases of Alloimmune Implantation Dysfunction with a Partial DQ alpha Match

Bear in mind that less than 1:2 embryos are chromosomally normal even in young women, and this decreases further with advancing age. Furthermore, where there is a partial DQ alpha match between partners, only 50% of the embryos will be non-matching, reducing the chances of successful implantation again by half. It is advisable to only transfer one embryo at a time in such cases. Indeed, a strong case could be made for full embryo karyotyping (using PGS) to allow for the selective transfer (one at a time) of only those embryos that are chromosomally normal (euploid). In most cases, this will require biopsying the fresh embryos for PGS testing, allowing them to progress to blastocysts and then cryopreserving these for subsequent single embryo transfer.  This would allow for more competent blastocysts to be available and for a much higher success rate per blastocyst transferred and accordingly, improved IVF outcomes.

Use of a Gestational Surrogate for Alloimmune Implantation Dysfunction

A gestational surrogate is used when there is a complete DQ alpha match with NK cell activation between the patient and the sperm provider. It has no real merit when there is only a partial match. Ordinarily, provided that an embryo recipient is NK negative, a DQa match between recipient and sperm provider should theoretically not preclude an ensuing pregnancy. Notwithstanding this, there should in our opinion be reluctance  to accept NK negative Gestational Surrogates (GS) who share a DQa match with the sperm provider……An exception could be made only if following full disclosure of this concern to both parties in advance of treatment that although unlikely, a pregnancy with a matching DQa, NK negative pair could (although unlikely) suddenly cause the newly pregnant embryo recipient to convert to NK+,  placing the pregnancy (as well as all future pregnancies) in jeopardy.

Use of a Sperm Donor in Cases of Alloimmune Implantation Dysfunction

This is an acceptable option in cases of a partial or complete DQ alpha match, provided that the sperm donor and the embryo recipient do not match and any coexisting NK cell/CTL activation is treated concurrently with IL/steroids.

Use of Medications in the Treatment of IID

  1. Intralipid (IL) Therapy:

About a decade ago, a Sher-IVF Reproductive Endocrinologist, along with a geneticist in an affiliated Reproductive immunology Laboratory in Chicago, IL, were the first to report on the potential advantage of supplanting IVIg therapy.

Intralipid (IL) is a solution of small lipid droplets suspended in water. When administered intravenously, IL provides essential fatty acids, linoleic acid (LA), an omega-6 fatty acid, alpha-linolenic acid (ALA), an omega-3 fatty acid. IL is made up of 20% soybean oil/fatty acids (comprising linoleic acid, oleic acid, palmitic acid, linolenic acid and stearic acid), 1.2% egg yolk phospholipids (1.2%), glycerin (2.25%) and water (76.5%).

IL exerts a modulating effect on certain immune cellular mechanisms largely by down-regulating cytotoxic /activated natural killer cells (NKa). This effect is enhanced through the concomitant administration of corticosteroids such as dexamethasone, prednisone, and prednisolone, by suppressing cytotoxic/activated T-lymphocytes. This effect of IL might be due to its ability to suppress pro-inflammatory cellular (Type-1) cytokines such as interferon gamma and TNF-alpha,

In-vitro testing has shown that IL successfully and completely down-regulates activated natural killer cells (NKa) within 2-3 weeks in 78% of women experiencing immunologic implantation dysfunction. In this regard it is just as effective as IVIg but at a fraction of the cost and with a far lower incidence of side-effects. Its effect lasts for 4-9 weeks when administered in early pregnancy.

Can in vitro tests done in the laboratory assess for an immediate benefit of Intralipid on NKa? Since the down-regulation of NKa through IL (or IVIg) therapy can take several weeks to become detectable, it follows that there is really no benefit in trying to assess the potential efficacy of such treatment by retesting NKa in the laboratory after adding IL (or IVIg) to the sample.

Treatment of Autoimmune NKa Using Intralipid: When it comes to NKa in  IVF cases complicated by autoimmune implantation dysfunction,  the combination of daily oral dexamethasone commencing with the onset of ovarian stimulation and continuing until the 10th week of pregnancy, combined with an initial infusion of IL (100ml, 20% IL dissolved in 500cc of saline solution, 10-14 days prior to embryo transfer and repeated once more (only), as  soon as the blood pregnancy test is positive), the anticipated chance of a viable pregnancy occurring within 2 completed IVF attempts (including fresh + frozen ET’s)  in women under 40Y (who have normal ovarian reserve)  is above 80%.

Treatment of Alloimmune NKa Using Intralipid:

Partial DQ alpha Match: IVF patients who have NKa associated with a partial alloimmune implantation dysfunction (DQ alpha match between partners) we use the same IL, infusion as with autoimmune-NKa, only here we prescribe oral prednisone rather than dexamethasone until the 10th week of pregnancy and IL infusions are repeated every 2-4 weeks following the chemical diagnosis of pregnancy until the 24th week. Additionally, (as alluded to elsewhere) in such cases we transfer only a single embryo at a time. This is because in such cases, the likelihood is that one out of two embryos will “match” and we are fearful that if we transfer >1 embryo, and one of the transferred embryos “matches” it could cause further activation of uterine NK cells  and so prejudice the implantation of all transferred embryos.  Since we presently have no way of determining which embryo carries the matching paternal DQ alpha gene and thus would transfer only one embryo at a time, it follows that the anticipated viable  pregnancy rate per cycle will be much lower than with autoimmune implantation dysfunction. It also follows that the only way to improve success with a single embryo being transferred would be to perform PGS on the embryos in advance of ET and then selectively transfer a “chromosomally normal, euploid (“competent”) embryos.

Total (Complete) DQ alpha Match: In cases where the partners have a total alloimmune (DQ alpha) match with accompanying NKa the chance of a viable pregnancy occurring or (if it does) resulting in a live birth at term, is so small as to be an indication for using a non-matching sperm donor or resorting to gestational surrogacy would in our opinion be preferable by far.

Contraindications and Cautions with Intralipid Infusion: IL is only contraindicated in conditions associated with severely disordered fat metabolism (e.g. severe liver damage, acute myocardial infarction and shock,

Rarely, hypersensitivity has been observed in patients allergic to soybean protein, egg yolk and egg whites and where fat metabolism may be disturbed (e.g. renal insufficiency, uncontrolled diabetes, certain metabolic disorders and in cases of severe infection (sepsis).

Adverse Reactions during Infusions of IL (Rare): These include transient fever, chills, nausea, vomiting, headache, and back or chest pain with shortness of breath and cyanosis.

Composition and Storage of IL: IL should be stored at a controlled room temperature below 25°C. It should not be frozen.

IVIg versus Intralipid Therapy:  Until about a decade ago, the only effective and available way (in the US) to down-regulate activated NK cells was through the intravenous administration of a blood product known as immunoglobulin-G (IVIg). The fear (albeit unfounded) that the administration of this product might lead to the transmission of viral infections such as HIV and hepatitis C, plus the high cost of IVIG along with the fact that significant side effects occurred about 20% of the time, led to bad press and bad publicity for the entire field of reproductive immunology. It was easier for Reproductive Endocrinologists (REs) to simply say “I don’t believe that IVIg works” and thereby avoid risk and bad publicity. But the thousands of women who had babies because of NK cell activity being down-regulated through its use, attests to IVIg’s efficacy. But those of us who felt morally obligated to many desperate patients who would not conceive without receiving IVIG were facing an uphill battle. The bad press caused by fear mongering took its toll and spawned a malicious controversy. It was only through the introduction of IL less (than a decade ago), that the tide began to turn in favor of those patients who required low cost, safe and effective immunotherapy to resolve their IID.

  1. Corticosteroid Therapy (Prednisone, Prednisolone, and Dexamethasone)

Corticosteroid therapy has become a mainstay in the treatment of most women undergoing IVF. It is believed by most to enhance implantation due to an overall immunomodulatory effect. Some IVF programs prescribe daily oral methyl prednisolone (Medrol) while others prefer prednisone or dexamethasone, commencing 10-14 days prior to egg retrieval and continuing until pregnancy is discounted or until the 10th week of pregnancy.

  1. Heparinoid Therapy

There is compelling evidence that the subcutaneous administration  of heparin twice daily or low molecular heparin (Clexane, Lovenox) once daily, (starting  with the onset of ovarian stimulation) can improve IVF birthrate in women who test positive for APAs and can prevent later pregnancy loss when certain thrombophilias (e.g. homozygous MTHFR mutation)

  1. What About Baby Aspirin?

In our opinion, aspirin has little (if any) value when it comes to IID, and besides, could even reduce the chance of success. The reason for this is that aspirin thins the blood and increases the potential to bleed. This effect can last for up to a week and could complicate an egg retrieval procedure or result in “concealed” intrauterine bleeding at the time of embryo transfer, thereby potentially compromising IVF success.

  1. TH-1 Cytokine Blockers (Enbrel, Humira)

TH-1 cytokine blockers, (Enbrel and Humira) are in our opinion relatively ineffective in the IVF setting. There has to date been no convincing data to support their use. Conversely, these blockers could have a role in the treatment of a threatened miscarriage thought to be due to CTL/NK activation, but not for IVF. The reason is that the very initial phase of implantation requires a cellular response involving TH-1 cytokines. To block them completely (rather than simply restore a TH-1: TH-2 balance as occurs with IL therapy) so very early on could compromise rather than benefit implantation.

  1. Leukocyte Immunization Therapy (LIT)

The subcutaneous injection of the male partner’s lymphocytes to the mother is thought to enhance the ability for the mother’s decidua (uterus) to recognize the DQ alpha matching embryo as “self” or “friend” and thereby avert its rejection. LIT has been shown to up-regulate Treg cells and thus down-regulate NK cell activation and thereby improve decidual TH-1: TH-2 balance. Thus there could be a therapeutic benefit from such therapy. However, the same benefit can be achieved through the use of IL plus corticosteroids. Besides, IL is much less expensive, and the use of LIT is prohibited by law in the U.S.A.

 

5 Comments

Megan

Dr Shur,

I have recently had a third failed round using Donor Eggs. I have had my nk cells tested which came back normal. Not further immune testing has been done however, my clinic has me on Tacrolimus, Granocyte, prednisone and intrapilids yet still no pregnancy. Do you encourage these sorts of medications especially when no elevated Nk cells? And also what testing would you suggest I do now moving forward.

Thank you
Megan

reply
Dr. Geoffrey Sher

The concentration of blood NK cells is irrelevant. It is blood NK cell activity as measured by the K-562 target cell test and/or endometrial cytokines that matters.

Unless tests for immunologic implantation dysfunction (IID) are performed correctly and conducted by a one of the few reliable reproductive immunology reference laboratory in the United States, treatment will likely be unsuccessful. . In this regard it is most important that the right tests be ordered and that these be performed by a competent laboratory. There are in my opinion only a handful of reliable Reproductive Immunology Laboratories in the world and most are in the U.S.A. Also, it is my opinion that far too often, testing is inappropriate with the many redundant and incorrect tests being requested from and conducted by suboptimal laboratories. Finally for treatment to have the best chance of being successful, it is vital that the underlying type of IID (autoimmune IID versus alloimmune) be identified correctly and that the type, dosage, concentration and timing of treatments be carefully devised and implemented. I recommend that my patients be tested by ReproSource Reproductive Immunology Reference Laboratory, Boston, MA.

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 15y 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
e. Ureaplasma Urealyticum (UU) Infection of cervical mucous and the endometrial lining of the uterus, can sometimes present as unexplained early pregnancy loss or unexplained failure following intrauterine insemination or IVF. The infection can also occur in the man, (prostatitis) and thus can go back and forth between partners, with sexual intercourse. This is the reason why both partners must be tested and if positive, should be treated contemporaneously.
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.

• The IVF Journey: The importance of “Planning the Trip” Before Taking the Ride”
• Controlled Ovarian Stimulation (COS) for IVF: Selecting the ideal protocol
• IVF: Factors Affecting Egg/Embryo “competency” during Controlled Ovarian Stimulation (COS)
• The Fundamental Requirements for Achieving Optimal IVF Success
• Use of GnRH Antagonists (Ganirelix/Cetrotide/Orgalutron) in IVF-Ovarian Stimulation Protocols.
• Ovarian Stimulation in Women Who have Diminished Ovarian Reserve (DOR): Introducing the Agonist/Antagonist Conversion protocol
• Anti Mullerian Hormone (AMH) Measurement to Assess Ovarian Reserve and Design the Optimal Protocol for Controlled Ovarian Stimulation (COS) in IVF.
• Human Growth Hormone Administration in IVF: Does it Enhances Egg/Embryo Quality and Outcome?
• The BCP: Does Launching a Cycle of Controlled Ovarian Stimulation (COS). Coming off the BCP Compromise Response?
• Blastocyst Embryo Transfers should be the Standard of Care in IVF
• IVF: How Many Attempts should be considered before Stopping?
• “Unexplained” Infertility: Often a matter of the Diagnosis Being Overlooked!
• IVF Failure and Implantation Dysfunction:
• The Role of Immunologic Implantation Dysfunction (IID) & Infertility (IID): PART 1-Background
• Immunologic Implantation Dysfunction (IID) & Infertility (IID): PART 2- Making a Diagnosis
• Immunologic Dysfunction (IID) & Infertility (IID): PART 3-Treatment
• Thyroid autoantibodies and Immunologic Implantation Dysfunction (IID)
• Immunologic Implantation Dysfunction: Importance of Meticulous Evaluation and Strategic Management 🙁 Case Report)
• Intralipid and IVIG therapy: Understanding the Basis for its use in the Treatment of Immunologic Implantation Dysfunction (IID)
• Intralipid (IL) Administration in IVF: It’s Composition; how it Works; Administration; Side-effects; Reactions and Precautions
• Natural Killer Cell Activation (NKa) and Immunologic Implantation Dysfunction in IVF: The Controversy!
• Endometrial Thickness, Uterine Pathology and Immunologic Factors
• Vaginally Administered Viagra is Often a Highly Effective Treatment to Help Thicken a Thin Uterine Lining
• Treating Out-of-State and Out-of-Country Patients at Sher-IVF in Las Vegas:
• A personalized, stepwise approach to IVF
• How Many Embryos should be transferred: A Critical Decision in IVF?
______________________________________________________
ADDENDUM: PLEASE READ!!
INTRODUCING SHER FERTILITY SOLUTIONS (SFS)
Founded in April 2019, Sher Fertility Solutions (SFS) offers online (Skype/FaceTime) consultations to patients from > 40 different countries. All consultations are followed by a detailed written report presenting my personal recommendations for treatment of what often constitute complex Reproductive Issues.

If you wish to schedule an online consultation with me, please contact my assistant (Patti Converse) by phone (800-780-7437/702-533-2691), email (concierge@SherIVF.com) or, enroll online on then home-page of my website (www.SherIVF.com).

PLEASE SPREAD THE WORD ABOUT SFS!

Geoff Sher

reply
Dr. Geoffrey Sher

The concentration of blood NK cells is irrelevant. It is blood NK cell activity as measured by the K-562 target cell test and/or endometrial cytokines that matters.

Unless tests for immunologic implantation dysfunction (IID) are performed correctly and conducted by a one of the few reliable reproductive immunology reference laboratory in the United States, treatment will likely be unsuccessful. . In this regard it is most important that the right tests be ordered and that these be performed by a competent laboratory. There are in my opinion only a handful of reliable Reproductive Immunology Laboratories in the world and most are in the U.S.A. Also, it is my opinion that far too often, testing is inappropriate with the many redundant and incorrect tests being requested from and conducted by suboptimal laboratories. Finally for treatment to have the best chance of being successful, it is vital that the underlying type of IID (autoimmune IID versus alloimmune) be identified correctly and that the type, dosage, concentration and timing of treatments be carefully devised and implemented. I recommend that my patients be tested by ReproSource Reproductive Immunology Reference Laboratory, Boston, MA.

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 15y 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
e. Ureaplasma Urealyticum (UU) Infection of cervical mucous and the endometrial lining of the uterus, can sometimes present as unexplained early pregnancy loss or unexplained failure following intrauterine insemination or IVF. The infection can also occur in the man, (prostatitis) and thus can go back and forth between partners, with sexual intercourse. This is the reason why both partners must be tested and if positive, should be treated contemporaneously.
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.

• The IVF Journey: The importance of “Planning the Trip” Before Taking the Ride”
• Controlled Ovarian Stimulation (COS) for IVF: Selecting the ideal protocol
• IVF: Factors Affecting Egg/Embryo “competency” during Controlled Ovarian Stimulation (COS)
• The Fundamental Requirements for Achieving Optimal IVF Success
• Use of GnRH Antagonists (Ganirelix/Cetrotide/Orgalutron) in IVF-Ovarian Stimulation Protocols.
• Ovarian Stimulation in Women Who have Diminished Ovarian Reserve (DOR): Introducing the Agonist/Antagonist Conversion protocol
• Anti Mullerian Hormone (AMH) Measurement to Assess Ovarian Reserve and Design the Optimal Protocol for Controlled Ovarian Stimulation (COS) in IVF.
• Human Growth Hormone Administration in IVF: Does it Enhances Egg/Embryo Quality and Outcome?
• The BCP: Does Launching a Cycle of Controlled Ovarian Stimulation (COS). Coming off the BCP Compromise Response?
• Blastocyst Embryo Transfers should be the Standard of Care in IVF
• IVF: How Many Attempts should be considered before Stopping?
• “Unexplained” Infertility: Often a matter of the Diagnosis Being Overlooked!
• IVF Failure and Implantation Dysfunction:
• The Role of Immunologic Implantation Dysfunction (IID) & Infertility (IID): PART 1-Background
• Immunologic Implantation Dysfunction (IID) & Infertility (IID): PART 2- Making a Diagnosis
• Immunologic Dysfunction (IID) & Infertility (IID): PART 3-Treatment
• Thyroid autoantibodies and Immunologic Implantation Dysfunction (IID)
• Immunologic Implantation Dysfunction: Importance of Meticulous Evaluation and Strategic Management 🙁 Case Report)
• Intralipid and IVIG therapy: Understanding the Basis for its use in the Treatment of Immunologic Implantation Dysfunction (IID)
• Intralipid (IL) Administration in IVF: It’s Composition; how it Works; Administration; Side-effects; Reactions and Precautions
• Natural Killer Cell Activation (NKa) and Immunologic Implantation Dysfunction in IVF: The Controversy!
• Endometrial Thickness, Uterine Pathology and Immunologic Factors
• Vaginally Administered Viagra is Often a Highly Effective Treatment to Help Thicken a Thin Uterine Lining
• Treating Out-of-State and Out-of-Country Patients at Sher-IVF in Las Vegas:
• A personalized, stepwise approach to IVF
• How Many Embryos should be transferred: A Critical Decision in IVF?
______________________________________________________
ADDENDUM: PLEASE READ!!
INTRODUCING SHER FERTILITY SOLUTIONS (SFS)
Founded in April 2019, Sher Fertility Solutions (SFS) offers online (Skype/FaceTime) consultations to patients from > 40 different countries. All consultations are followed by a detailed written report presenting my personal recommendations for treatment of what often constitute complex Reproductive Issues.

If you wish to schedule an online consultation with me, please contact my assistant (Patti Converse) by phone (800-780-7437/702-533-2691), email (concierge@SherIVF.com) or, enroll online on then home-page of my website (www.SherIVF.com).

PLEASE SPREAD THE WORD ABOUT SFS!

Geoff Sher

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Leah

Dr, Shur,

The only 2 times i have had successful implantation has been on a course of Lovenox/20 mg prednisone/and anti-histamines in addition to the typical progresterone and estrogen.I am newly pregnant (second beta confirmed today). I have stopped the Lovenox (previous pregnancy ended in a miscarriage caused by a subchorionic hemorrage, thought to have been made worse by the Lovenox i was on). Now I am wondering if I should continue on the Prednisone, and for how long. The only “immune testing” I’ve done is the standard recurrent loss panel- I was Normal for everything but still an unexplained infertility diagnosis. Has prednisone “done it’s job” now that implantation has been successful and I can start tapering off or is there still great concern for an immune response against the developing embryo? I’m trying to weigh out the risk vs rewards. Thanks!

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Dr. Geoffrey Sher

It is probably too late to expand on the immune testing now. I suggest you discuss the empiric treatment you were on last time with your treating Physician, since I cannot comment authoritatively without access to much more information about your case.

Good luck and G-d bless!

Geoff Sher

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