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If any are”mosaic” they could auto correct in the uterus. Discuss with your RE.

EMBRYO MOSAICISM: WHAT IS IT AND WHAT ARE THE CONSEQUENCES?

Geoffrey Sher MD

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 preimplantation embryo development and represents a major cause of early pregnancy loss. More than 15 years ago, we 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.

Many IVF programs that offer PGS/PGT-A 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, a  growing  body of evidence  suggests  that following embryo transfer, some aneuploid embryos will in the process of ongoing development,  convert to the euploid state (i.e. “autocorrect”) and then go on to develop into chromosomally normal offspring. In fact, I am personally aware of several such cases having occurred in my own practice. So clearly, 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 aneuploid embryos the possibility exists that we could 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/PGT-A 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 “autocorrection” lies in the fact that some embryos found through PGS/PGT-A-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.”

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 “autocorrection”. 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 (“Mosaicism”) occurs when following fertilization and subsequent cell replication (cleavage), some cells (blastomeres) of a meiotically normal (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 likely 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 reliably differentiate between these two varieties of aneuploidy would potentially be of considerable clinical value. The recent introduction of a variety of preimplantation genetic screening (PGS) known as next generation gene sequencing (NGS) has vastly improved the ability to reliably and accurately karyotype embryos and thus to diagnose embryo “mosaicism”.

Most complex aneuploidies are meiotic in origin and will thus almost invariably fail to propagate viable pregnancies. The ability of mosaic embryos to autocorrect is influenced by stage of embryo development in which the diagnosis is made, which chromosomes are affected, whether the aneuploidy involves a single chromosome (simple) or involves 3 or more chromosomes (complex), and the percentage of cells that are aneuploid. Many embryos diagnosed as being mosaic prior to their development into blastocysts (in the cleaved state), subsequently undergo autocorrection to the euploid state (normal numerical chromosomal configuration) as they develop to blastocysts in the Petri dish. This is one reason why “mosaicism” is more commonly detected in early embryos than in blastocysts. Embryos with segmental mosaic aneuploidies, i.e. the addition (duplication) or subtraction (deletion), are also more likely to autocorrect.  Finally, the lower the percentage of mitotically aneuploid (mosaic) cells in the blastocyst the greater the propensity for autocorrection and propagation of chromosomally normal (euploid) offspring. A blastocyst with <30% mosaicism could yield a 30% likelihood of a healthy baby rate with 10-15% miscarriage rate, while with >50% mosaicism the baby rate is roughly halved and the miscarriage rate double.

As stated, the transfer of embryos with autosomal meiotic trisomy, will invariably result in failed implantation, early miscarriage or the birth of a defective child. Those with autosomal mitotic (“mosaic”) trisomies, while having the ability to autocorrect in-utero and result in the birth of a healthy baby can, depending on the percentage of mosaic (mitotically aneuploid) cells present, the number of aneuploid chromosomes and the type of mosaicism (single or segmental) either autocorrect and propagate a normal baby, result in failed implantation, miscarry or cause a birth defect (especially with trisomies 13, 18 or 21). This is why when it comes to giving consideration to transferring trisomic embryos, suspected of being “mosaic”, I advise patients to undergo prenatal genetic testing once pregnant and to be willing to undergo termination of pregnancy in the event of the baby being affected. Conversely, when it comes to meiotic autosomal monosomy, there is almost no chance of a viable pregnancy. in most cases implantation will fail to occur and if it does, the pregnancy will with rare exceptions, miscarry. “Mosaic” (mitotically aneuploid) autosomally monosomic embryos where a chromosome is missing), can and often will “autocorrect” in-utero and propagate a viable pregnancy. It is for this reason that I readily recommend the transfer of such embryos, while still (for safety’s sake) advising prenatal genetic testing in the event that a pregnancy results.

What should be done with “mosaic embryos? While the ability to identify “mosaicism” through karyotyping of embryos has vastly improved, it is far from being absolutely reliable. In fact, I personally have witnessed a number of healthy/normal babies born after the transfer of aneuploid embryos, previously reported on as revealing no evidence of “mosaicism”.  However, the question arises as to which “mosaic” embryos are capable of autocorrecting in-utero and propagating viable pregnancies. Research suggests that that embryos with autosomal monosomy very rarely will propagate viable pregnancies. Thus, it is in my opinion virtually risk-free to transfer embryos with monosomies involving up to two (2) autosomes. The same applies to the transfer of trisomic embryos where up to 2 autosomes are involved. Only here, there is a risk of birth defects (e.g. trisomy 21/18, etc.) and any resulting pregnancies need to be carefully assessed and if needed/desired, be ended. Regardless, it is essential to make full disclosure to the patient (s), and to ensure the completion of a detailed informed consent agreement which would include a commitment by the patient (s) to undergo prenatal genetic testing (amniocentesis/CVS) 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. Blastocysts with aneuploidies involving > 2 autosomes  are complex abnormal and should in my opinion, be discarded.

I strongly recommend that you visit www.SherIVF.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.

• A Fresh Look at the Indications for IVF
• The IVF Journey: The importance of “Planning the Trip” Before Taking the Ride”
• Controlled Ovarian Stimulation (COS) for IVF: Selecting the ideal protocol
• IVF: Factors Affecting Egg/Embryo “competency” during Controlled Ovarian Stimulation(COS)
• The Fundamental Requirements For Achieving Optimal IVF Success
• Use of GnRH Antagonists (Ganirelix/Cetrotide/Orgalutron) in IVF-Ovarian Stimulation Protocols.
• Anti Mullerian Hormone (AMH) Measurement to Assess Ovarian Reserve and Design the Optimal Protocol for Controlled Ovarian Stimulation (COS) in IVF.
• Controlled Ovarian Stimulation (COS) in Older women and Women who have Diminished Ovarian Reserve (DOR): A Rational Basis for Selecting a Stimulation Protocol
• Optimizing Response to Ovarian Stimulation in Women with Compromised Ovarian Response to Ovarian Stimulation: A Personal Approach.
• Hereditary Clotting Defects (Thrombophilia)
• Blastocyst Embryo Transfers done 5-6 Days Following Fertilization are Fast Replacing Earlier day 2-3 Transfers of Cleaved Embryos.
• Embryo Transfer Procedure: The “Holy Grail in IVF.
• Timing of ET: Transferring Blastocysts on Day 5-6 Post-Fertilization, Rather Than on Day 2-3 as Cleaved Embryos.
• IVF: Approach to Selecting the Best Embryos for Transfer to the Uterus.
• Fresh versus Frozen Embryo Transfers (FET) Enhance IVF Outcome
• Frozen Embryo Transfer (FET): A Rational Approach to Hormonal Preparation and How new Methodology is Impacting IVF.
• Staggered IVF
• Staggered IVF with PGS- Selection of “Competent” Embryos Greatly Enhances the Utility & Efficiency of IVF.
• Staggered IVF: An Excellent Option When. Advancing Age and Diminished Ovarian Reserve (DOR) Reduces IVF Success Rate
• Embryo Banking/Stockpiling: Slows the “Biological Clock” and offers a Selective Alternative to IVF-Egg Donation
• Preimplantation Genetic Testing (PGS) in IVF: It should be Used Selectively and NOT be Routine.
• IVF: Selecting the Best Quality Embryos to Transfer
• Preimplantation Genetic Sampling (PGS) Using: Next Generation Gene Sequencing (NGS): Method of Choice.
• PGS and Assessment of Egg/Embryo “competency”: How Method, Timing and Methodology Could Affect Reliability
• IVF outcome: How Does Advancing Age and Diminished Ovarian Reserve (DOR) Affect Egg/Embryo “Competency” and How Should the Problem be addressed.

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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). 

__________________________________________________________________________________________\

ADDITIONAL INFORMATION:

I am attaching online links to two E-books which I recently  co-authored with  my partner at SFS-NY  (Drew Tortoriello MD)……. for your reading pleasure:

1.From In Vitro Fertilization to Family: A Journey with Sher Fertility Solutions (SFS) “

http://sherfertilitysolutions.com/sher-fertility-solutions-ebook.pdf

1. “Recurrent Pregnancy Loss and Unexplained IVF Failure: The Immunologic Link

https://drive.google.com/file/d/1iYKz-EkAjMqwMa1ZcufIloRdxnAfDH8L/view

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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).

1. 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.

1. 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:

1. A“ thin uterine lining”
2. A uterus with surface lesions in the cavity (polyps, fibroids, scar tissue)
3. Immunologic implantation dysfunction (IID)
4. Endocrine/molecular endometrial receptivity issues
5. 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 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

______________________________________________________________________

ADDITIONAL INFORMATION:

I am attaching online links to two E-books which I recently  co-authored with  my partner at SFS-NY  (Drew Tortoriello MD)……. for your reading pleasure:

1.From In Vitro Fertilization to Family: A Journey with Sher Fertility Solutions (SFS) “

http://sherfertilitysolutions.com/sher-fertility-solutions-ebook.pdf

1. “Recurrent Pregnancy Loss and Unexplained IVF Failure: The Immunologic Link

https://drive.google.com/file/d/1iYKz-EkAjMqwMa1ZcufIloRdxnAfDH8L/view

………………………………………………………………..

It is primarily the egg (rather than the sperm) that determines the chromosomal integrity (karyotype) of the embryo, the most important determinant of egg/embryo competency”. A “competent” egg is therefore one that has a normal karyotype and has the best potential to propagate a “competent” embryo. In turn, a “competent embryo is one that possesses the highest potential to implant and develop into a normal, healthy, baby.

When it comes to reproductive performance, humans are the least efficient of all mammals. Even in young women under 35y, at best only 2 out of 3 eggs are chromosomally numerically normal (euploid). The remainder will have an irregular number of chromosomes (aneuploid) and are thus “incompetent”. The incidence of egg aneuploidy increases with age such by age 39 years, 3 in 4 are “competent”, and by the mid-forties, at best one in 10 are likely to be aneuploid. The fertilization of an aneuploid egg will inevitably lead to embryo aneuploidy (“incompetence”). As previously stated,   an aneuploid embryo cannot propagate a normal pregnancy

Within 38-42 hours of the initiation of the spontaneous pre-ovulatory luteinizing hormone (LH) surge (and also following administration of the human chorionic gonadotropin (hCG) “trigger” shot, given to induce egg maturation after ovarian stimulation with fertility drugs), the egg embarks on a rapid maturational process that involves halving of its 46 chromosomes to 23. During this process, (known as meiosis) 23 chromosomes are retained within the nucleus of the egg while the remaining 23 chromosomes are expelled in a membrane envelopment, from the egg nucleus. This small structure known as the polar body, comes to lie immediately below the “shell” of the egg (the zona pellucida) and is known as the 1st polar body or PB-1. The sperm, in the process of its maturation also undergoes meiosis divides into two separate functional gametes, each containing 23 chromosomes (half its original number of 46 chromosomes).  With subsequent fertilization, the 23 chromosomes of the egg now fuse with the 23 chromosomes of the mature sperm resulting in the development of an embryo with  46 chromosomes (the normal human genome) comprising a combination of the genetic material from both partners. For the embryo to have exactly 46 chromosomes (the euploid number), both the mature egg and mature spermatozoon must contain exactly 23 chromosomes. Only such euploid embryos are “competent” (capable of developing into healthy babies). Those with an irregular number of chromosomes (aneuploid embryos) are “incompetent” and are incapable of propagating healthy babies. While embryo “incompetence” can result from either egg or sperm aneuploidy, it usually stems from egg aneuploidy. However, in cases of moderate or severe male factor infertility, the sperm’s contribution to aneuploidy of the embryo can be significantly greater.

While embryo ploidy (numerical chromosomal integrity) is not the only determinant of its “competency, it is by far the most important and in fact is a rate-limiting factor in human reproduction. It is causal in the vast majority of cases of “failed nidation which in turn is responsible for most cases of a failed pregnancy (natural or assisted) and causes most sporadic early pregnancy losses (both chemical gestations and miscarriages) as well as  many chromosomal birth defects such as Turner syndrome (X-monosomy ) Down syndrome (trisomy 21) and Edward syndrome (trisomy 18) .

In most cases, embryos that develop too slowly as well as those that grow too fast (i.e. ones that by day 3 post-fertilization comprise fewer than 6 cells or more than 9 cells) and/or embryos that contain cell debris or “fragments” are usually aneuploid and are thus unable to propagate a healthy pregnancy (“incompetent”). Additionally, embryos that fail to survive in culture to the blastocyst stage are also almost always aneuploid/”incompetent”.

At a certain point in the later stage of a woman’s reproductive career, the number of remaining eggs in her ovaries falls below a certain threshold, upon which she is unable to respond optimally to fertility drugs. Often times this is signaled by a rising day 3 basal blood follicle stimulating hormone (FSH) level (>9.0MIU/ml) and a falling blood anti-Mullerian hormone (AMH) level (<2.0ng/ml or <15nmol/L). Such women who have  diminished ovarian reserve (DOR) produce fewer eggs in response to ovarian stimulation. While DOR is most commonly encountered in women over 40 years of age it can and indeed also can occur in much younger women.

A few important (but often overlooked concepts should be considered in this regard:

• Age: It is advancing chronologic age and NOT declining ovarian reserve (as evidenced by abnormal blood AMH or FSH that results in an increased incidence of egg/embryo “incompetence” due to aneuploidy
• The ovaries and developing eggs of women with DOR (regardless of age) are highly susceptible to the adverse effect of excessive Luteinizing Hormone (LH)-induced, ovarian overproduction of male hormones (e,g. testosterone and androstenedione). While a little testosterone produced by the ovary promotes normal follicle growth and orderly egg development excessive testosterone has a converse effect. That is why in older women and those who regardless of their age have DOR (and thus excessive LH bioavailability and increased ovarian testosterone production), the use of ovarian stimulation protocols that fail to down-regulate LH activity prior to initiating ovarian stimulation with gonadotropins, often prejudices egg/embryo quality and IVF outcome.
• Simply stated, while age is certainly the most important factor in determining the incidence of egg/embryo aneuploidy, women with DOR (regardless of their age), are less likely to propagate euploid (competent) eggs/embryos. While virtually nothing can be done to lower the incidence of age related aneuploidy, it is indeed possible to avoid a further decrease in egg/embryo “competency”  by individualizing the protocols of ovarian stimulation used.
• My preferred protocols for women who have relatively normal ovarian reserve:
• The conventional long pituitary down regulation protocol: BCP are commenced early in the cycle and continued for at least 10 days. Starting 3 days before the BCP is to be discontinued, it is overlapped with an agonist such as Lupron 10U daily for three (3) days and continued until menstruation begins (which should ensue within 5-7 days of stopping the BCP). At that point an US examination is done along with a baseline measurement of blood estradiol to exclude a functional ovarian cyst. Daily Lupron (10U) is continued and an FSH-dominant gonadotropin such as Follistim, Puregon or Gonal-f daily is administered daily falong with 37.5U of Menopur (an FSH/LH combination) for 2 days. On the 3^rd day the gonadotropin dosage is reduced by about one half and the dosage of Menopur is increased to 75U daily. Daily ultrasound and blood estradiol measurements are conducted starting on the 7^th or 8^th day of gonadotropin administration and continued until daily ultrasound follicle assessments indicate that most follicles have fully developed. At this point egg maturation is “triggered” using an intramuscular injection of a recombinant hCGr (Ovidrel) 500mcg or urinary derived hCGu (Pregnyl/Profasi/Novarel) 10,000U. And an egg retrieval is scheduled for 36h later.
• The agonist/antagonist conversion protocol (A/ACP): This is essentially the same as the conventional long down regulation protocol (see “a”-as above), except that with the onset of post-BCP menstruation, the agonist is supplanted by daily administration of a GnRH antagonist (e.g. Ganirelix, Cetrotide or Orgalutron) at a dosage of 125-250mcg daily until the day of the “trigger”. When it comes to women who have DOR I favor the use of the A/ACP, adding supplementary human growth hormone (HGH). In cases where the DOR is regarded as severe (AMH=<0.2), I often augment  the AACP protocol by using estrogen priming for 7-9 days prior to or with the commencement of gonadotropin therapy; For this I prescribe E2 skin patches  or intramuscular  estradiol valerate (Delestrogen), prior to or sometimes concurrent with, the  commencement of the GnRH antagonist administration.
• The following Ovarian stimulation protocols are in my opinion best avoided in stimulating olderf women and /or thosed who regardless of age , have  DOR :

1. Microdose agonist (e.g. Lupron) “flare” protocols which result in an out-pouring of pituitary-LH at the critical time that ovarian follicles and eggs start developing/growing.
2. High dosages of LH -containing fertility drugs (e.g. Menopur).
3. Supplementation with preparations that are testosterone-based
4. Supplementation with DHEA (which is converted to testosterone in the ovaries.
5. Clomiphene citrate or Letrozole which cause increased release of LH and thus increase ovarian male hormone (testosterone and androstenedione output.
6. “Triggering” egg maturation using too low a dosage of hCG (e.g. 5,000U rather than 10,000U) or Ovidrel (e.g. 250mcg of Ovidrel rather than 500mcg)
7. “Triggering” women who have DOR, with an agonist (alone)such as Lupron Superfact/ Buserelin/Aminopeptidyl/Decapeptyl.

• Preimplantation Genetic Screening (PGS):

The introduction of preimplantation genetic testing/screening (PGT/PGS) for e permits identification of all the chromosomes in the egg and embryo (full karyotyping) allowing for the  identification of the most “competent” (euploid) embryos for selective transfer to the uterus. This vastly improves the efficiency and success of the IVF process and renders us fare better equipped us to manage older women and those who regardless of their age, have DOR.

Please visit my new Blog on this very site, www. SherIVF.com, 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
• 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 Approach
• Anti Mullerian Hormone (AMH) Measurement to Assess Ovarian Reserve and Design the Optimal Protocol for Controlled Ovarian Stimulation (COS) in IVF.
• The “Biological Clock” and how it should Influence the Selection and Design of Ovarian Stimulation Protocols for IVF.
• A Rational Basis for selecting Controlled Ovarian Stimulation (COS) protocols in women with Diminished Ovarian Reserve (DOR)
• Diagnosing and Treating Infertility due to Diminished Ovarian Reserve (DOR)
• Controlled Ovarian Stimulation (COS) in Older women and Women who have Diminished Ovarian Reserve (DOR): A Rational Basis for Selecting a Stimulation Protocol
• 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
• Frozen Embryo Transfer (FET) versus “Fresh” ET: How to Make the Decision
• Frozen Embryo Transfer (FET): A Rational Approach to Hormonal Preparation and How new Methodology is Impacting IVF.
• Staggered IVF: An Excellent Option When. Advancing Age and Diminished Ovarian Reserve (DOR) Reduces IVF Success Rate
• Embryo Banking/Stockpiling: Slows the “Biological Clock” and offers a Selective Alternative to IVF-Egg Donation.
• Preimplantation Genetic Testing (PGS) in IVF: It Should be Used Selectively and NOT be Routine.
• Preimplantation Genetic Sampling (PGS) Using: Next Generation Gene Sequencing (NGS): Method of Choice.
• PGS in IVF: Are Some Chromosomally Abnormal Embryos Capable of Resulting in Normal Babies and Being Wrongly Discarded?
• PGS and Assessment of Egg/Embryo “competency”: How Method, Timing and Methodology Could Affect Reliability
• 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
• Premature Luteinization (“the premature LH surge): Why it happens and how it can be prevented.
• IVF Egg Donation: A Comprehensive Overview

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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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ADDITIONAL INFORMATION:

I am attaching online links to two E-books which I recently  co-authored with  my partner at SFS-NY  (Drew Tortoriello MD)……. for your reading pleasure:

1.From In Vitro Fertilization to Family: A Journey with Sher Fertility Solutions (SFS) “

http://sherfertilitysolutions.com/sher-fertility-solutions-ebook.pdf

1. “Recurrent Pregnancy Loss and Unexplained IVF Failure: The Immunologic Link

https://drive.google.com/file/d/1iYKz-EkAjMqwMa1ZcufIloRdxnAfDH8L/view

………………………………………………………………..

I doubt this is a “molar’ pregnancy but it could be a “multiple gestation”.

Measuring and interpreting Blood hCG to Assess Pregnancy Viability Following ART Treatments.

Geoffrey Sher MD

I know of no medical announcement associated with the degree of emotional anticipation and anguish as that associated with a pending diagnosis/confirmation of pregnancy following infertility treatment. In fact, hardly a day goes by where I am not confronted by a patient anxiously seeking interpretation of a pregnancy test result.

Testing urine or blood for the presence of human chorionic gonadotropin (hCG) is the most effective and reliable way to confirm conception. The former, is far less expensive than the latter and is the most common method used. It is also more convenient because it can be performed in the convenience of the home setting. However, urine hCG testing for pregnancy is not nearly as reliable or as sensitive e as is blood hCG testing. Blood testing can detect implantation several days earlier than can a urine test. Modern pregnancy urine test kits can detect hCG about 16-18 days following ovulation (or 2-3 days after having missed a menstrual period), while blood tests can detect hCG, 12-13 days post-ovulation (i.e. even prior to menstruation).

The ability to detect hCG in the blood as early as possible and thereupon to track its increase, is particularly valuable in women undergoing controlled ovarian stimulation (COS) with or without intrauterine insemination (IUI) or after IVF. The earlier hCG can be detected in the blood and its concentration measured, the sooner levels can be tracked serially over time and so provide valuable information about the effectiveness of implantation, and the potential viability of the developing conceptus.

There are a few important points that should be considered when it comes to measuring interpreting blood hCG levels. These include the following:

• All modern day blood (and urine) hCG tests are highly specific in that they measure exclusively for hCG. There is in fact no cross-reactivity with other hormones such as estrogen, progesterone or LH.
• Post conception hCG levels, measured 10 days post ovulation or egg retrieval can vary widely (ranging from 5mIU/ml to above 400mIU/ml. The level will double every 48–72 hours up to the 6th week of gestation whereupon the doubling rate starts to slow down to about 96 hours. An hCG level of 13,000-290, 0000 mIU/ml is reached by the end of the 1st trimester (12 weeks) whereupon it slowly declines to approximately 26,000– 300,000 mIU/ml by full term. Below are the average hCG levels during the first trimester:

• • 3 weeks LMP: 5 – 50 mIU/ml
  • 4 weeks LMP: 5 – 426 mIU/ml
  • 5 weeks LMP: 18 – 7,340 mIU/ml
  • 6 weeks LMP: 1,080 – 56,500 mIU/ml
  • 7 – 8 weeks LMP: 7, 650 – 229,000 mIU/ml
  • 9 – 12 weeks LMP: 25,700 – 288,000 mIU/ml

• A single hCG blood level is not sufficient to assess the viability of an implanting embryo. Caution should be used in making too much of an initial hCG level. This is because a normal pregnancy can start with relatively low hCG blood levels. It is the rate of the rise of the blood hCG level that is relevant.
• In some cases the initially hCG level is within the normal range, but then fails to double in the ensuing 48-72hours. In some cases it might even plateau or decline, only to start doubling appropriately thereafter. When this happens, it could be due to:
  • A recovering implantation, destined to develop into a clinical gestation
  • A failing implantation (a chemical pregnancy)
  • A multiple pregnancy which is spontaneously reducing (i.e., one or more of the concepti is being lost) or,
  • An ectopic pregnancy which will either absorb spontaneously (a chemical-tubal gestation), or evolve into a full blown tubal pregnancy continue and declare itself through characteristic symptoms and signs of an intraperitoneal bleed.
• The blood hCG test needs to be repeated at least once after 48h and in some cases it will need to be repeated one or more times (at 48h intervals) thereafter, to confirm that implantation is progressing normally.
• Ultimately the diagnosis of a viable pregnancy requires confirmation of the presence of an intrauterine gestational sac by ultrasound examination. The earliest that this can be achieved is when the beta hCG level exceeds 1,000mIU/ml (i.e., around 5-6 weeks).
• Most physicians prefer to defer the performance of a routine US diagnosis of pregnancy until closer to the 7th week. This is because by that time, cardiac activity should be clearly detectable, allowing for more reliable assessment of pregnancy viability.
• There are cases where the blood beta hCG level is extraordinarily high or the rate of rise is well above the normal doubling rate. The commonest explanation is that more than one pregnancy has implanted. However in some cases it can point to a molar pregnancy
• Finally, there on rare occasions, conditions unrelated to pregnancy can result in detectable hCG levels in blood and urine. They include ovarian tumors that produce hCG, such as certain types of cystic teratomas (dermoid cysts) and some ovarian cancers such as dysgerminomas.

Geoff Sher

________________________________________________________________

ADDITIONAL INFORMATION:

I am attaching online links to two E-books which I recently  co-authored with  my partner at SFS-NY  (Drew Tortoriello MD)……. for your reading pleasure:

1.From In Vitro Fertilization to Family: A Journey with Sher Fertility Solutions (SFS) “

http://sherfertilitysolutions.com/sher-fertility-solutions-ebook.pdf

1. “Recurrent Pregnancy Loss and Unexplained IVF Failure: The Immunologic Link

https://drive.google.com/file/d/1iYKz-EkAjMqwMa1ZcufIloRdxnAfDH8L/view

………………………………………………………………..

There are only t 4 Reproductive Immunology Labs in the US that in my opinion, can do the immune tests adequately. If these were not used, the results are probably erroneous.

Implantation dysfunction is unfortunately often overlooked as an important cause of IVF failure. This is especially relevant in cases of unexplained IVF failure, recurrent pregnancy loss (RPL), and in women with underlying endo-uterine surface lesions, thickness of the uterine lining (endometrium) and /or immunologic factors.

IVF success rates have been improving over the last decade. The average live birth rate per embryo transfer in the U.S.A for women under 40y using their own eggs is currently better than 1:3 women. However, there is still a wide variation from program to program for IVF live birth rates, ranging from 20% to near 50%. Based upon these statistics, most women undergoing IVF in the United States require two or more attempts to have a baby. IVF practitioners in the United States commonly attribute the wide dichotomy in IVF success rates to variability in expertise of the various embryology laboratories. This is far from accurate. In fact, other factors such as wide variations in patient selection and the failure to develop individualized protocols for ovarian stimulation or to address those infectious, anatomical, and immunologic factors that influence embryo implantation are at least equally important.

About 80% of IVF failures are due to “embryo incompetency” that is largely due to aneuploidy      usually related to advancing age of the woman and is further influenced by other factors such as the protocol selected for ovarian stimulation, diminished ovarian reserve (DOR), and severe male factor infertility. However, in about 20% of dysfunctional cases embryo implantation is the cause of failure.

This section will focus on implantation dysfunction and IVF failure due to:

ANATOMICAL ENDO-UTERINE SURFACE LESIONS

            It has long been suspected that anatomical defects of the uterus might result in infertility. While the presence of uterine fibroids, in general, are unlikely to cause infertility, an association between their presence and infertility has been observed in cases where the myomas distort the uterine cavity or protrude through the endometrial lining.  Even small fibroids that lie immediately under the endometrium (submucous fibroids) and protrude into the uterine cavity have the potential to lower embryo implantation.  Multiple fibroids in the uterine wall (intramural fibroids) that encroach upon the uterine cavity can sometimes so compromise blood flow that estrogen delivery is impaired, and the endometrium is unable to thicken properly. This can usually be diagnosed by ultrasound examination during the proliferative phase of the menstrual cycle.  It is likely that any surface lesion in the uterine cavity, whether submucous fibroids, intrauterine adhesions a small endometrial or a placental polyp, has the potential to interfere with implantation by producing a local inflammatory response, not too dissimilar in nature from that which is caused by an intrauterine contraceptive device (IUD).       

            Clearly, since even small uterine lesions have the potential to adversely affect implantation, the high cost (financial, physical, and emotional) associated with IVF and related procedures, justifies the routine performance of diagnostic procedures such as an HSG, hysterosonogram (fluid ultrasound examination), or hysteroscopy prior to initiating IVF.  Identifiable uterine lesions that have the potential of impairing implantation usually require surgical intervention.  In most cases, dilatation and curettage (D & C) or hysteroscopic resection will suffice. Some cases might require the performance of a laparotomy.  Such intervention will often result in subsequent improvement of the endometrial response.      

Sonohysterography [Fluid ultrasonography (FUS)]: Fluid ultrasonography is a procedure whereby a sterile solution of saline is injected via a catheter through the cervix and into the uterine cavity. The fluid-distended cavity is examined by vaginal ultrasound for any irregularities that might point to surface lesions such as polyps, fibroid tumors, scarring, or a uterine septum. If performed by an expert, a FUS is highly effective in recognizing even the smallest lesion and can replace hysteroscopy under such circumstances. FUS is less expensive, less traumatic, and equally as effective as hysteroscopy. The only disadvantage lies in the fact that if a lesion is detected, it may require the subsequent performance of hysteroscopy to treat the problem anyway.

Hysteroscopy: Diagnostic hysteroscopy is an office procedure that is performed under intravenous sedation, general anesthesia, or paracervical block with minimal discomfort to the patient. This procedure involves the insertion of a thin, lighted, telescope like instrument known as a hysteroscope through the vagina and cervix into the uterus to fully examine the uterine cavity. The uterus is first distended with normal saline, which is passed through a sleeve adjacent to the hysteroscope. As is the case with FUS, diagnostic hysteroscopy facilitates examination of the inside of the uterus under direct vision for defects that might interfere with implantation. We have observed that approximately one in eight candidates for IVF have lesions that require attention prior to undergoing IVF in order to optimize the chances of a successful outcome. We strongly recommend that all patients undergo therapeutic surgery (usually by hysteroscopy) to correct the pathology prior to IVF.  Depending on the severity and nature of the pathology, therapeutic hysteroscopy may require general anesthesia and, in such cases, should be performed in an outpatient surgical facility or conventional operating room where facilities are available for laparotomy, a procedure in which an incision is made in the abdomen to expose the abdominal contents for diagnosis, or for surgery should this be required.       

THICKNESS OF THE UTERINE LINING (ENDOMETRIUM):

As far back as in 1989 we first reported on the finding that ultrasound assessment of the late proliferative phase endometrium can identify those candidates who are least likely to conceive. We noted that the ideal thickness of the endometrium at the time of ovulation or egg retrieval is >8 mm and that thinner linings are associated with decreased implantation rates.

More than 30 years ago we first showed that in normal and “stimulated” cycles, pre-ovulatory endometrial thickness and ultrasound appearance is predictive of embryo implantation (pregnancy) potential following ET. With conventional IVF and with FET, endometrial lining at the time of the “trigger shot” or with the initiation of progesterone needs to preferably be at least 8 mm in sagittal thickness with a triple line (trilaminar) appearance. Anything less than an 8mm endometrial thickness       is associated with a reduction in live birth rate per ET. An 8-9mm thickness represents a transitional measurement…a “gray zone”.  Hitherto, attempts to augment endometrial growth in women with poor endometrial linings by bolstering circulating estrogen blood levels (through the administration of increased doses of fertility drugs, aspirin administration and by supplementary estrogen therapy) yielded disappointing results.

            A “poor” uterine lining is usually the result of the innermost layer of endometrium (the basal or germinal endometrium from which endometrium grows) not being able to respond to estrogen by propagating an outer, “functional” layer thick enough to support optimal embryo implantation and development of a healthy placenta (placentation). The “functional” layer ultimately comprises 2/3 of the full endometrial thickness and is the layer that sheds with menstruation if no pregnancy occurs.

The main causes of a “poor” uterine lining are:

• Damage to the basal endometrium because of:
• Inflammation of the endometrium (endometritis) most commonly resulting from infected products left over following abortion, miscarriage, or birth
• Surgical trauma due to traumatic uterine scraping, (i.e. due to an over-aggressive D & C)
• Insensitivity of the basal endometrium to estrogen due to:
• Prolonged, over-use/misuse of clomiphene citrate
• Prenatal exposure to diethylstilbestrol (DES). This is a drug that was given to pregnant women in the 1960’s to help prevent miscarriage
• Over-exposure of the uterine lining to ovarian male hormones (mainly testosterone): Older women, women with diminished ovarian reserve (poor responders) and women with polycystic ovarian syndrome -PCOS tend to have raised LH biological activity. This causes the connective tissue in the ovary (stroma/theca) to overproduce testosterone. The effect may be further exaggerated when certain methods for ovarian stimulation such as “flare” protocols and high dosages of Menopur are used in such cases.
• Reduced blood flow to the basal endometrium: Examples include.
• Multiple uterine fibroids – especially when these are present under the endometrium (submucosal)
• Uterine adenomyosis (excessive, abnormal invasion of the uterine muscle by endometrial glands).

Vaginal Viagra: About 35 years ago, after reporting on the benefit of administering vaginal Sildenafil (Viagra) to women who had implantation dysfunction due to thin endometrial linings we announced the birth of the world’s first “Viagra baby.”  Viagra administered vaginally, but not orally, in affected women improves uterine blood flow causing more estrogen to be delivered to the basal endometrium and increasing the endometrial thickening.  Following vaginal administration, Viagra is rapidly absorbed and quickly reaches the uterine blood system in high concentrations. Thereupon it dilutes out as it is absorbed into the systemic circulation. This probably explains why treatment is virtually devoid of systemic side effects.  It is important to recognize that Viagra will NOT be effective in improving endometrial thickness in all cases. In fact, about one third of women treated fail to show any improvement. This is because in certain cases of thin uterine linings, the basal endometrium will have been permanently damaged and left unresponsive to estrogen. This happens in cases of severe endometrial damage due mainly to post-pregnancy endometritis (inflammation), chronic granulomatous inflammation due to uterine tuberculosis (hardly ever seen in the United States) and following extensive surgical injury to the basal endometrium (as sometimes occurs following over-zealous D&C’s).

• Immunologic factors: These also play a role in IVF failure (see “Immunologic factors and Implantation” …see below.

IMMUNOLOGIC IMPLANTATION DYSFUNCTION (IID)

            Currently, with few exceptions, practitioners of assisted reproduction tend to attribute “unexplained and/or repeated” IVF failure(s), almost exclusively to poor embryo quality, advocating adjusted protocols for ovarian stimulation and/or gamete and embryo preparation as a potential remedy. The idea, having failed IVF, that all it takes to ultimately succeed is to keep trying the same recipe is over-simplistic.

            The implantation process begins six or seven days after fertilization of the egg. At this time, specialized embryonic cells (i.e., trophoblasts), that later become the placenta begin growing into the uterine lining. When the trophoblast and the uterine lining meet, they, along with immune cells in the lining, become involved in a “cross talk” through mutual exchange of hormone-like substances called cytokines. Because of this complex immunologic interplay, the uterus can foster the embryo’s successful growth. Thus, from the earliest stage, the trophoblast establishes the very foundation for the nutritional, hormonal and respiratory interchange between mother and baby.  In this manner, the interactive process of implantation is not only central to survival in early pregnancy but also to the quality of life after birth.

There is an ever growing realization, recognition, and acceptance of the fact that uterine immunologic dysfunction can lead to immunologic implantation dysfunction (IID) with “unexplained” infertility, IVF failure, and recurrent pregnancy loss (RPL).

DIAGNOSIS 

Because immunologic problems may lead to implantation failure, it is important to properly evaluate women with risk factors such as:

• Unexplained or recurrent IVF failures
• Unexplained infertility or a family history of autoimmune diseases (e.g., rheumatoid arthritis, lupus erythematosus and hypothyroidism).
• Recurrent Pregnancy Loss (RPL)
• Endometriosis
• A personal or family history of autoimmune conditions, e.g., Rheumatoid Arthritis, Lupus erythematosus, autoimmune hypothyroidism (Hashimoto’s disease) etc.

            Considering its importance, it is not surprising that the failure of a properly functioning immunologic interaction during implantation has been implicated as a cause of recurrent miscarriage, late pregnancy fetal loss, IVF failure and infertility. A partial list of immunologic factors that may be involved in these situations includes:

• Antiphospholipid antibodies (APA)
• Antithyroid antibodies (ATA/AMA)
• Activated natural killer cells (NKa)

ACTIVATED NATURAL KILLER CELLS (NKa):

Following ovulation and during early pregnancy, NK cells and T-cells comprise more than 80% of the lymphocyte-immune cells that frequent the uterine lining. These lymphocytes (white blood cells) journey from the bone marrow to the uterus and under hormonal regulation, proliferate there. After exposure to progesterone (due to induced /spontaneous exogenous administration), they begin to produce TH-1 and TH-2 cytokines. TH-2 cytokines are humoral in nature and induce the trophoblast (“root system of the embryo”) to permeate the uterine lining while TH-I cytokines induce a process referred to as apoptosis (cell suicide) thereby confining placental development to the inner part of the uterus. Optimal placental development (placentation) mandates that there be a balance between TH1 and TH-2 cytokines. Most of the cytokine production originates from NK cells (rather than from cytotoxic T-cells/Lymphocytes (CTL)). Excessive production/release of TH-1 cytokines, is toxic to the trophoblast and to endometrial cells, leading to programmed death/suicide (apoptosis) and subsequently to IID.

Functional NK cells reach a maximal concentration in the endometrium by about t day 6-7 days after exposure to progesterone …. This timing corresponds with when the embryo implants into the uterine lining (endometrium).

It is important to bear in mind that measurement of the concentration of blood NK cells has little or no relevance when it comes to assessing NK cell activation (NKa). Rather, it is the NK cell activation that matters. In fact, there are certain conditions (such as with endometriosis) where the NK cell blood concentration is below normal, but NK cell activation is markedly increased.

There are several methods by which NK cell activation (cytotoxicity) can be assessed in the laboratory. Methods such as immunohistochemical assessment of uterine NK cells and/or through measurement of uterine or blood TH-1 cytokines. However, the K-562 target cell blood test still remains the gold standard. With this test, NK cells, isolated from the woman’s blood using Flow Cytometry are incubated in the presence of specific “target cells”. The percentage (%) of “target cells” killed is then quantified. More than 12% killing suggests a level of NK cell activation that usually requires treatment.

Currently, there are less than a half dozen Reproductive Immunology Reference Laboratories in the U.S.A that are capable of performing the K-562 target cell test reliably.

There exists a pervasive but blatant misconception on the part of many, that the addition of IL or IVIg to a concentration of NK cells could have an immediate down-regulatory effect on NK cell activity. Neither IVIg nor IL is capable of significantly suppressing already activated “functional NK cells”. They are believed to work through “regulating” NK cell progenitors which only thereupon will start to propagate down-regulated NK cells. Thus, testing for a therapeutic effect would require that the IL/IVIg infusion be done about 14 days prior to ovulation or progesterone administration…  in order to allow for a sufficient number of normal (non-activated) “functional” NK cell” to be present at the implantation site when the embryos are transferred.

Failure to recognize this reality has, in our opinion, established an erroneous demand by practicing IVF doctors, that Reproductive Immunology Reference Laboratories report on NK cell activity before and again, immediately following laboratory exposure to IVIg and/or IL in different concentrations. Allegedly, this is to allow the treating physician to report back to their patient(s) on whether an IL or IVIG infusion will be effective in downregulating their Nka.  But, since already activated NK cells (NKa) cannot be deactivated in the laboratory, effective NKa down-regulation can only be adequately accomplished through deactivation of NK cell “progenitors /parental” NK cells in order to allow them thereupon, to s propagate normal “functional” NK cells and his takes about 10-14 days, such practice would be of little clinical benefit. This is because even if blood were to be drawn 10 -14 days after IL/IVIg treatment it would require at least an additional 10 -14days to receive results from the laboratory, by which time it would be far too late to be of practical advantage.

ANTIPHOSPHOLIPID ANTIBODIES:

 Many women who experience “unexplained” IVF failure, women with RPL, those with a personal or family history of autoimmune diseases such as lupus erythematosus, rheumatoid arthritis, scleroderma, and dermatomyositis (etc.)  as well as women who have endometriosis (“silent” or overt) test positive for APAs. More than 30 years ago, we were the first to propose that women who test positive for APA’s be treated with a mini-dose heparin to improve IVF implantation and thus birth rates. This approach was based upon research that suggested that heparin repels APAs from the surface of the trophoblast (the embryo’s “root system) thereby reducing its ant-implantation effects.  We subsequently demonstrated that such therapy only improved IVF outcome in women whose APAs were directed against two specific IgG and/or IgM phospholipids [i.e., phosphatidylethanolamine (PE) and phosphatidylserine (PS)].  More recently low dosage heparin therapy has been supplanted using longer acting low molecular weight heparinoids such as Lovenox and Clexane.   It is very possible that APAs alone do not cause IID but that their presence might help to identify a population at risk due to concomitant activation of uterine natural killer cells (Nka) which through excessive TH-1 cytokine production causes in IID: This is supported by the following observations:

• The presence of female APAs in cases of male factor cases appears to bear no relationship to IID.
• Only APA positive women who also test positive for abnormal NK activity appear to benefit from selective immunotherapy with intralipid/IVIg/ steroids.
• Most APA positive women who have increased NK cell activity also harbor IgG or IgM phosphatidylethanolamine (PE) and phosphatidylserine (PS) antibodies.

ANTITHYROID ANTIBODIES: (ATA).

 A clear relationship has been established between ATA and reproductive failure (especially recurrent miscarriage and infertility).

Between 2% and 5% of women of the childbearing age have reduced thyroid hormone activity (hypothyroidism). Women with hypothyroidism often manifest with reproductive failure i.e., infertility, unexplained (often repeated) IVF failure, or recurrent pregnancy loss (RPL). The condition is 5-10 times more common in women than in men. In most cases hypothyroidism is caused by damage to the thyroid gland resulting from of thyroid autoimmunity (Hashimoto’s disease) caused by damage done to the thyroid gland by antithyroglobulin and antimicrosomal auto-antibodies. 

The increased prevalence of hypothyroidism and thyroid autoimmunity (TAI) in women is likely the result of a combination of genetic factors, estrogen-related effects, and chromosome X abnormalities.  This having been said, there is significantly increased incidence of thyroid antibodies in non-pregnant women with a history of infertility and recurrent pregnancy loss and thyroid antibodies ^can be present asymptomatically in women without them manifesting with overt clinical or endocrinologic evidence of thyroid disease. In addition, these antibodies may persist in women who have suffered from hyper- or hypothyroidism even after normalization of their thyroid function by appropriate pharmacological treatment. The manifestations of reproductive dysfunction thus seem to be linked more to the presence of thyroid autoimmunity (TAI) than to clinical existence of hypothyroidism and treatment of the latter does not routinely result in a subsequent improvement in reproductive performance.

It follows, that if antithyroid autoantibodies are associated with reproductive dysfunction they may serve as useful markers for predicting poor outcome in patients undergoing assisted reproductive technologies.

Some years back, I reported on the fact that 47% of women who harbor thyroid autoantibodies, regardless of the absence or presence of clinical hypothyroidism, have activated uterine natural killer cells (NKa) cells and cytotoxic lymphocytes (CTL) and that such women often present with reproductive dysfunction. We demonstrated that appropriate immunotherapy with IVIG or intralipid (IL) and steroids, subsequently often results in a significant improvement in reproductive performance in such cases.

The fact that almost 50% of women who harbor antithyroid antibodies do not have activated CTL/NK cells suggests that it is NOT the antithyroid antibodies themselves that cause reproductive dysfunction. The activation of CTL and NK cells that occurs in half of the cases with TAI is probably an epiphenomenon with the associated reproductive dysfunction being due to CTL/NK cell activation that damages the early “root system” (trophoblast) of the implanting embryo. We have shown that treatment of those women who have thyroid antibodies + NKa/CTL using IL/steroids, improves subsequent reproductive performance while women with thyroid antibodies who do not harbor NKa/CTL do not require or benefit from such treatment

TEATMENT OF IID:

The mainstay of treatment involves the selective use of:

• Intralipid (IL) infusion
• IVIg therapy
• Corticosteroids (Prednisone/dexamethasone)
• Heparinoids (Lovenox/Clexane)

Intralipid (IL) Therapy:  IL is a suspension of soybean lipid droplets in water and is primarily used as source of parenteral nutrition. When administered intravenously, IL provides essential fatty acids, linoleic acid (LA), an omega-6 fatty acid, and alpha-linolenic acid (ALA), an omega-3 fatty acid.     

It is thought that fatty acids within the emulsion serve as ligands that activate peroxisome proliferator-activated receptors (PPARs) expressed by the NK cells. This is believed to decrease NK cell cytotoxic activity, and thereby enhance implantation A growing number of IVF programs, including ours, perform egg retrieval under conscious sedation using Propofol, a short acting hypnotic agent.

            Whatever the exact mechanism of action might be, Intralipid acts primarily to suppress NK cell over-production of TH-I cytokines. It 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, prednisolone and prednisone which augment immune modulation of T cells. The combined effect of IL + steroid therapy suppresses pro-inflammatory cellular TH1 cytokines such as interferon gamma and TNF-alpha that are produced in excess by activated NK cells and cytotoxic lymphocytes/T-cells (CTL).   IL will, in about 80% of cases, successfully down-regulate activated natural killer cells (NKa) over a period of 2-3 weeks. It is likely to be just as effective as IVIg in this respect but at a fraction of the cost and with a far lower incidence of side-effects. Its effect lasts for ~ 4-6 weeks when administered in early pregnancy.

Intralipid is a suspension of soybean lipid droplets in water and is primarily used as source of parenteral nutrition. When administered intravenously, IL provides essential fatty acids, linoleic acid (LA), an omega-6 fatty acid, and alpha-linolenic acid (ALA), an omega-3 fatty acid.     

It is thought that fatty acids within the emulsion serve as ligands that activate peroxisome proliferator-activated receptors (PPARs) expressed by the NK cells. This is believed to decrease NK cell cytotoxic activity, and thereby enhance implantation A growing number of IVF programs, including ours, perform egg retrieval under conscious sedation using Propofol, a short acting hypnotic agent.

            Whatever the exact mechanism of action might be, Intralipid acts primarily to suppress NK cell over-production of TH-I cytokines. It 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, prednisolone and prednisone which augment immune modulation of T cells. The combined effect of IL + steroid therapy suppresses pro-inflammatory cellular TH1 cytokines such as interferon gamma and TNF-alpha that are produced in excess by activated NK cells and cytotoxic lymphocytes/T-cells (CTL).   IL will, in about 80% of cases, successfully down-regulate activated natural killer cells (NKa) over a period of 2-3 weeks. It is likely to be just as effective as IVIg in this respect but at a fraction of the cost and with a far lower incidence of side-effects. Its effect lasts for ~ 4-6 weeks when administered in early pregnancy.

            Can laboratory testing be used to assess for an immediate effect of IL on Nka suppression?  Since the downregulation of NKa through IL (or IVIg) therapy can take several weeks to become measurable, 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 cells being tested.

IVIg 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 RE’s to simply say “I don’t believe IVIg works” and thereby avoid risk and bad publicity. But the thousands of women who had babies because of NK cell activity being downregulated 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 (about 15-20 years ago ), that the tide began to turn in favor of those patients who required low cost, safe and effective immunotherapy to resolve their IID.

 Corticosteroid Therapy (e.g., Prednisone, 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. Corticosteroids reduce TH-1 cytokine production by CTL. When given in combination with IL or IVIG they augment the implantation process. The prednisone or dexamethasone therapy must commence (along with IL/IVIg) 10-14 days prior to egg retrieval and continue until pregnancy is discounted or until the 10th week of pregnancy.

 Heparinoid Therapy: There is compelling evidence that the subcutaneous administration of 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 might prevent later pregnancy loss when used to treat certain thrombophilias (e.g., homozygous MTHFR mutation)

What About Baby Aspirin? In our opinion, aspirin has little (if any) value when it comes to IID, and besides, it 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.

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. However, 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.

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 thereby improving 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.

There are two categories of immunologic implantation dysfunction (IID) linked to NK cell activation (NKa).

Autoimmune Implantation Dysfunction: Here, the woman will often have a personal or family history of autoimmune conditions such as Rheumatoid arthritis, Lupus Erythematosus, and thyroid autoimmune activity (e.g., Hashimoto’s disease) etc. Autoimmune as well as in about one third of cases of endometriosis, regardless of severity.  Autoimmune sometimes also occurs in the absence of a personal or family history of autoimmune disease.

When it comes to treating  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 PGT-normal 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 39Y (who have normal ovarian reserve)  is approximately  65%.

Alloimmune Implantation Dysfunction: Here, NK cell activation results from uterine exposure to an embryo derived through fertilization by a spermatozoon that shares certain genotypic (HLA/DQ alpha) similarities with that of the embryo recipient.

Partial DQ alpha/HLA match:  Couples who upon genotyping are shown to share only one DQ alpha/HLA gene are labeled as having a “partial match”. The detection of a “partial match” in association with NKa puts the couple at a considerable disadvantage with regard to IVF outcome. It should be emphasized however, that in the absence of associated Nka, DQ alpha/HLA matching whether “partial” or “total (see below) will NOT cause an IID. Since we presently have no way of determining which embryo carries a matching paternal DQ alpha gene, it follows that each embryo transferred will have about half the chance of propagating a viable pregnancy. Treatment of a partial DQ alpha/HLA match (+ Nka) involves the same IL, infusion as for autoimmune-Nka with one important caveat, namely that here we prescribe oral prednisone as adjunct therapy (rather than dexamethasone) and the IL infusion is repeated every 2-4 weeks following the diagnosis of pregnancy and continued until the 24th week of gestation. Additionally, (as alluded to elsewhere) in such cases we transfer a single (1) embryo at a time. This is because, the likelihood is that one out of two embryos will “match” and we are fearful that if we transfer >1 embryo, and one transferred embryos “matches” it could cause further activation of uterine NK cells and so prejudice the implantation of all transferred embryos. Here it should be emphasized that if associated with Nka, a matching embryo will still be at risk of rejection even in the presence of Intralipid (or IVIg) therapy.

Total (complete) DQ alpha Match:   Here the husband’s DQ alpha genotype matches both of that of his partner’s. While this occurs very infrequently, a total alloimmune (DQ alpha) match with accompanying Nka, means that the chance of a viable pregnancy resulting in a live birth at term, is unfortunately greatly diminished.  Several instances in our experience have required the use of a gestational surrogate.

It is indeed unfortunate that so many patients are being denied the ability to go from “infertility to family” simply because (for whatever reason) so many reproductive specialists refuse to embrace the role of immunologic factors in the genesis of intractable reproductive dysfunction. Hopefully this will change, and the sooner the better.

______________________________________________________________________

I urge you to  visit my website at  www.SherIVF.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.

• A Fresh Look at the Indications for IVF
• 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.
• Human Growth Hormone Administration in IVF: Does it Enhances Egg/Embryo Quality and Outcome?
• IVF and the use of Supplementary Human Growth Hormone (HGH) : Is it Worth Trying and who needs it?
• 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
• Anti Mullerian Hormone (AMH) Measurement to Assess Ovarian Reserve and Design the Optimal Protocol for Controlled Ovarian Stimulation (COS) in IVF.
• IVF: Approach to Selecting the Best Embryos for Transfer to the Uterus.
• Fresh versus Frozen Embryo Transfers (FET) Enhance IVF Outcome
• Frozen Embryo Transfer (FET): A Rational Approach to Hormonal Preparation and How new Methodology is Impacting IVF.
• Genetically Testing Embryos for IVF
• Staggered IVF
• Staggered IVF with PGS- Selection of “Competent” Embryos Greatly Enhances the Utility & Efficiency of IVF.
• Preimplantation Genetic Testing (PGS) in IVF: It should be Used Selectively and NOT be Routine.
• IVF: Selecting the Best Quality Embryos to Transfer
• Preimplantation Genetic Sampling (PGS) Using: Next Generation Gene Sequencing (NGS): Method of Choice.
• PGS in IVF: Are Some Chromosomally abnormal Embryos Capable of Resulting in Normal Babies and Being Wrongly Discarded?
• PGS and Assessment of Egg/Embryo “competency”: How Method, Timing and Methodology Could Affect Reliability
• Endometrial Receptivity Array (ERA): Is There an actual “There, There”?
• IVF Failure and Implantation Dysfunction:
• Diagnosing and Treating Immunologic Implantation Dysfunction (IID)
• 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
• A Thin Uterine Lining: Vaginal Viagra is Often the Answer (update)
• Cervical Ureaplasma Urealyticum Infection: How can it Affect IUI/IVF Outcome?
• The Role of Nutritional Supplements in Preparing for IVF
• The Basic Infertility Work-Up
• Defining and Addressing an Abnormal Luteal Phase
• Male Factor Infertility
• Routine Fertilization by Intracytoplasmic Sperm Injection (ICSI): An Argument in Favor
• Hormonal Treatment of Male Infertility
• Hormonal Treatment of Male Infertility
• Antisperm Antibodies, Infertility and the Role of IVF with Intracytoplasmic Sperm Injection (ICSI)
• Endometriosis and Infertily
• Endometriosis and Immunologic Implantation Dysfunction (IID) and IVF
• Endometriosis and Infertility: Why IVF Rather than IUI or Surgery Should be the Treatment of Choice.
• Endometriosis and Infertility: The Influence of Age and Severity on Treatment Options
• Early -Endometriosis-related Infertility: Ovulation Induction (with or without Intrauterine Insemination) and Reproductive Surgery  Versus IVF
• Deciding Between Intrauterine Insemination (IUI) and In Vitro Fertilization (IVF).
• Intrauterine Insemination (IUI): Who Needs it & who Does Not: Pro’s & Con’s!IUI-Reflecting upon its Use and Misuse: Time for a Serious “Reality Check
• Mode of Action, Indications, Benefits, Limitations and Contraindications for its ue
• Clomiphene Induction of Ovulation: Its Use and Misuse!

_______________________________________________________________________________\

ADDITIONAL INFORMATION:

I am attaching online links to two E-books which I recently  co-authored with  my partner at SFS-NY  (Drew Tortoriello MD)……. for your reading pleasure:

1.From In Vitro Fertilization to Family: A Journey with Sher Fertility Solutions (SFS) “

http://sherfertilitysolutions.com/sher-fertility-solutions-ebook.pdf

1. “Recurrent Pregnancy Loss and Unexplained IVF Failure: The Immunologic Link

https://drive.google.com/file/d/1iYKz-EkAjMqwMa1ZcufIloRdxnAfDH8L/view

………………………………………………………………..

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).

1. 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.

1. 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:

1. A“ thin uterine lining”
2. A uterus with surface lesions in the cavity (polyps, fibroids, scar tissue)
3. Immunologic implantation dysfunction (IID)
4. Endocrine/molecular endometrial receptivity issues
5. 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 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

_________________________________________________________________________

ADDITIONAL INFORMATION:

I am attaching online links to two E-books which I recently  co-authored with  my partner at SFS-NY  (Drew Tortoriello MD)……. for your reading pleasure:

1.From In Vitro Fertilization to Family: A Journey with Sher Fertility Solutions (SFS) “

http://sherfertilitysolutions.com/sher-fertility-solutions-ebook.pdf

1. “Recurrent Pregnancy Loss and Unexplained IVF Failure: The Immunologic Link

https://drive.google.com/file/d/1iYKz-EkAjMqwMa1ZcufIloRdxnAfDH8L/view

………………………………………………………………..

10-14 days prior to transfer.!

Geoff Sher

________________________________________________________________

ADDITIONAL INFORMATION:

I am attaching online links to two E-books which I recently  co-authored with  my partner at SFS-NY  (Drew Tortoriello MD)……. for your reading pleasure:

1.From In Vitro Fertilization to Family: A Journey with Sher Fertility Solutions (SFS) “

http://sherfertilitysolutions.com/sher-fertility-solutions-ebook.pdf

1. “Recurrent Pregnancy Loss and Unexplained IVF Failure: The Immunologic Link

https://drive.google.com/file/d/1iYKz-EkAjMqwMa1ZcufIloRdxnAfDH8L/view

………………………………………………………………..

Yes you can!

Geoff sher

Same answer!

Geoff Sher

I strongly doubt any adverse effect!

Good luck!

Geoff Sher

_______________________________________________________

ADDITIONAL INFORMATION:

I am attaching online links to two E-books which I recently  co-authored with  my partner at SFS-NY  (Drew Tortoriello MD)……. for your reading pleasure:

1.From In Vitro Fertilization to Family: A Journey with Sher Fertility Solutions (SFS) “

http://sherfertilitysolutions.com/sher-fertility-solutions-ebook.pdf

1. “Recurrent Pregnancy Loss and Unexplained IVF Failure: The Immunologic Link

https://drive.google.com/file/d/1iYKz-EkAjMqwMa1ZcufIloRdxnAfDH8L/view

………………………………………………………………..

I doubt that the heterozygous  PAI-1 and one copy of MTHFR can explain the losses. the thyroid antibodies is however another matter …see below.

Geoff Sher

_________________________________________________________________________

Between 2% and 5% of women of the childbearing age have reduced thyroid hormone activity (hypothyroidism). Women with hypothyroidism often manifest with reproductive failure i.e. infertility, unexplained (often repeated) IVF failure, or recurrent pregnancy loss (RPL). The condition is 5-10 times more common in women than in men. In most cases hypothyroidism is caused by damage to the thyroid gland resulting from of thyroid autoimmunity (Hashimoto’s disease) caused by damage done to the thyroid gland by antithyroglobulin and antimicrosomal auto-antibodies. 

The increased prevalence of hypothyroidism and thyroid autoimmunity (TAI) in women is likely the result of a combination of genetic factors, estrogen-related effects and chromosome X abnormalities.  This having been said, there is significantly increased incidence of thyroid antibodies in non-pregnant women with a history of infertility and recurrent pregnancy loss and thyroid antibodies ^can be present asymptomatically in women without them manifesting with overt clinical or endocrinologic evidence of thyroid disease. In addition, these antibodies may persist in women who have suffered from hyper- or hypothyroidism even after normalization of their thyroid function by appropriate pharmacological treatment. The manifestations of reproductive dysfunction thus seem to be linked more to the presence of thyroid autoimmunity (TAI) than to clinical existence of hypothyroidism and treatment of the latter does not routinely result in a subsequent improvement in reproductive performance.

It follows, that if antithyroid autoantibodies are associated with reproductive dysfunction they may serve as useful markers for predicting poor outcome in patients undergoing assisted reproductive technologies.

Some years back, I reported on the fact that 47% of women who harbor thyroid autoantibodies, regardless of the absence or presence of clinical hypothyroidism, have activated uterine natural killer cells (NKa) cells and cytotoxic lymphocytes (CTL) and  that such women often present with reproductive dysfunction. We demonstrated that appropriate immunotherapy with IVIG or intralipid (IL) and steroids, subsequently often results in a significant improvement in reproductive performance in such cases.

The fact that almost 50% of women who harbor antithyroid antibodies do not have activated CTL/NK cells suggests that it is NOT the antithyroid antibodies themselves that cause reproductive dysfunction. The activation of CTL and NK cells that occurs in half of the cases with TAI is probably an epiphenomenon with the associated reproductive dysfunction being due to CTL/NK cell activation that damages the early “root system” (trophoblast) of the implanting embryo. We have shown that treatment of those women who have thyroid antibodies + NKa/CTL using IL/steroids, improves subsequent reproductive performance while women with thyroid antibodies who do not harbor NKa/CTL do not require or benefit from such treatment.

I strongly recommend that you visit 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.
• 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) Why did my IVF Fail
• Recurrent Pregnancy Loss (RPL): Why do I keep losing my Pregnancies
• Genetically Testing Embryos for IVF
• Staggered IVF
• Staggered IVF with PGS- Selection of “Competent” Embryos Greatly Enhances the Utility & Efficiency of IVF.
• Embryo Banking/Stockpiling: Slows the “Biological Clock” and offers a Selective Alternative to IVF-Egg Donation
• Preimplantation Genetic Testing (PGS) in IVF: It should be Used Selectively and NOT be Routine.
• IVF: Selecting the Best Quality Embryos to Transfer
• Preimplantation Genetic Sampling (PGS) Using: Next Generation Gene Sequencing (NGS): Method of Choice.
• PGS in IVF: Are Some Chromosomally abnormal Embryos Capable of Resulting in Normal Babies and Being Wrongly Discarded?
• 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!
• Natural Killer Cell Activation (NKa) and Immunologic Implantation Dysfunction in IVF: The Controversy!
• Treating Out-of-State and Out-of-Country Patients at Sher-IVF in Las Vegas
• Should IVF Treatment Cycles be provided uninterrupted or be Conducted in several Pre-scheduled “Batches” per Year
• A personalized, stepwise approach to 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!

__________________________________________________________________

ADDITIONAL INFORMATION:

I am attaching online links to two E-books which I recently  co-authored with  my partner at SFS-NY  (Drew Tortoriello MD)……. for your reading pleasure:

1.From In Vitro Fertilization to Family: A Journey with Sher Fertility Solutions (SFS) “

http://sherfertilitysolutions.com/sher-fertility-solutions-ebook.pdf

1. “Recurrent Pregnancy Loss and Unexplained IVF Failure: The Immunologic Link

https://drive.google.com/file/d/1iYKz-EkAjMqwMa1ZcufIloRdxnAfDH8L/view

………………………………………………………………..

I think your chance of success is good. I personally am willing to transfer up to 2 embryos at a time unless there is a specific obstetrics contraindication against twins.

Geoff Sher

__________________________________________________________________________

ADDITIONAL INFORMATION:

I am attaching online links to two E-books which I recently  co-authored with  my partner at SFS-NY  (Drew Tortoriello MD)……. for your reading pleasure:

1.From In Vitro Fertilization to Family: A Journey with Sher Fertility Solutions (SFS) “

http://sherfertilitysolutions.com/sher-fertility-solutions-ebook.pdf

1. “Recurrent Pregnancy Loss and Unexplained IVF Failure: The Immunologic Link

https://drive.google.com/file/d/1iYKz-EkAjMqwMa1ZcufIloRdxnAfDH8L/view

………………………………………………………………..

In my opinion it is safe! However, that does not mean it is a judicious approach. Perhaps we should talk. I invite you to call my assistant Patti Converse at 702-533-2691 and set up an online consultation with me.

Geoff Sher

____________________________________________________________________________________________

ADDITIONAL INFORMATION:

I am attaching online links to two E-books which I recently  co-authored with  my partner at SFS-NY  (Drew Tortoriello MD)……. for your reading pleasure:

1.From In Vitro Fertilization to Family: A Journey with Sher Fertility Solutions (SFS) “

http://sherfertilitysolutions.com/sher-fertility-solutions-ebook.pdf

1. “Recurrent Pregnancy Loss and Unexplained IVF Failure: The Immunologic Link

https://drive.google.com/file/d/1iYKz-EkAjMqwMa1ZcufIloRdxnAfDH8L/view

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My bet is that this is normal!

Geoff Sher

Measuring and interpreting Blood hCG to Assess Pregnancy Viability Following ART Treatments.

Geoffrey Sher MD

I know of no medical announcement associated with the degree of emotional anticipation and anguish as that associated with a pending diagnosis/confirmation of pregnancy following infertility treatment. In fact, hardly a day goes by where I am not confronted by a patient anxiously seeking interpretation of a pregnancy test result.

Testing urine or blood for the presence of human chorionic gonadotropin (hCG) is the most effective and reliable way to confirm conception. The former, is far less expensive than the latter and is the most common method used. It is also more convenient because it can be performed in the convenience of the home setting. However, urine hCG testing for pregnancy is not nearly as reliable or as sensitive e as is blood hCG testing. Blood testing can detect implantation several days earlier than can a urine test. Modern pregnancy urine test kits can detect hCG about 16-18 days following ovulation (or 2-3 days after having missed a menstrual period), while blood tests can detect hCG, 12-13 days post-ovulation (i.e. even prior to menstruation).

The ability to detect hCG in the blood as early as possible and thereupon to track its increase, is particularly valuable in women undergoing controlled ovarian stimulation (COS) with or without intrauterine insemination (IUI) or after IVF. The earlier hCG can be detected in the blood and its concentration measured, the sooner levels can be tracked serially over time and so provide valuable information about the effectiveness of implantation, and the potential viability of the developing conceptus.

There are a few important points that should be considered when it comes to measuring interpreting blood hCG levels. These include the following:

• All modern day blood (and urine) hCG tests are highly specific in that they measure exclusively for hCG. There is in fact no cross-reactivity with other hormones such as estrogen, progesterone or LH.
• Post conception hCG levels, measured 10 days post ovulation or egg retrieval can vary widely (ranging from 5mIU/ml to above 400mIU/ml. The level will double every 48–72 hours up to the 6th week of gestation whereupon the doubling rate starts to slow down to about 96 hours. An hCG level of 13,000-290, 0000 mIU/ml is reached by the end of the 1st trimester (12 weeks) whereupon it slowly declines to approximately 26,000– 300,000 mIU/ml by full term. Below are the average hCG levels during the first trimester:

• • 3 weeks LMP: 5 – 50 mIU/ml
  • 4 weeks LMP: 5 – 426 mIU/ml
  • 5 weeks LMP: 18 – 7,340 mIU/ml
  • 6 weeks LMP: 1,080 – 56,500 mIU/ml
  • 7 – 8 weeks LMP: 7, 650 – 229,000 mIU/ml
  • 9 – 12 weeks LMP: 25,700 – 288,000 mIU/ml

• A single hCG blood level is not sufficient to assess the viability of an implanting embryo. Caution should be used in making too much of an initial hCG level. This is because a normal pregnancy can start with relatively low hCG blood levels. It is the rate of the rise of the blood hCG level that is relevant.
• In some cases the initially hCG level is within the normal range, but then fails to double in the ensuing 48-72hours. In some cases it might even plateau or decline, only to start doubling appropriately thereafter. When this happens, it could be due to:
  • A recovering implantation, destined to develop into a clinical gestation
  • A failing implantation (a chemical pregnancy)
  • A multiple pregnancy which is spontaneously reducing (i.e., one or more of the concepti is being lost) or,
  • An ectopic pregnancy which will either absorb spontaneously (a chemical-tubal gestation), or evolve into a full blown tubal pregnancy continue and declare itself through characteristic symptoms and signs of an intraperitoneal bleed.
• The blood hCG test needs to be repeated at least once after 48h and in some cases it will need to be repeated one or more times (at 48h intervals) thereafter, to confirm that implantation is progressing normally.
• Ultimately the diagnosis of a viable pregnancy requires confirmation of the presence of an intrauterine gestational sac by ultrasound examination. The earliest that this can be achieved is when the beta hCG level exceeds 1,000mIU/ml (i.e., around 5-6 weeks).
• Most physicians prefer to defer the performance of a routine US diagnosis of pregnancy until closer to the 7th week. This is because by that time, cardiac activity should be clearly detectable, allowing for more reliable assessment of pregnancy viability.
• There are cases where the blood beta hCG level is extraordinarily high or the rate of rise is well above the normal doubling rate. The commonest explanation is that more than one pregnancy has implanted. However in some cases it can point to a molar pregnancy
• Finally, there on rare occasions, conditions unrelated to pregnancy can result in detectable hCG levels in blood and urine. They include ovarian tumors that produce hCG, such as certain types of cystic teratomas (dermoid cysts) and some ovarian cancers such as dysgerminomas.

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ADDITIONAL INFORMATION:

I am attaching online links to two E-books which I recently  co-authored with  my partner at SFS-NY  (Drew Tortoriello MD)……. for your reading pleasure:

1.From In Vitro Fertilization to Family: A Journey with Sher Fertility Solutions (SFS) “

http://sherfertilitysolutions.com/sher-fertility-solutions-ebook.pdf

1. “Recurrent Pregnancy Loss and Unexplained IVF Failure: The Immunologic Link

https://drive.google.com/file/d/1iYKz-EkAjMqwMa1ZcufIloRdxnAfDH8L/view

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Ureaplasma urealyticum is a bacterium that belongs to the mycoplasma family. It can be detected in the reproductive tract of as many as 40% of individuals (male and female). Ureaplasma probably does not prevent normal conception in the majority of cases, because by and large, the uterine cavity remains  free of such pathogenic bacteria even in women whose cervical mucous cultures positive for the organism. However, when present in the woman’s cervical secretions, the organism can be unintentionally dragged into the uterine cavity through introduction of a catheter into the uterus at the time of embryo transfer (ET) or intrauterine insemination (IUI). Molecular biologists have shown that contamination of rapidly growing cell cultures, by this organism and its close “relative”, mycoplasma hominis rapidly destroys such cells. The implanting embryo is indeed an example of an organism that comprises rapidly growing cells in a biological culture medium (the uterine lining), and as such, the cells of the trophoblast that form the “root system” of the embryo are vulnerable to intrauterine infection with Ureaplasma. However, even if the uterine cavity were to become infected, the infection willl be purged with the shedding of the infected lining at the time of the next menstruation.

While , aside from a non-specific vaginal discharge,  infection with Ureaplasma rarely produces symptoms in the woman, it sometimes causes symptomatic prostatitis or epydidimitis in men. Although ureaplasma can be transmitted from one partner to the other by sexual intercourse, it may also be acquired by other means, since a large percentage of couples in monogamous relationships will culture positive for the organism. It is very difficult for the organism to grow in the laboratory. Accordingly, the reproductive secretions of both partners should be evaluated (sperm and cervical mucus) individually. Successful culturing of ureaplasma requires a specialized media in which the specimens can be transported safely from the physician’s office to the microbiology laboratory.

If both partners culture negative, we can assume that there is no infection present. However, if one partner cultures positive and the other negative, we would err on the side of caution, by assuming that the negative result was caused by the difficulty in culturing the organism. When ureaplasma is detected in the reproductive secretions of either partner, both should be treated concurrently with the appropriate antibiotic (doxycycline, zithromax, erythromycin, ciprofloxin, or metronidazole; cleomycin).

Unfortunately, in approximately 30-40% of couples infected ureaplasma urealyticum, the bacteria will have built resistance to mainstay traditional antibiotics such as tetracyclines (e.g. doxycycline) and erythromycin (e.g. Zythromax) derivatives. In such cases, ciprofloxin or metronidazole (Flagyl) therapy might be needed. This is the reason that we prefer to document cure by reculturing each partner prior to beginning ovarian stimulation for an IVF cycle.

Several authors have shown a difference in pregnancy rates among patients with ureaplasma infection who were treated with antibiotics and those who were not. Other reports have not been able to identify an effect on outcome from ureaplasma infection. Thus, until the final verdict is in regarding the roll of ureaplasma with regard to its effect on IVF implantation, we prefer to err on the side of caution and ensure that this organism is absent in cervical secretions and semen before transferring embryos. To this end, my patients all receive prophylactic antibiotic therapy around the time of embryo transfer. This is administered as oral ciprofloxin. A day or two prior to embryo transfer, vaginal cleomycin suppositories are added.

Geoff Sher

___________________________________________________________

ADDITIONAL INFORMATION:

I am attaching online links to two E-books which I recently  co-authored with  my partner at SFS-NY  (Drew Tortoriello MD)……. for your reading pleasure:

1.From In Vitro Fertilization to Family: A Journey with Sher Fertility Solutions (SFS) “

http://sherfertilitysolutions.com/sher-fertility-solutions-ebook.pdf

1. “Recurrent Pregnancy Loss and Unexplained IVF Failure: The Immunologic Link

https://drive.google.com/file/d/1iYKz-EkAjMqwMa1ZcufIloRdxnAfDH8L/view

………………………………………………………………..

Sometimes they do!

Geoff Sher

______________________________________________________________________________

ADDITIONAL INFORMATION:

I am attaching online links to two E-books which I recently  co-authored with  my partner at SFS-NY  (Drew Tortoriello MD)……. for your reading pleasure:

1.From In Vitro Fertilization to Family: A Journey with Sher Fertility Solutions (SFS) “

http://sherfertilitysolutions.com/sher-fertility-solutions-ebook.pdf

1. “Recurrent Pregnancy Loss and Unexplained IVF Failure: The Immunologic Link

https://drive.google.com/file/d/1iYKz-EkAjMqwMa1ZcufIloRdxnAfDH8L/view

………………………………………………………………..

Implantation dysfunction is unfortunately often overlooked as an important cause of IVF failure. This is especially relevant in cases of unexplained IVF failure, recurrent pregnancy loss (RPL), and in women with underlying endo-uterine surface lesions, thickness of the uterine lining (endometrium) and /or immunologic factors.

IVF success rates have been improving over the last decade. The average live birth rate per embryo transfer in the U.S.A for women under 40y using their own eggs is currently better than 1:3 women. However, there is still a wide variation from program to program for IVF live birth rates, ranging from 20% to near 50%. Based upon these statistics, most women undergoing IVF in the United States require two or more attempts to have a baby. IVF practitioners in the United States commonly attribute the wide dichotomy in IVF success rates to variability in expertise of the various embryology laboratories. This is far from accurate. In fact, other factors such as wide variations in patient selection and the failure to develop individualized protocols for ovarian stimulation or to address those infectious, anatomical, and immunologic factors that influence embryo implantation are at least equally important.

About 80% of IVF failures are due to “embryo incompetency” that is largely due to aneuploidy      usually related to advancing age of the woman and is further influenced by other factors such as the protocol selected for ovarian stimulation, diminished ovarian reserve (DOR), and severe male factor infertility. However, in about 20% of dysfunctional cases embryo implantation is the cause of failure.

This section will focus on implantation dysfunction and IVF failure due to:

ANATOMICAL ENDO-UTERINE SURFACE LESIONS

            It has long been suspected that anatomical defects of the uterus might result in infertility. While the presence of uterine fibroids, in general, are unlikely to cause infertility, an association between their presence and infertility has been observed in cases where the myomas distort the uterine cavity or protrude through the endometrial lining.  Even small fibroids that lie immediately under the endometrium (submucous fibroids) and protrude into the uterine cavity have the potential to lower embryo implantation.  Multiple fibroids in the uterine wall (intramural fibroids) that encroach upon the uterine cavity can sometimes so compromise blood flow that estrogen delivery is impaired, and the endometrium is unable to thicken properly. This can usually be diagnosed by ultrasound examination during the proliferative phase of the menstrual cycle.  It is likely that any surface lesion in the uterine cavity, whether submucous fibroids, intrauterine adhesions a small endometrial or a placental polyp, has the potential to interfere with implantation by producing a local inflammatory response, not too dissimilar in nature from that which is caused by an intrauterine contraceptive device (IUD).       

            Clearly, since even small uterine lesions have the potential to adversely affect implantation, the high cost (financial, physical, and emotional) associated with IVF and related procedures, justifies the routine performance of diagnostic procedures such as an HSG, hysterosonogram (fluid ultrasound examination), or hysteroscopy prior to initiating IVF.  Identifiable uterine lesions that have the potential of impairing implantation usually require surgical intervention.  In most cases, dilatation and curettage (D & C) or hysteroscopic resection will suffice. Some cases might require the performance of a laparotomy.  Such intervention will often result in subsequent improvement of the endometrial response.      

Sonohysterography [Fluid ultrasonography (FUS)]: Fluid ultrasonography is a procedure whereby a sterile solution of saline is injected via a catheter through the cervix and into the uterine cavity. The fluid-distended cavity is examined by vaginal ultrasound for any irregularities that might point to surface lesions such as polyps, fibroid tumors, scarring, or a uterine septum. If performed by an expert, a FUS is highly effective in recognizing even the smallest lesion and can replace hysteroscopy under such circumstances. FUS is less expensive, less traumatic, and equally as effective as hysteroscopy. The only disadvantage lies in the fact that if a lesion is detected, it may require the subsequent performance of hysteroscopy to treat the problem anyway.

Hysteroscopy: Diagnostic hysteroscopy is an office procedure that is performed under intravenous sedation, general anesthesia, or paracervical block with minimal discomfort to the patient. This procedure involves the insertion of a thin, lighted, telescope like instrument known as a hysteroscope through the vagina and cervix into the uterus to fully examine the uterine cavity. The uterus is first distended with normal saline, which is passed through a sleeve adjacent to the hysteroscope. As is the case with FUS, diagnostic hysteroscopy facilitates examination of the inside of the uterus under direct vision for defects that might interfere with implantation. We have observed that approximately one in eight candidates for IVF have lesions that require attention prior to undergoing IVF in order to optimize the chances of a successful outcome. We strongly recommend that all patients undergo therapeutic surgery (usually by hysteroscopy) to correct the pathology prior to IVF.  Depending on the severity and nature of the pathology, therapeutic hysteroscopy may require general anesthesia and, in such cases, should be performed in an outpatient surgical facility or conventional operating room where facilities are available for laparotomy, a procedure in which an incision is made in the abdomen to expose the abdominal contents for diagnosis, or for surgery should this be required.       

THICKNESS OF THE UTERINE LINING (ENDOMETRIUM):

As far back as in 1989 we first reported on the finding that ultrasound assessment of the late proliferative phase endometrium can identify those candidates who are least likely to conceive. We noted that the ideal thickness of the endometrium at the time of ovulation or egg retrieval is >8 mm and that thinner linings are associated with decreased implantation rates.

More than 30 years ago we first showed that in normal and “stimulated” cycles, pre-ovulatory endometrial thickness and ultrasound appearance is predictive of embryo implantation (pregnancy) potential following ET. With conventional IVF and with FET, endometrial lining at the time of the “trigger shot” or with the initiation of progesterone needs to preferably be at least 8 mm in sagittal thickness with a triple line (trilaminar) appearance. Anything less than an 8mm endometrial thickness       is associated with a reduction in live birth rate per ET. An 8-9mm thickness represents a transitional measurement…a “gray zone”.  Hitherto, attempts to augment endometrial growth in women with poor endometrial linings by bolstering circulating estrogen blood levels (through the administration of increased doses of fertility drugs, aspirin administration and by supplementary estrogen therapy) yielded disappointing results.

            A “poor” uterine lining is usually the result of the innermost layer of endometrium (the basal or germinal endometrium from which endometrium grows) not being able to respond to estrogen by propagating an outer, “functional” layer thick enough to support optimal embryo implantation and development of a healthy placenta (placentation). The “functional” layer ultimately comprises 2/3 of the full endometrial thickness and is the layer that sheds with menstruation if no pregnancy occurs.

The main causes of a “poor” uterine lining are:

• Damage to the basal endometrium because of:
• Inflammation of the endometrium (endometritis) most commonly resulting from infected products left over following abortion, miscarriage, or birth
• Surgical trauma due to traumatic uterine scraping, (i.e. due to an over-aggressive D & C)
• Insensitivity of the basal endometrium to estrogen due to:
• Prolonged, over-use/misuse of clomiphene citrate
• Prenatal exposure to diethylstilbestrol (DES). This is a drug that was given to pregnant women in the 1960’s to help prevent miscarriage
• Over-exposure of the uterine lining to ovarian male hormones (mainly testosterone): Older women, women with diminished ovarian reserve (poor responders) and women with polycystic ovarian syndrome -PCOS tend to have raised LH biological activity. This causes the connective tissue in the ovary (stroma/theca) to overproduce testosterone. The effect may be further exaggerated when certain methods for ovarian stimulation such as “flare” protocols and high dosages of Menopur are used in such cases.
• Reduced blood flow to the basal endometrium: Examples include.
• Multiple uterine fibroids – especially when these are present under the endometrium (submucosal)
• Uterine adenomyosis (excessive, abnormal invasion of the uterine muscle by endometrial glands).

Vaginal Viagra: About 35 years ago, after reporting on the benefit of administering vaginal Sildenafil (Viagra) to women who had implantation dysfunction due to thin endometrial linings we announced the birth of the world’s first “Viagra baby.”  Viagra administered vaginally, but not orally, in affected women improves uterine blood flow causing more estrogen to be delivered to the basal endometrium and increasing the endometrial thickening.  Following vaginal administration, Viagra is rapidly absorbed and quickly reaches the uterine blood system in high concentrations. Thereupon it dilutes out as it is absorbed into the systemic circulation. This probably explains why treatment is virtually devoid of systemic side effects.  It is important to recognize that Viagra will NOT be effective in improving endometrial thickness in all cases. In fact, about one third of women treated fail to show any improvement. This is because in certain cases of thin uterine linings, the basal endometrium will have been permanently damaged and left unresponsive to estrogen. This happens in cases of severe endometrial damage due mainly to post-pregnancy endometritis (inflammation), chronic granulomatous inflammation due to uterine tuberculosis (hardly ever seen in the United States) and following extensive surgical injury to the basal endometrium (as sometimes occurs following over-zealous D&C’s).

• Immunologic factors: These also play a role in IVF failure (see “Immunologic factors and Implantation” …see below.

IMMUNOLOGIC IMPLANTATION DYSFUNCTION (IID)

            Currently, with few exceptions, practitioners of assisted reproduction tend to attribute “unexplained and/or repeated” IVF failure(s), almost exclusively to poor embryo quality, advocating adjusted protocols for ovarian stimulation and/or gamete and embryo preparation as a potential remedy. The idea, having failed IVF, that all it takes to ultimately succeed is to keep trying the same recipe is over-simplistic.

            The implantation process begins six or seven days after fertilization of the egg. At this time, specialized embryonic cells (i.e., trophoblasts), that later become the placenta begin growing into the uterine lining. When the trophoblast and the uterine lining meet, they, along with immune cells in the lining, become involved in a “cross talk” through mutual exchange of hormone-like substances called cytokines. Because of this complex immunologic interplay, the uterus can foster the embryo’s successful growth. Thus, from the earliest stage, the trophoblast establishes the very foundation for the nutritional, hormonal and respiratory interchange between mother and baby.  In this manner, the interactive process of implantation is not only central to survival in early pregnancy but also to the quality of life after birth.

There is an ever growing realization, recognition, and acceptance of the fact that uterine immunologic dysfunction can lead to immunologic implantation dysfunction (IID) with “unexplained” infertility, IVF failure, and recurrent pregnancy loss (RPL).

DIAGNOSIS 

Because immunologic problems may lead to implantation failure, it is important to properly evaluate women with risk factors such as:

• Unexplained or recurrent IVF failures
• Unexplained infertility or a family history of autoimmune diseases (e.g., rheumatoid arthritis, lupus erythematosus and hypothyroidism).
• Recurrent Pregnancy Loss (RPL)
• Endometriosis
• A personal or family history of autoimmune conditions, e.g., Rheumatoid Arthritis, Lupus erythematosus, autoimmune hypothyroidism (Hashimoto’s disease) etc.

            Considering its importance, it is not surprising that the failure of a properly functioning immunologic interaction during implantation has been implicated as a cause of recurrent miscarriage, late pregnancy fetal loss, IVF failure and infertility. A partial list of immunologic factors that may be involved in these situations includes:

• Antiphospholipid antibodies (APA)
• Antithyroid antibodies (ATA/AMA)
• Activated natural killer cells (NKa)

ACTIVATED NATURAL KILLER CELLS (NKa):

Following ovulation and during early pregnancy, NK cells and T-cells comprise more than 80% of the lymphocyte-immune cells that frequent the uterine lining. These lymphocytes (white blood cells) journey from the bone marrow to the uterus and under hormonal regulation, proliferate there. After exposure to progesterone (due to induced /spontaneous exogenous administration), they begin to produce TH-1 and TH-2 cytokines. TH-2 cytokines are humoral in nature and induce the trophoblast (“root system of the embryo”) to permeate the uterine lining while TH-I cytokines induce a process referred to as apoptosis (cell suicide) thereby confining placental development to the inner part of the uterus. Optimal placental development (placentation) mandates that there be a balance between TH1 and TH-2 cytokines. Most of the cytokine production originates from NK cells (rather than from cytotoxic T-cells/Lymphocytes (CTL)). Excessive production/release of TH-1 cytokines, is toxic to the trophoblast and to endometrial cells, leading to programmed death/suicide (apoptosis) and subsequently to IID.

Functional NK cells reach a maximal concentration in the endometrium by about t day 6-7 days after exposure to progesterone …. This timing corresponds with when the embryo implants into the uterine lining (endometrium).

It is important to bear in mind that measurement of the concentration of blood NK cells has little or no relevance when it comes to assessing NK cell activation (NKa). Rather, it is the NK cell activation that matters. In fact, there are certain conditions (such as with endometriosis) where the NK cell blood concentration is below normal, but NK cell activation is markedly increased.

There are several methods by which NK cell activation (cytotoxicity) can be assessed in the laboratory. Methods such as immunohistochemical assessment of uterine NK cells and/or through measurement of uterine or blood TH-1 cytokines. However, the K-562 target cell blood test still remains the gold standard. With this test, NK cells, isolated from the woman’s blood using Flow Cytometry are incubated in the presence of specific “target cells”. The percentage (%) of “target cells” killed is then quantified. More than 12% killing suggests a level of NK cell activation that usually requires treatment.

Currently, there are less than a half dozen Reproductive Immunology Reference Laboratories in the U.S.A that are capable of performing the K-562 target cell test reliably.

There exists a pervasive but blatant misconception on the part of many, that the addition of IL or IVIg to a concentration of NK cells could have an immediate down-regulatory effect on NK cell activity. Neither IVIg nor IL is capable of significantly suppressing already activated “functional NK cells”. They are believed to work through “regulating” NK cell progenitors which only thereupon will start to propagate down-regulated NK cells. Thus, testing for a therapeutic effect would require that the IL/IVIg infusion be done about 14 days prior to ovulation or progesterone administration…  in order to allow for a sufficient number of normal (non-activated) “functional” NK cell” to be present at the implantation site when the embryos are transferred.

Failure to recognize this reality has, in our opinion, established an erroneous demand by practicing IVF doctors, that Reproductive Immunology Reference Laboratories report on NK cell activity before and again, immediately following laboratory exposure to IVIg and/or IL in different concentrations. Allegedly, this is to allow the treating physician to report back to their patient(s) on whether an IL or IVIG infusion will be effective in downregulating their Nka.  But, since already activated NK cells (NKa) cannot be deactivated in the laboratory, effective NKa down-regulation can only be adequately accomplished through deactivation of NK cell “progenitors /parental” NK cells in order to allow them thereupon, to s propagate normal “functional” NK cells and his takes about 10-14 days, such practice would be of little clinical benefit. This is because even if blood were to be drawn 10 -14 days after IL/IVIg treatment it would require at least an additional 10 -14days to receive results from the laboratory, by which time it would be far too late to be of practical advantage.

ANTIPHOSPHOLIPID ANTIBODIES:

 Many women who experience “unexplained” IVF failure, women with RPL, those with a personal or family history of autoimmune diseases such as lupus erythematosus, rheumatoid arthritis, scleroderma, and dermatomyositis (etc.)  as well as women who have endometriosis (“silent” or overt) test positive for APAs. More than 30 years ago, we were the first to propose that women who test positive for APA’s be treated with a mini-dose heparin to improve IVF implantation and thus birth rates. This approach was based upon research that suggested that heparin repels APAs from the surface of the trophoblast (the embryo’s “root system) thereby reducing its ant-implantation effects.  We subsequently demonstrated that such therapy only improved IVF outcome in women whose APAs were directed against two specific IgG and/or IgM phospholipids [i.e., phosphatidylethanolamine (PE) and phosphatidylserine (PS)].  More recently low dosage heparin therapy has been supplanted using longer acting low molecular weight heparinoids such as Lovenox and Clexane.   It is very possible that APAs alone do not cause IID but that their presence might help to identify a population at risk due to concomitant activation of uterine natural killer cells (Nka) which through excessive TH-1 cytokine production causes in IID: This is supported by the following observations:

• The presence of female APAs in cases of male factor cases appears to bear no relationship to IID.
• Only APA positive women who also test positive for abnormal NK activity appear to benefit from selective immunotherapy with intralipid/IVIg/ steroids.
• Most APA positive women who have increased NK cell activity also harbor IgG or IgM phosphatidylethanolamine (PE) and phosphatidylserine (PS) antibodies.

ANTITHYROID ANTIBODIES: (ATA).

 A clear relationship has been established between ATA and reproductive failure (especially recurrent miscarriage and infertility).

Between 2% and 5% of women of the childbearing age have reduced thyroid hormone activity (hypothyroidism). Women with hypothyroidism often manifest with reproductive failure i.e., infertility, unexplained (often repeated) IVF failure, or recurrent pregnancy loss (RPL). The condition is 5-10 times more common in women than in men. In most cases hypothyroidism is caused by damage to the thyroid gland resulting from of thyroid autoimmunity (Hashimoto’s disease) caused by damage done to the thyroid gland by antithyroglobulin and antimicrosomal auto-antibodies. 

The increased prevalence of hypothyroidism and thyroid autoimmunity (TAI) in women is likely the result of a combination of genetic factors, estrogen-related effects, and chromosome X abnormalities.  This having been said, there is significantly increased incidence of thyroid antibodies in non-pregnant women with a history of infertility and recurrent pregnancy loss and thyroid antibodies ^can be present asymptomatically in women without them manifesting with overt clinical or endocrinologic evidence of thyroid disease. In addition, these antibodies may persist in women who have suffered from hyper- or hypothyroidism even after normalization of their thyroid function by appropriate pharmacological treatment. The manifestations of reproductive dysfunction thus seem to be linked more to the presence of thyroid autoimmunity (TAI) than to clinical existence of hypothyroidism and treatment of the latter does not routinely result in a subsequent improvement in reproductive performance.

It follows, that if antithyroid autoantibodies are associated with reproductive dysfunction they may serve as useful markers for predicting poor outcome in patients undergoing assisted reproductive technologies.

Some years back, I reported on the fact that 47% of women who harbor thyroid autoantibodies, regardless of the absence or presence of clinical hypothyroidism, have activated uterine natural killer cells (NKa) cells and cytotoxic lymphocytes (CTL) and that such women often present with reproductive dysfunction. We demonstrated that appropriate immunotherapy with IVIG or intralipid (IL) and steroids, subsequently often results in a significant improvement in reproductive performance in such cases.

The fact that almost 50% of women who harbor antithyroid antibodies do not have activated CTL/NK cells suggests that it is NOT the antithyroid antibodies themselves that cause reproductive dysfunction. The activation of CTL and NK cells that occurs in half of the cases with TAI is probably an epiphenomenon with the associated reproductive dysfunction being due to CTL/NK cell activation that damages the early “root system” (trophoblast) of the implanting embryo. We have shown that treatment of those women who have thyroid antibodies + NKa/CTL using IL/steroids, improves subsequent reproductive performance while women with thyroid antibodies who do not harbor NKa/CTL do not require or benefit from such treatment

TEATMENT OF IID:

The mainstay of treatment involves the selective use of:

• Intralipid (IL) infusion
• IVIg therapy
• Corticosteroids (Prednisone/dexamethasone)
• Heparinoids (Lovenox/Clexane)

Intralipid (IL) Therapy:  IL is a suspension of soybean lipid droplets in water and is primarily used as source of parenteral nutrition. When administered intravenously, IL provides essential fatty acids, linoleic acid (LA), an omega-6 fatty acid, and alpha-linolenic acid (ALA), an omega-3 fatty acid.     

It is thought that fatty acids within the emulsion serve as ligands that activate peroxisome proliferator-activated receptors (PPARs) expressed by the NK cells. This is believed to decrease NK cell cytotoxic activity, and thereby enhance implantation A growing number of IVF programs, including ours, perform egg retrieval under conscious sedation using Propofol, a short acting hypnotic agent.

            Whatever the exact mechanism of action might be, Intralipid acts primarily to suppress NK cell over-production of TH-I cytokines. It 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, prednisolone and prednisone which augment immune modulation of T cells. The combined effect of IL + steroid therapy suppresses pro-inflammatory cellular TH1 cytokines such as interferon gamma and TNF-alpha that are produced in excess by activated NK cells and cytotoxic lymphocytes/T-cells (CTL).   IL will, in about 80% of cases, successfully down-regulate activated natural killer cells (NKa) over a period of 2-3 weeks. It is likely to be just as effective as IVIg in this respect but at a fraction of the cost and with a far lower incidence of side-effects. Its effect lasts for ~ 4-6 weeks when administered in early pregnancy.

Intralipid is a suspension of soybean lipid droplets in water and is primarily used as source of parenteral nutrition. When administered intravenously, IL provides essential fatty acids, linoleic acid (LA), an omega-6 fatty acid, and alpha-linolenic acid (ALA), an omega-3 fatty acid.     

It is thought that fatty acids within the emulsion serve as ligands that activate peroxisome proliferator-activated receptors (PPARs) expressed by the NK cells. This is believed to decrease NK cell cytotoxic activity, and thereby enhance implantation A growing number of IVF programs, including ours, perform egg retrieval under conscious sedation using Propofol, a short acting hypnotic agent.

            Whatever the exact mechanism of action might be, Intralipid acts primarily to suppress NK cell over-production of TH-I cytokines. It 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, prednisolone and prednisone which augment immune modulation of T cells. The combined effect of IL + steroid therapy suppresses pro-inflammatory cellular TH1 cytokines such as interferon gamma and TNF-alpha that are produced in excess by activated NK cells and cytotoxic lymphocytes/T-cells (CTL).   IL will, in about 80% of cases, successfully down-regulate activated natural killer cells (NKa) over a period of 2-3 weeks. It is likely to be just as effective as IVIg in this respect but at a fraction of the cost and with a far lower incidence of side-effects. Its effect lasts for ~ 4-6 weeks when administered in early pregnancy.

            Can laboratory testing be used to assess for an immediate effect of IL on Nka suppression?  Since the downregulation of NKa through IL (or IVIg) therapy can take several weeks to become measurable, 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 cells being tested.

IVIg 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 RE’s to simply say “I don’t believe IVIg works” and thereby avoid risk and bad publicity. But the thousands of women who had babies because of NK cell activity being downregulated 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 (about 15-20 years ago ), that the tide began to turn in favor of those patients who required low cost, safe and effective immunotherapy to resolve their IID.

 Corticosteroid Therapy (e.g., Prednisone, 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. Corticosteroids reduce TH-1 cytokine production by CTL. When given in combination with IL or IVIG they augment the implantation process. The prednisone or dexamethasone therapy must commence (along with IL/IVIg) 10-14 days prior to egg retrieval and continue until pregnancy is discounted or until the 10th week of pregnancy.

 Heparinoid Therapy: There is compelling evidence that the subcutaneous administration of 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 might prevent later pregnancy loss when used to treat certain thrombophilias (e.g., homozygous MTHFR mutation)

What About Baby Aspirin? In our opinion, aspirin has little (if any) value when it comes to IID, and besides, it 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.

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. However, 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.

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 thereby improving 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.

There are two categories of immunologic implantation dysfunction (IID) linked to NK cell activation (NKa).

Autoimmune Implantation Dysfunction: Here, the woman will often have a personal or family history of autoimmune conditions such as Rheumatoid arthritis, Lupus Erythematosus, and thyroid autoimmune activity (e.g., Hashimoto’s disease) etc. Autoimmune as well as in about one third of cases of endometriosis, regardless of severity.  Autoimmune sometimes also occurs in the absence of a personal or family history of autoimmune disease.

When it comes to treating  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 PGT-normal 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 39Y (who have normal ovarian reserve)  is approximately  65%.

Alloimmune Implantation Dysfunction: Here, NK cell activation results from uterine exposure to an embryo derived through fertilization by a spermatozoon that shares certain genotypic (HLA/DQ alpha) similarities with that of the embryo recipient.

Partial DQ alpha/HLA match:  Couples who upon genotyping are shown to share only one DQ alpha/HLA gene are labeled as having a “partial match”. The detection of a “partial match” in association with NKa puts the couple at a considerable disadvantage with regard to IVF outcome. It should be emphasized however, that in the absence of associated Nka, DQ alpha/HLA matching whether “partial” or “total (see below) will NOT cause an IID. Since we presently have no way of determining which embryo carries a matching paternal DQ alpha gene, it follows that each embryo transferred will have about half the chance of propagating a viable pregnancy. Treatment of a partial DQ alpha/HLA match (+ Nka) involves the same IL, infusion as for autoimmune-Nka with one important caveat, namely that here we prescribe oral prednisone as adjunct therapy (rather than dexamethasone) and the IL infusion is repeated every 2-4 weeks following the diagnosis of pregnancy and continued until the 24th week of gestation. Additionally, (as alluded to elsewhere) in such cases we transfer a single (1) embryo at a time. This is because, the likelihood is that one out of two embryos will “match” and we are fearful that if we transfer >1 embryo, and one transferred embryos “matches” it could cause further activation of uterine NK cells and so prejudice the implantation of all transferred embryos. Here it should be emphasized that if associated with Nka, a matching embryo will still be at risk of rejection even in the presence of Intralipid (or IVIg) therapy.

Total (complete) DQ alpha Match:   Here the husband’s DQ alpha genotype matches both of that of his partner’s. While this occurs very infrequently, a total alloimmune (DQ alpha) match with accompanying Nka, means that the chance of a viable pregnancy resulting in a live birth at term, is unfortunately greatly diminished.  Several instances in our experience have required the use of a gestational surrogate.

It is indeed unfortunate that so many patients are being denied the ability to go from “infertility to family” simply because (for whatever reason) so many reproductive specialists refuse to embrace the role of immunologic factors in the genesis of intractable reproductive dysfunction. Hopefully this will change, and the sooner the better.

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I urge you to  visit my website at  www.SherIVF.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.

• A Fresh Look at the Indications for IVF
• 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.
• Human Growth Hormone Administration in IVF: Does it Enhances Egg/Embryo Quality and Outcome?
• IVF and the use of Supplementary Human Growth Hormone (HGH) : Is it Worth Trying and who needs it?
• 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
• Anti Mullerian Hormone (AMH) Measurement to Assess Ovarian Reserve and Design the Optimal Protocol for Controlled Ovarian Stimulation (COS) in IVF.
• IVF: Approach to Selecting the Best Embryos for Transfer to the Uterus.
• Fresh versus Frozen Embryo Transfers (FET) Enhance IVF Outcome
• Frozen Embryo Transfer (FET): A Rational Approach to Hormonal Preparation and How new Methodology is Impacting IVF.
• Genetically Testing Embryos for IVF
• Staggered IVF
• Staggered IVF with PGS- Selection of “Competent” Embryos Greatly Enhances the Utility & Efficiency of IVF.
• Preimplantation Genetic Testing (PGS) in IVF: It should be Used Selectively and NOT be Routine.
• IVF: Selecting the Best Quality Embryos to Transfer
• Preimplantation Genetic Sampling (PGS) Using: Next Generation Gene Sequencing (NGS): Method of Choice.
• PGS in IVF: Are Some Chromosomally abnormal Embryos Capable of Resulting in Normal Babies and Being Wrongly Discarded?
• PGS and Assessment of Egg/Embryo “competency”: How Method, Timing and Methodology Could Affect Reliability
• Endometrial Receptivity Array (ERA): Is There an actual “There, There”?
• IVF Failure and Implantation Dysfunction:
• Diagnosing and Treating Immunologic Implantation Dysfunction (IID)
• 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
• A Thin Uterine Lining: Vaginal Viagra is Often the Answer (update)
• Cervical Ureaplasma Urealyticum Infection: How can it Affect IUI/IVF Outcome?
• The Role of Nutritional Supplements in Preparing for IVF
• The Basic Infertility Work-Up
• Defining and Addressing an Abnormal Luteal Phase
• Male Factor Infertility
• Routine Fertilization by Intracytoplasmic Sperm Injection (ICSI): An Argument in Favor
• Hormonal Treatment of Male Infertility
• Hormonal Treatment of Male Infertility
• Antisperm Antibodies, Infertility and the Role of IVF with Intracytoplasmic Sperm Injection (ICSI)
• Endometriosis and Infertily
• Endometriosis and Immunologic Implantation Dysfunction (IID) and IVF
• Endometriosis and Infertility: Why IVF Rather than IUI or Surgery Should be the Treatment of Choice.
• Endometriosis and Infertility: The Influence of Age and Severity on Treatment Options
• Early -Endometriosis-related Infertility: Ovulation Induction (with or without Intrauterine Insemination) and Reproductive Surgery  Versus IVF
• Deciding Between Intrauterine Insemination (IUI) and In Vitro Fertilization (IVF).
• Intrauterine Insemination (IUI): Who Needs it & who Does Not: Pro’s & Con’s!IUI-Reflecting upon its Use and Misuse: Time for a Serious “Reality Check
• Mode of Action, Indications, Benefits, Limitations and Contraindications for its ue
• Clomiphene Induction of Ovulation: Its Use and Misuse!

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ADDITIONAL INFORMATION:

I am attaching online links to two E-books which I recently  co-authored with  my partner at SFS-NY  (Drew Tortoriello MD)……. for your reading pleasure:

1.From In Vitro Fertilization to Family: A Journey with Sher Fertility Solutions (SFS) “

http://sherfertilitysolutions.com/sher-fertility-solutions-ebook.pdf

1. “Recurrent Pregnancy Loss and Unexplained IVF Failure: The Immunologic Link

https://drive.google.com/file/d/1iYKz-EkAjMqwMa1ZcufIloRdxnAfDH8L/view

………………………………………………………………..

There is a possibility that the hydrosalpinges could be playing a role here. However, it is important to also consider the possibility of an anatomical and/or immunologic implantation dysfunction.

Please read below and then, if you are interested, contact my assistant Patti Converse (702-533-2691) and set up an online consultation so we can talk substantively.

Geoff Sher

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ADDITIONAL INFORMATION:

A: IMPLANTATION DYSFUNCTION

Implantation dysfunction is unfortunately often overlooked as an important cause of IVF failure. This is especially relevant in cases of unexplained IVF failure, recurrent pregnancy loss (RPL), and in women with underlying endo-uterine surface lesions, thickness of the uterine lining (endometrium) and /or immunologic factors.

IVF success rates have been improving over the last decade. The average live birth rate per embryo transfer in the U.S.A for women under 40y using their own eggs is currently better than 1:3 women. However, there is still a wide variation from program to program for IVF live birth rates, ranging from 20% to near 50%. Based upon these statistics, most women undergoing IVF in the United States require two or more attempts to have a baby. IVF practitioners in the United States commonly attribute the wide dichotomy in IVF success rates to variability in expertise of the various embryology laboratories. This is far from accurate. In fact, other factors such as wide variations in patient selection and the failure to develop individualized protocols for ovarian stimulation or to address those infectious, anatomical, and immunologic factors that influence embryo implantation are at least equally important.

About 80% of IVF failures are due to “embryo incompetency” that is largely due to aneuploidy      usually related to advancing age of the woman and is further influenced by other factors such as the protocol selected for ovarian stimulation, diminished ovarian reserve (DOR), and severe male factor infertility. However, in about 20% of dysfunctional cases embryo implantation is the cause of failure.

This section will focus on implantation dysfunction and IVF failure due to:

ANATOMICAL ENDO-UTERINE SURFACE LESIONS

            It has long been suspected that anatomical defects of the uterus might result in infertility. While the presence of uterine fibroids, in general, are unlikely to cause infertility, an association between their presence and infertility has been observed in cases where the myomas distort the uterine cavity or protrude through the endometrial lining.  Even small fibroids that lie immediately under the endometrium (submucous fibroids) and protrude into the uterine cavity have the potential to lower embryo implantation.  Multiple fibroids in the uterine wall (intramural fibroids) that encroach upon the uterine cavity can sometimes so compromise blood flow that estrogen delivery is impaired, and the endometrium is unable to thicken properly. This can usually be diagnosed by ultrasound examination during the proliferative phase of the menstrual cycle.  It is likely that any surface lesion in the uterine cavity, whether submucous fibroids, intrauterine adhesions a small endometrial or a placental polyp, has the potential to interfere with implantation by producing a local inflammatory response, not too dissimilar in nature from that which is caused by an intrauterine contraceptive device (IUD).       

            Clearly, since even small uterine lesions have the potential to adversely affect implantation, the high cost (financial, physical, and emotional) associated with IVF and related procedures, justifies the routine performance of diagnostic procedures such as an HSG, hysterosonogram (fluid ultrasound examination), or hysteroscopy prior to initiating IVF.  Identifiable uterine lesions that have the potential of impairing implantation usually require surgical intervention.  In most cases, dilatation and curettage (D & C) or hysteroscopic resection will suffice. Some cases might require the performance of a laparotomy.  Such intervention will often result in subsequent improvement of the endometrial response.      

Sonohysterography [Fluid ultrasonography (FUS)]: Fluid ultrasonography is a procedure whereby a sterile solution of saline is injected via a catheter through the cervix and into the uterine cavity. The fluid-distended cavity is examined by vaginal ultrasound for any irregularities that might point to surface lesions such as polyps, fibroid tumors, scarring, or a uterine septum. If performed by an expert, a FUS is highly effective in recognizing even the smallest lesion and can replace hysteroscopy under such circumstances. FUS is less expensive, less traumatic, and equally as effective as hysteroscopy. The only disadvantage lies in the fact that if a lesion is detected, it may require the subsequent performance of hysteroscopy to treat the problem anyway.

Hysteroscopy: Diagnostic hysteroscopy is an office procedure that is performed under intravenous sedation, general anesthesia, or paracervical block with minimal discomfort to the patient. This procedure involves the insertion of a thin, lighted, telescope like instrument known as a hysteroscope through the vagina and cervix into the uterus to fully examine the uterine cavity. The uterus is first distended with normal saline, which is passed through a sleeve adjacent to the hysteroscope. As is the case with FUS, diagnostic hysteroscopy facilitates examination of the inside of the uterus under direct vision for defects that might interfere with implantation. We have observed that approximately one in eight candidates for IVF have lesions that require attention prior to undergoing IVF in order to optimize the chances of a successful outcome. We strongly recommend that all patients undergo therapeutic surgery (usually by hysteroscopy) to correct the pathology prior to IVF.  Depending on the severity and nature of the pathology, therapeutic hysteroscopy may require general anesthesia and, in such cases, should be performed in an outpatient surgical facility or conventional operating room where facilities are available for laparotomy, a procedure in which an incision is made in the abdomen to expose the abdominal contents for diagnosis, or for surgery should this be required.       

THICKNESS OF THE UTERINE LINING (ENDOMETRIUM):

As far back as in 1989 we first reported on the finding that ultrasound assessment of the late proliferative phase endometrium can identify those candidates who are least likely to conceive. We noted that the ideal thickness of the endometrium at the time of ovulation or egg retrieval is >8 mm and that thinner linings are associated with decreased implantation rates.

More than 30 years ago we first showed that in normal and “stimulated” cycles, pre-ovulatory endometrial thickness and ultrasound appearance is predictive of embryo implantation (pregnancy) potential following ET. With conventional IVF and with FET, endometrial lining at the time of the “trigger shot” or with the initiation of progesterone needs to preferably be at least 8 mm in sagittal thickness with a triple line (trilaminar) appearance. Anything less than an 8mm endometrial thickness       is associated with a reduction in live birth rate per ET. An 8-9mm thickness represents a transitional measurement…a “gray zone”.  Hitherto, attempts to augment endometrial growth in women with poor endometrial linings by bolstering circulating estrogen blood levels (through the administration of increased doses of fertility drugs, aspirin administration and by supplementary estrogen therapy) yielded disappointing results.

            A “poor” uterine lining is usually the result of the innermost layer of endometrium (the basal or germinal endometrium from which endometrium grows) not being able to respond to estrogen by propagating an outer, “functional” layer thick enough to support optimal embryo implantation and development of a healthy placenta (placentation). The “functional” layer ultimately comprises 2/3 of the full endometrial thickness and is the layer that sheds with menstruation if no pregnancy occurs.

The main causes of a “poor” uterine lining are:

• Damage to the basal endometrium because of:
• Inflammation of the endometrium (endometritis) most commonly resulting from infected products left over following abortion, miscarriage, or birth
• Surgical trauma due to traumatic uterine scraping, (i.e. due to an over-aggressive D & C)
• Insensitivity of the basal endometrium to estrogen due to:
• Prolonged, over-use/misuse of clomiphene citrate
• Prenatal exposure to diethylstilbestrol (DES). This is a drug that was given to pregnant women in the 1960’s to help prevent miscarriage
• Over-exposure of the uterine lining to ovarian male hormones (mainly testosterone): Older women, women with diminished ovarian reserve (poor responders) and women with polycystic ovarian syndrome -PCOS tend to have raised LH biological activity. This causes the connective tissue in the ovary (stroma/theca) to overproduce testosterone. The effect may be further exaggerated when certain methods for ovarian stimulation such as “flare” protocols and high dosages of Menopur are used in such cases.
• Reduced blood flow to the basal endometrium: Examples include.
• Multiple uterine fibroids – especially when these are present under the endometrium (submucosal)
• Uterine adenomyosis (excessive, abnormal invasion of the uterine muscle by endometrial glands).

Vaginal Viagra: About 35 years ago, after reporting on the benefit of administering vaginal Sildenafil (Viagra) to women who had implantation dysfunction due to thin endometrial linings we announced the birth of the world’s first “Viagra baby.”  Viagra administered vaginally, but not orally, in affected women improves uterine blood flow causing more estrogen to be delivered to the basal endometrium and increasing the endometrial thickening.  Following vaginal administration, Viagra is rapidly absorbed and quickly reaches the uterine blood system in high concentrations. Thereupon it dilutes out as it is absorbed into the systemic circulation. This probably explains why treatment is virtually devoid of systemic side effects.  It is important to recognize that Viagra will NOT be effective in improving endometrial thickness in all cases. In fact, about one third of women treated fail to show any improvement. This is because in certain cases of thin uterine linings, the basal endometrium will have been permanently damaged and left unresponsive to estrogen. This happens in cases of severe endometrial damage due mainly to post-pregnancy endometritis (inflammation), chronic granulomatous inflammation due to uterine tuberculosis (hardly ever seen in the United States) and following extensive surgical injury to the basal endometrium (as sometimes occurs following over-zealous D&C’s).

• Immunologic factors: These also play a role in IVF failure (see “Immunologic factors and Implantation” …see below.

IMMUNOLOGIC IMPLANTATION DYSFUNCTION (IID)

            Currently, with few exceptions, practitioners of assisted reproduction tend to attribute “unexplained and/or repeated” IVF failure(s), almost exclusively to poor embryo quality, advocating adjusted protocols for ovarian stimulation and/or gamete and embryo preparation as a potential remedy. The idea, having failed IVF, that all it takes to ultimately succeed is to keep trying the same recipe is over-simplistic.

            The implantation process begins six or seven days after fertilization of the egg. At this time, specialized embryonic cells (i.e., trophoblasts), that later become the placenta begin growing into the uterine lining. When the trophoblast and the uterine lining meet, they, along with immune cells in the lining, become involved in a “cross talk” through mutual exchange of hormone-like substances called cytokines. Because of this complex immunologic interplay, the uterus can foster the embryo’s successful growth. Thus, from the earliest stage, the trophoblast establishes the very foundation for the nutritional, hormonal and respiratory interchange between mother and baby.  In this manner, the interactive process of implantation is not only central to survival in early pregnancy but also to the quality of life after birth.

There is an ever growing realization, recognition, and acceptance of the fact that uterine immunologic dysfunction can lead to immunologic implantation dysfunction (IID) with “unexplained” infertility, IVF failure, and recurrent pregnancy loss (RPL).

DIAGNOSIS 

Because immunologic problems may lead to implantation failure, it is important to properly evaluate women with risk factors such as:

• Unexplained or recurrent IVF failures
• Unexplained infertility or a family history of autoimmune diseases (e.g., rheumatoid arthritis, lupus erythematosus and hypothyroidism).
• Recurrent Pregnancy Loss (RPL)
• Endometriosis
• A personal or family history of autoimmune conditions, e.g., Rheumatoid Arthritis, Lupus erythematosus, autoimmune hypothyroidism (Hashimoto’s disease) etc.

            Considering its importance, it is not surprising that the failure of a properly functioning immunologic interaction during implantation has been implicated as a cause of recurrent miscarriage, late pregnancy fetal loss, IVF failure and infertility. A partial list of immunologic factors that may be involved in these situations includes:

• Antiphospholipid antibodies (APA)
• Antithyroid antibodies (ATA/AMA)
• Activated natural killer cells (NKa)

ACTIVATED NATURAL KILLER CELLS (NKa):

Following ovulation and during early pregnancy, NK cells and T-cells comprise more than 80% of the lymphocyte-immune cells that frequent the uterine lining. These lymphocytes (white blood cells) journey from the bone marrow to the uterus and under hormonal regulation, proliferate there. After exposure to progesterone (due to induced /spontaneous exogenous administration), they begin to produce TH-1 and TH-2 cytokines. TH-2 cytokines are humoral in nature and induce the trophoblast (“root system of the embryo”) to permeate the uterine lining while TH-I cytokines induce a process referred to as apoptosis (cell suicide) thereby confining placental development to the inner part of the uterus. Optimal placental development (placentation) mandates that there be a balance between TH1 and TH-2 cytokines. Most of the cytokine production originates from NK cells (rather than from cytotoxic T-cells/Lymphocytes (CTL)). Excessive production/release of TH-1 cytokines, is toxic to the trophoblast and to endometrial cells, leading to programmed death/suicide (apoptosis) and subsequently to IID.

Functional NK cells reach a maximal concentration in the endometrium by about t day 6-7 days after exposure to progesterone …. This timing corresponds with when the embryo implants into the uterine lining (endometrium).

It is important to bear in mind that measurement of the concentration of blood NK cells has little or no relevance when it comes to assessing NK cell activation (NKa). Rather, it is the NK cell activation that matters. In fact, there are certain conditions (such as with endometriosis) where the NK cell blood concentration is below normal, but NK cell activation is markedly increased.

There are several methods by which NK cell activation (cytotoxicity) can be assessed in the laboratory. Methods such as immunohistochemical assessment of uterine NK cells and/or through measurement of uterine or blood TH-1 cytokines. However, the K-562 target cell blood test still remains the gold standard. With this test, NK cells, isolated from the woman’s blood using Flow Cytometry are incubated in the presence of specific “target cells”. The percentage (%) of “target cells” killed is then quantified. More than 12% killing suggests a level of NK cell activation that usually requires treatment.

Currently, there are less than a half dozen Reproductive Immunology Reference Laboratories in the U.S.A that are capable of performing the K-562 target cell test reliably.

There exists a pervasive but blatant misconception on the part of many, that the addition of IL or IVIg to a concentration of NK cells could have an immediate down-regulatory effect on NK cell activity. Neither IVIg nor IL is capable of significantly suppressing already activated “functional NK cells”. They are believed to work through “regulating” NK cell progenitors which only thereupon will start to propagate down-regulated NK cells. Thus, testing for a therapeutic effect would require that the IL/IVIg infusion be done about 14 days prior to ovulation or progesterone administration…  in order to allow for a sufficient number of normal (non-activated) “functional” NK cell” to be present at the implantation site when the embryos are transferred.

Failure to recognize this reality has, in our opinion, established an erroneous demand by practicing IVF doctors, that Reproductive Immunology Reference Laboratories report on NK cell activity before and again, immediately following laboratory exposure to IVIg and/or IL in different concentrations. Allegedly, this is to allow the treating physician to report back to their patient(s) on whether an IL or IVIG infusion will be effective in downregulating their Nka.  But, since already activated NK cells (NKa) cannot be deactivated in the laboratory, effective NKa down-regulation can only be adequately accomplished through deactivation of NK cell “progenitors /parental” NK cells in order to allow them thereupon, to s propagate normal “functional” NK cells and his takes about 10-14 days, such practice would be of little clinical benefit. This is because even if blood were to be drawn 10 -14 days after IL/IVIg treatment it would require at least an additional 10 -14days to receive results from the laboratory, by which time it would be far too late to be of practical advantage.

ANTIPHOSPHOLIPID ANTIBODIES:

 Many women who experience “unexplained” IVF failure, women with RPL, those with a personal or family history of autoimmune diseases such as lupus erythematosus, rheumatoid arthritis, scleroderma, and dermatomyositis (etc.)  as well as women who have endometriosis (“silent” or overt) test positive for APAs. More than 30 years ago, we were the first to propose that women who test positive for APA’s be treated with a mini-dose heparin to improve IVF implantation and thus birth rates. This approach was based upon research that suggested that heparin repels APAs from the surface of the trophoblast (the embryo’s “root system) thereby reducing its ant-implantation effects.  We subsequently demonstrated that such therapy only improved IVF outcome in women whose APAs were directed against two specific IgG and/or IgM phospholipids [i.e., phosphatidylethanolamine (PE) and phosphatidylserine (PS)].  More recently low dosage heparin therapy has been supplanted using longer acting low molecular weight heparinoids such as Lovenox and Clexane.   It is very possible that APAs alone do not cause IID but that their presence might help to identify a population at risk due to concomitant activation of uterine natural killer cells (Nka) which through excessive TH-1 cytokine production causes in IID: This is supported by the following observations:

• The presence of female APAs in cases of male factor cases appears to bear no relationship to IID.
• Only APA positive women who also test positive for abnormal NK activity appear to benefit from selective immunotherapy with intralipid/IVIg/ steroids.
• Most APA positive women who have increased NK cell activity also harbor IgG or IgM phosphatidylethanolamine (PE) and phosphatidylserine (PS) antibodies.

ANTITHYROID ANTIBODIES: (ATA).

 A clear relationship has been established between ATA and reproductive failure (especially recurrent miscarriage and infertility).

Between 2% and 5% of women of the childbearing age have reduced thyroid hormone activity (hypothyroidism). Women with hypothyroidism often manifest with reproductive failure i.e., infertility, unexplained (often repeated) IVF failure, or recurrent pregnancy loss (RPL). The condition is 5-10 times more common in women than in men. In most cases hypothyroidism is caused by damage to the thyroid gland resulting from of thyroid autoimmunity (Hashimoto’s disease) caused by damage done to the thyroid gland by antithyroglobulin and antimicrosomal auto-antibodies. 

The increased prevalence of hypothyroidism and thyroid autoimmunity (TAI) in women is likely the result of a combination of genetic factors, estrogen-related effects, and chromosome X abnormalities.  This having been said, there is significantly increased incidence of thyroid antibodies in non-pregnant women with a history of infertility and recurrent pregnancy loss and thyroid antibodies ^can be present asymptomatically in women without them manifesting with overt clinical or endocrinologic evidence of thyroid disease. In addition, these antibodies may persist in women who have suffered from hyper- or hypothyroidism even after normalization of their thyroid function by appropriate pharmacological treatment. The manifestations of reproductive dysfunction thus seem to be linked more to the presence of thyroid autoimmunity (TAI) than to clinical existence of hypothyroidism and treatment of the latter does not routinely result in a subsequent improvement in reproductive performance.

It follows, that if antithyroid autoantibodies are associated with reproductive dysfunction they may serve as useful markers for predicting poor outcome in patients undergoing assisted reproductive technologies.

Some years back, I reported on the fact that 47% of women who harbor thyroid autoantibodies, regardless of the absence or presence of clinical hypothyroidism, have activated uterine natural killer cells (NKa) cells and cytotoxic lymphocytes (CTL) and that such women often present with reproductive dysfunction. We demonstrated that appropriate immunotherapy with IVIG or intralipid (IL) and steroids, subsequently often results in a significant improvement in reproductive performance in such cases.

The fact that almost 50% of women who harbor antithyroid antibodies do not have activated CTL/NK cells suggests that it is NOT the antithyroid antibodies themselves that cause reproductive dysfunction. The activation of CTL and NK cells that occurs in half of the cases with TAI is probably an epiphenomenon with the associated reproductive dysfunction being due to CTL/NK cell activation that damages the early “root system” (trophoblast) of the implanting embryo. We have shown that treatment of those women who have thyroid antibodies + NKa/CTL using IL/steroids, improves subsequent reproductive performance while women with thyroid antibodies who do not harbor NKa/CTL do not require or benefit from such treatment

TEATMENT OF IID:

The mainstay of treatment involves the selective use of:

• Intralipid (IL) infusion
• IVIg therapy
• Corticosteroids (Prednisone/dexamethasone)
• Heparinoids (Lovenox/Clexane)

Intralipid (IL) Therapy:  IL is a suspension of soybean lipid droplets in water and is primarily used as source of parenteral nutrition. When administered intravenously, IL provides essential fatty acids, linoleic acid (LA), an omega-6 fatty acid, and alpha-linolenic acid (ALA), an omega-3 fatty acid.     

It is thought that fatty acids within the emulsion serve as ligands that activate peroxisome proliferator-activated receptors (PPARs) expressed by the NK cells. This is believed to decrease NK cell cytotoxic activity, and thereby enhance implantation A growing number of IVF programs, including ours, perform egg retrieval under conscious sedation using Propofol, a short acting hypnotic agent.

            Whatever the exact mechanism of action might be, Intralipid acts primarily to suppress NK cell over-production of TH-I cytokines. It 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, prednisolone and prednisone which augment immune modulation of T cells. The combined effect of IL + steroid therapy suppresses pro-inflammatory cellular TH1 cytokines such as interferon gamma and TNF-alpha that are produced in excess by activated NK cells and cytotoxic lymphocytes/T-cells (CTL).   IL will, in about 80% of cases, successfully down-regulate activated natural killer cells (NKa) over a period of 2-3 weeks. It is likely to be just as effective as IVIg in this respect but at a fraction of the cost and with a far lower incidence of side-effects. Its effect lasts for ~ 4-6 weeks when administered in early pregnancy.

Intralipid is a suspension of soybean lipid droplets in water and is primarily used as source of parenteral nutrition. When administered intravenously, IL provides essential fatty acids, linoleic acid (LA), an omega-6 fatty acid, and alpha-linolenic acid (ALA), an omega-3 fatty acid.     

It is thought that fatty acids within the emulsion serve as ligands that activate peroxisome proliferator-activated receptors (PPARs) expressed by the NK cells. This is believed to decrease NK cell cytotoxic activity, and thereby enhance implantation A growing number of IVF programs, including ours, perform egg retrieval under conscious sedation using Propofol, a short acting hypnotic agent.

            Whatever the exact mechanism of action might be, Intralipid acts primarily to suppress NK cell over-production of TH-I cytokines. It 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, prednisolone and prednisone which augment immune modulation of T cells. The combined effect of IL + steroid therapy suppresses pro-inflammatory cellular TH1 cytokines such as interferon gamma and TNF-alpha that are produced in excess by activated NK cells and cytotoxic lymphocytes/T-cells (CTL).   IL will, in about 80% of cases, successfully down-regulate activated natural killer cells (NKa) over a period of 2-3 weeks. It is likely to be just as effective as IVIg in this respect but at a fraction of the cost and with a far lower incidence of side-effects. Its effect lasts for ~ 4-6 weeks when administered in early pregnancy.

            Can laboratory testing be used to assess for an immediate effect of IL on Nka suppression?  Since the downregulation of NKa through IL (or IVIg) therapy can take several weeks to become measurable, 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 cells being tested.

IVIg 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 RE’s to simply say “I don’t believe IVIg works” and thereby avoid risk and bad publicity. But the thousands of women who had babies because of NK cell activity being downregulated 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 (about 15-20 years ago ), that the tide began to turn in favor of those patients who required low cost, safe and effective immunotherapy to resolve their IID.

 Corticosteroid Therapy (e.g., Prednisone, 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. Corticosteroids reduce TH-1 cytokine production by CTL. When given in combination with IL or IVIG they augment the implantation process. The prednisone or dexamethasone therapy must commence (along with IL/IVIg) 10-14 days prior to egg retrieval and continue until pregnancy is discounted or until the 10th week of pregnancy.

 Heparinoid Therapy: There is compelling evidence that the subcutaneous administration of 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 might prevent later pregnancy loss when used to treat certain thrombophilias (e.g., homozygous MTHFR mutation)

What About Baby Aspirin? In our opinion, aspirin has little (if any) value when it comes to IID, and besides, it 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.

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. However, 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.

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 thereby improving 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.

There are two categories of immunologic implantation dysfunction (IID) linked to NK cell activation (NKa).

Autoimmune Implantation Dysfunction: Here, the woman will often have a personal or family history of autoimmune conditions such as Rheumatoid arthritis, Lupus Erythematosus, and thyroid autoimmune activity (e.g., Hashimoto’s disease) etc. Autoimmune as well as in about one third of cases of endometriosis, regardless of severity.  Autoimmune sometimes also occurs in the absence of a personal or family history of autoimmune disease.

When it comes to treating  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 PGT-normal 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 39Y (who have normal ovarian reserve)  is approximately  65%.

Alloimmune Implantation Dysfunction: Here, NK cell activation results from uterine exposure to an embryo derived through fertilization by a spermatozoon that shares certain genotypic (HLA/DQ alpha) similarities with that of the embryo recipient.

Partial DQ alpha/HLA match:  Couples who upon genotyping are shown to share only one DQ alpha/HLA gene are labeled as having a “partial match”. The detection of a “partial match” in association with NKa puts the couple at a considerable disadvantage with regard to IVF outcome. It should be emphasized however, that in the absence of associated Nka, DQ alpha/HLA matching whether “partial” or “total (see below) will NOT cause an IID. Since we presently have no way of determining which embryo carries a matching paternal DQ alpha gene, it follows that each embryo transferred will have about half the chance of propagating a viable pregnancy. Treatment of a partial DQ alpha/HLA match (+ Nka) involves the same IL, infusion as for autoimmune-Nka with one important caveat, namely that here we prescribe oral prednisone as adjunct therapy (rather than dexamethasone) and the IL infusion is repeated every 2-4 weeks following the diagnosis of pregnancy and continued until the 24th week of gestation. Additionally, (as alluded to elsewhere) in such cases we transfer a single (1) embryo at a time. This is because, the likelihood is that one out of two embryos will “match” and we are fearful that if we transfer >1 embryo, and one transferred embryos “matches” it could cause further activation of uterine NK cells and so prejudice the implantation of all transferred embryos. Here it should be emphasized that if associated with Nka, a matching embryo will still be at risk of rejection even in the presence of Intralipid (or IVIg) therapy.

Total (complete) DQ alpha Match:   Here the husband’s DQ alpha genotype matches both of that of his partner’s. While this occurs very infrequently, a total alloimmune (DQ alpha) match with accompanying Nka, means that the chance of a viable pregnancy resulting in a live birth at term, is unfortunately greatly diminished.  Several instances in our experience have required the use of a gestational surrogate.

It is indeed unfortunate that so many patients are being denied the ability to go from “infertility to family” simply because (for whatever reason) so many reproductive specialists refuse to embrace the role of immunologic factors in the genesis of intractable reproductive dysfunction. Hopefully this will change, and the sooner the better.

B. MANAGING IMMUNOLOGIC IMPLANTATION DYSFUNCTION (IID)

Currently, with few exceptions, practitioners of assisted reproduction tend to attribute “unexplained and/or repeated” IVF failure(s), almost exclusively to poor embryo quality, advocating adjusted protocols for ovarian stimulation and/or gamete and embryo preparation as a potential remedy. The idea, having failed IVF, that all it takes to ultimately succeed is to keep trying the same recipe is over-simplistic.

The implantation process begins six or seven days after fertilization of the egg. At this time, specialized embryonic cells (i.e., trophoblasts), that later become the placenta begin growing into the uterine lining. When the trophoblast and the uterine lining meet, they, along with immune cells in the lining, become involved in a “cross talk” through mutual exchange of hormone-like substances called cytokines. Because of this complex immunologic interplay, the uterus can foster the embryo’s successful growth. Thus, from the earliest stage, the trophoblast establishes the very foundation for the nutritional, hormonal and respiratory interchange between mother and baby.  In this manner, the interactive process of implantation is not only central to survival in early pregnancy but also to the quality of life after birth.

There is an ever growing realization, recognition, and acceptance of the fact that uterine immunologic dysfunction can lead to immunologic implantation dysfunction (IID) with “unexplained” infertility, IVF failure, and recurrent pregnancy loss (RPL).

DIAGNOSIS 

Because immunologic problems may lead to implantation failure, it is important to properly evaluate women with risk factors such as:

• Unexplained or recurrent IVF failures
• Unexplained infertility or a family history of autoimmune diseases (e.g., rheumatoid arthritis, lupus erythematosus and hypothyroidism).
• Recurrent Pregnancy Loss (RPL)
• Endometriosis
• A personal or family history of autoimmune conditions, e.g., Rheumatoid Arthritis, Lupus erythematosus, autoimmune hypothyroidism (Hashimoto’s disease) etc.

Considering its importance, it is not surprising that the failure of a properly functioning immunologic interaction during implantation has been implicated as a cause of recurrent miscarriage, late pregnancy fetal loss, IVF failure and infertility. A partial list of immunologic factors that may be involved in these situations includes:

• Antiphospholipid antibodies (APA)
• Antithyroid antibodies (ATA/AMA)
• Activated natural killer cells (NKa)

ACTIVATED NATURAL KILLER CELLS (NKa):

Following ovulation and during early pregnancy, NK cells and T-cells comprise more than 80% of the lymphocyte-immune cells that frequent the uterine lining. These lymphocytes (white blood cells) journey from the bone marrow to the uterus and under hormonal regulation, proliferate there. After exposure to progesterone (due to induced /spontaneous exogenous administration), they begin to produce TH-1 and TH-2 cytokines. TH-2 cytokines are humoral in nature and induce the trophoblast (“root system of the embryo”) to permeate the uterine lining while TH-I cytokines induce a process referred to as apoptosis (cell suicide) thereby confining placental development to the inner part of the uterus. Optimal placental development (placentation) mandates that there be a balance between TH1 and TH-2 cytokines. Most of the cytokine production originates from NK cells (rather than from cytotoxic T-cells/Lymphocytes (CTL)). Excessive production/release of TH-1 cytokines, is toxic to the trophoblast and to endometrial cells, leading to programmed death/suicide (apoptosis) and subsequently to IID.

Functional NK cells reach a maximal concentration in the endometrium by about t day 6-7 days after exposure to progesterone …. This timing corresponds with when the embryo implants into the uterine lining (endometrium).

It is important to bear in mind that measurement of the concentration of blood NK cells has little or no relevance when it comes to assessing NK cell activation (NKa). Rather, it is the NK cell activation that matters. In fact, there are certain conditions (such as with endometriosis) where the NK cell blood concentration is below normal, but NK cell activation is markedly increased.

There are several methods by which NK cell activation (cytotoxicity) can be assessed in the laboratory. Methods such as immunohistochemical assessment of uterine NK cells and/or through measurement of uterine or blood TH-1 cytokines. However, the K-562 target cell blood test still remains the gold standard. With this test, NK cells, isolated from the woman’s blood using Flow Cytometry are incubated in the presence of specific “target cells”. The percentage (%) of “target cells” killed is then quantified. More than 12% killing suggests a level of NK cell activation that usually requires treatment.

Currently, there are less than a half dozen Reproductive Immunology Reference Laboratories in the U.S.A that are capable of performing the K-562 target cell test reliably.

There exists a pervasive but blatant misconception on the part of many, that the addition of IL or IVIg to a concentration of NK cells could have an immediate down-regulatory effect on NK cell activity. Neither IVIg nor IL is capable of significantly suppressing already activated “functional NK cells”. They are believed to work through “regulating” NK cell progenitors which only thereupon will start to propagate down-regulated NK cells. Thus, testing for a therapeutic effect would require that the IL/IVIg infusion be done about 14 days prior to ovulation or progesterone administration…  in order to allow for a sufficient number of normal (non-activated) “functional” NK cell” to be present at the implantation site when the embryos are transferred.

Failure to recognize this reality has, in our opinion, established an erroneous demand by practicing IVF doctors, that Reproductive Immunology Reference Laboratories report on NK cell activity before and again, immediately following laboratory exposure to IVIg and/or IL in different concentrations. Allegedly, this is to allow the treating physician to report back to their patient(s) on whether an  IL or IVIG infusion will be effective in down-regulating their Nka.  But, since already activated NK cells (NKa) cannot be deactivated in the laboratory, effective NKa down-regulation can only be adequately accomplished through deactivation of NK cell “progenitors /parental” NK cells in order too allow them thereupon, to s propagate normal “functional” NK cells and his takes about 10-14 days, such practice  would be of little clinical benefit. This is because even if blood were to be drawn 10 -14 days after IL/IVIg treatment it would require at least  an additional 10 -14days to receive results from the laboratory, by which time it would be far too late to be of practical advantage.

ANTIPHOSPHOLIPID ANTIBODIES:

 Many women who experience “unexplained” IVF failure, women with RPL, those with a personal or family history of autoimmune diseases such as lupus erythematosus, rheumatoid arthritis, scleroderma, and dermatomyositis (etc.)  as well as women who have endometriosis (“silent” or overt) test positive for APAs. More than 30 years ago, we were the first to propose that women who test positive for APA’s be treated with a mini-dose heparin to improve IVF implantation and thus birth rates. This approach was based upon research that suggested that heparin repels APAs from the surface of the trophoblast (the embryo’s “root system) thereby reducing its ant-implantation effects.  We subsequently demonstrated that such therapy only improved IVF outcome in women whose APAs were directed against two specific IgG and/or IgM phospholipids [i.e., phosphatidylethanolamine (PE) and phosphatidylserine (PS)].  More recently low dosage heparin therapy has been supplanted using longer acting low molecular weight heparinoids such as Lovenox and Clexane.   It is very possible that APAs alone do not cause IID but that their presence might help to identify a population at risk due to concomitant activation of uterine natural killer cells (Nka) which through excessive TH-1 cytokine production causes in IID: This is supported by the following observations:

• The presence of female APAs in cases of male factor cases appears to bear no relationship to IID.
• Only APA positive women who also test positive for abnormal NK activity appear to benefit from selective immunotherapy with intralipid/IVIg/ steroids.
• Most APA positive women who have increased NK cell activity also harbor IgG or IgM phosphatidylethanolamine (PE) and phosphatidylserine (PS) antibodies.

ANTITHYROID ANTIBODIES: (ATA).

 A clear relationship has been established between ATA and reproductive failure (especially recurrent miscarriage and infertility).

Between 2% and 5% of women of the childbearing age have reduced thyroid hormone activity (hypothyroidism). Women with hypothyroidism often manifest with reproductive failure i.e., infertility, unexplained (often repeated) IVF failure, or recurrent pregnancy loss (RPL). The condition is 5-10 times more common in women than in men. In most cases hypothyroidism is caused by damage to the thyroid gland resulting from of thyroid autoimmunity (Hashimoto’s disease) caused by damage done to the thyroid gland by antithyroglobulin and antimicrosomal auto-antibodies. 

The increased prevalence of hypothyroidism and thyroid autoimmunity (TAI) in women is likely the result of a combination of genetic factors, estrogen-related effects, and chromosome X abnormalities.  This having been said, there is significantly increased incidence of thyroid antibodies in non-pregnant women with a history of infertility and recurrent pregnancy loss and thyroid antibodies ^can be present asymptomatically in women without them manifesting with overt clinical or endocrinologic evidence of thyroid disease. In addition, these antibodies may persist in women who have suffered from hyper- or hypothyroidism even after normalization of their thyroid function by appropriate pharmacological treatment. The manifestations of reproductive dysfunction thus seem to be linked more to the presence of thyroid autoimmunity (TAI) than to clinical existence of hypothyroidism and treatment of the latter does not routinely result in a subsequent improvement in reproductive performance.

It follows, that if antithyroid autoantibodies are associated with reproductive dysfunction they may serve as useful markers for predicting poor outcome in patients undergoing assisted reproductive technologies.

Some years back, I reported on the fact that 47% of women who harbor thyroid autoantibodies, regardless of the absence or presence of clinical hypothyroidism, have activated uterine natural killer cells (NKa) cells and cytotoxic lymphocytes (CTL) and that such women often present with reproductive dysfunction. We demonstrated that appropriate immunotherapy with IVIG or intralipid (IL) and steroids, subsequently often results in a significant improvement in reproductive performance in such cases.

The fact that almost 50% of women who harbor antithyroid antibodies do not have activated CTL/NK cells suggests that it is NOT the antithyroid antibodies themselves that cause reproductive dysfunction. The activation of CTL and NK cells that occurs in half of the cases with TAI is probably an epiphenomenon with the associated reproductive dysfunction being due to CTL/NK cell activation that damages the early “root system” (trophoblast) of the implanting embryo. We have shown that treatment of those women who have thyroid antibodies + NKa/CTL using IL/steroids, improves subsequent reproductive performance while women with thyroid antibodies who do not harbor NKa/CTL do not require or benefit from such treatment

TEATMENT OF IID:

The mainstay of treatment involves the selective use of :

• Intralipid (IL) infusion
• IVIg therapy
• Corticosteroids (Prednisone/dexamethasone)
• Heparinoids (Lovenox/Clexane)

Intralipid (IL) Therapy:  IL is a suspension of soybean lipid droplets in water and is primarily used as source of parenteral nutrition. When administered intravenously, IL provides essential fatty acids, linoleic acid (LA), an omega-6 fatty acid, and alpha-linolenic acid (ALA), an omega-3 fatty acid.     

It is thought that fatty acids within the emulsion serve as ligands that activate peroxisome proliferator-activated receptors (PPARs) expressed by the NK cells. This is believed to decrease NK cell cytotoxic activity, and thereby enhance implantation A growing number of IVF programs, including ours, perform egg retrieval under conscious sedation using Propofol, a short acting hypnotic agent.

            Whatever the exact mechanism of action might be, Intralipid acts primarily to suppress NK cell over-production of TH-I cytokines. It 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, prednisolone and prednisone which augment immune modulation of T cells. The combined effect of IL + steroid therapy suppresses pro-inflammatory cellular TH1 cytokines such as interferon gamma and TNF-alpha that are produced in excess by activated NK cells and cytotoxic lymphocytes/T-cells (CTL).   IL will, in about 80% of cases, successfully down-regulate activated natural killer cells (NKa) over a period of 2-3 weeks. It is likely to be just as effective as IVIg in this respect but at a fraction of the cost and with a far lower incidence of side-effects. Its effect lasts for ~ 4-6 weeks when administered in early pregnancy.

Intralipid is a suspension of soybean lipid droplets in water and is primarily used as source of parenteral nutrition. When administered intravenously, IL provides essential fatty acids, linoleic acid (LA), an omega-6 fatty acid, and alpha-linolenic acid (ALA), an omega-3 fatty acid.     

It is thought that fatty acids within the emulsion serve as ligands that activate peroxisome proliferator-activated receptors (PPARs) expressed by the NK cells. This is believed to decrease NK cell cytotoxic activity, and thereby enhance implantation A growing number of IVF programs, including ours, perform egg retrieval under conscious sedation using Propofol, a short acting hypnotic agent.

            Whatever the exact mechanism of action might be, Intralipid acts primarily to suppress NK cell over-production of TH-I cytokines. It 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, prednisolone and prednisone which augment immune modulation of T cells. The combined effect of IL + steroid therapy suppresses pro-inflammatory cellular TH1 cytokines such as interferon gamma and TNF-alpha that are produced in excess by activated NK cells and cytotoxic lymphocytes/T-cells (CTL).   IL will, in about 80% of cases, successfully down-regulate activated natural killer cells (NKa) over a period of 2-3 weeks. It is likely to be just as effective as IVIg in this respect but at a fraction of the cost and with a far lower incidence of side-effects. Its effect lasts for ~ 4-6 weeks when administered in early pregnancy.

            Can laboratory testing be used to assess for an immediate effect of IL on Nka suppression?  Since the downregulation of NKa through IL (or IVIg) therapy can take several weeks to become measurable, 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 cells being tested.

IVIg 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 RE’s to simply say “I don’t believe IVIg works” and thereby avoid risk and bad publicity. But the thousands of women who had babies because of NK cell activity being downregulated 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 (about 15-20 years ago ), that the tide began to turn in favor of those patients who required low cost, safe and effective immunotherapy to resolve their IID.

 Corticosteroid Therapy (e.g., Prednisone, 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. Corticosteroids reduce TH-1 cytokine production by CTL. When given in combination with IL or IVIG they augment the implantation process. The prednisone or dexamethasone therapy must commence (along with IL/IVIg)  10-14 days prior to egg retrieval and continue until pregnancy is discounted or until the 10th week of pregnancy.

 Heparinoid Therapy: There is compelling evidence that the subcutaneous administration of 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 might prevent later pregnancy loss when used to treat certain thrombophilias (e.g. homozygous MTHFR mutation)

What About Baby Aspirin? In our opinion, aspirin has little (if any) value when it comes to IID, and besides, it 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.

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. However, 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.

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 thereby improving 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.

There are two categories of immunologic implantation dysfunction (IID) linked to NK cell activation (NKa).

Autoimmune Implantation Dysfunction: Here, the woman will often have a personal or family history of autoimmune conditions such as Rheumatoid arthritis, Lupus Erythematosus, and thyroid autoimmune activity (e.g., Hashimoto’s disease) etc. Autoimmune as well as in about one third of cases of endometriosis, regardless of severity.  Autoimmune sometimes also occurs in the absence of a personal or family history of autoimmune disease.

When it comes to treating  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 PGT-normal 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 39Y (who have normal ovarian reserve)  is approximately  65%.

Alloimmune Implantation Dysfunction: Here, NK cell activation results from uterine exposure to an embryo derived through fertilization by a spermatozoon that shares certain genotypic (HLA/DQ alpha) similarities  with that of the embryo recipient.

Partial DQ alpha/HLA match:  Couples who upon genotyping are shown to share only one DQ alpha/HLA gene are labeled as having a “partial match”. The detection of a “partial match” in association with NKa puts the couple at a considerable disadvantage with regard to IVF outcome. It should be emphasized however, that in the absence of associated Nka, DQ alpha/HLA matching whether “partial” or “total (see below) will NOT cause an IID. Since we presently have no way of determining which embryo carries a matching paternal DQ alpha gene, it follows that each embryo transferred will have about half the chance of propagating a viable pregnancy. Treatment of a partial DQ alpha/HLA match (+ Nka) involves the same IL, infusion as for autoimmune-Nka with one important caveat, namely that here we prescribe oral prednisone as adjunct therapy (rather than dexamethasone) and the IL infusion is repeated every 2-4 weeks following the diagnosis of pregnancy and continued until the 24th week of gestation. Additionally, (as alluded to elsewhere) in such cases we transfer a single (1) embryo at a time. This is because, the likelihood is that one out of two embryos will “match” and we are fearful that if we transfer >1 embryo, and one transferred embryos “matches” it could cause further activation of uterine NK cells and so prejudice the implantation of all transferred embryos. Here it should be emphasized that if associated with Nka, a matching embryo will still be at risk of rejection even in the presence of Intralipid (or IVIg) therapy.

Total (complete) DQ alpha Match:   Here the husband’s DQ alpha genotype matches both of that of his partner’s. While this occurs very infrequently, a total alloimmune (DQ alpha) match with accompanying Nka, means that the chance of a viable pregnancy resulting in a live birth at term, is unfortunately greatly diminished.  Several instances in our experience have required the use of a gestational surrogate.

It is indeed unfortunate that so many patients are being denied the ability to go from “infertility to family” simply because (for whatever reason) so many reproductive specialists refuse to embrace the role of immunologic factors in the genesis of intractable reproductive dysfunction. Hopefully this will change, and the sooner the better.

I strongly recommend that you visit 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.
• 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) Why did my IVF Fail
• Recurrent Pregnancy Loss (RPL): Why do I keep losing my PregnanciesGenetically Testing Embryos for IVF
• Staggered IVF
• Staggered IVF with PGS- Selection of “Competent” Embryos Greatly Enhances the Utility & Efficiency of IVF.
• Embryo Banking/Stockpiling: Slows the “Biological Clock” and offers a Selective Alternative to IVF-Egg Donation
• Preimplantation Genetic Testing (PGS) in IVF: It should be Used Selectively and NOT be Routine.
• IVF: Selecting the Best Quality Embryos to Transfer
• Preimplantation Genetic Sampling (PGS) Using: Next Generation Gene Sequencing (NGS): Method of Choice.
• PGS in IVF: Are Some Chromosomally abnormal Embryos Capable of Resulting in Normal Babies and Being Wrongly Discarded?
• 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!
• Natural Killer Cell Activation (NKa) and Immunologic Implantation Dysfunction in IVF: The Controversy!

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I am attaching online links to two E-books which I recently  co-authored with  my partner at SFS-NY  (Drew Tortoriello MD)……. for your reading pleasure:

1.From In Vitro Fertilization to Family: A Journey with Sher Fertility Solutions (SFS) “

http://sherfertilitysolutions.com/sher-fertility-solutions-ebook.pdf

1. “Recurrent Pregnancy Loss and Unexplained IVF Failure: The Immunologic Link

https://drive.google.com/file/d/1iYKz-EkAjMqwMa1ZcufIloRdxnAfDH8L/view

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I would be delighted to consult with you. Please contact my assistant, Patti Converse at 702-533-2691 and set up an online consultation with me.

I look forward to meeting both you and your husband.

Geoff Sher

ADDITIONAL INFORMATION:

I am attaching online links to two E-books which I recently  co-authored with  my partner at SFS-NY  (Drew Tortoriello MD)……. for your reading pleasure:

1.From In Vitro Fertilization to Family: A Journey with Sher Fertility Solutions (SFS) “

http://sherfertilitysolutions.com/sher-fertility-solutions-ebook.pdf

1. “Recurrent Pregnancy Loss and Unexplained IVF Failure: The Immunologic Link

https://drive.google.com/file/d/1iYKz-EkAjMqwMa1ZcufIloRdxnAfDH8L/view

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Respectfully,

This is  likely NOT a lab issue but rather due to a combination of diminished ovarian reserve and the protocol used for ovarian stimulation. We should talk before you go any further.

It is primarily the egg (rather than the sperm) that determines the chromosomal integrity (karyotype) of the embryo, the most important determinant of egg/embryo competency”. A “competent” egg is therefore one that has a normal karyotype and has the best potential to propagate a “competent” embryo. In turn, a “competent embryo is one that possesses the highest potential to implant and develop into a normal, healthy, baby.

When it comes to reproductive performance, humans are the least efficient of all mammals. Even in young women under 35y, at best only 2 out of 3 eggs are chromosomally numerically normal (euploid). The remainder will have an irregular number of chromosomes (aneuploid) and are thus “incompetent”. The incidence of egg aneuploidy increases with age such by age 39 years, 3 in 4 are “competent”, and by the mid-forties, at best one in 10 are likely to be aneuploid. The fertilization of an aneuploid egg will inevitably lead to embryo aneuploidy (“incompetence”). As previously stated,   an aneuploid embryo cannot propagate a normal pregnancy

Within 38-42 hours of the initiation of the spontaneous pre-ovulatory luteinizing hormone (LH) surge (and also following administration of the human chorionic gonadotropin (hCG) “trigger” shot, given to induce egg maturation after ovarian stimulation with fertility drugs), the egg embarks on a rapid maturational process that involves halving of its 46 chromosomes to 23. During this process, (known as meiosis) 23 chromosomes are retained within the nucleus of the egg while the remaining 23 chromosomes are expelled in a membrane envelopment, from the egg nucleus. This small structure known as the polar body, comes to lie immediately below the “shell” of the egg (the zona pellucida) and is known as the 1st polar body or PB-1. The sperm, in the process of its maturation also undergoes meiosis divides into two separate functional gametes, each containing 23 chromosomes (half its original number of 46 chromosomes).  With subsequent fertilization, the 23 chromosomes of the egg now fuse with the 23 chromosomes of the mature sperm resulting in the development of an embryo with  46 chromosomes (the normal human genome) comprising a combination of the genetic material from both partners. For the embryo to have exactly 46 chromosomes (the euploid number), both the mature egg and mature spermatozoon must contain exactly 23 chromosomes. Only such euploid embryos are “competent” (capable of developing into healthy babies). Those with an irregular number of chromosomes (aneuploid embryos) are “incompetent” and are incapable of propagating healthy babies. While embryo “incompetence” can result from either egg or sperm aneuploidy, it usually stems from egg aneuploidy. However, in cases of moderate or severe male factor infertility, the sperm’s contribution to aneuploidy of the embryo can be significantly greater.

While embryo ploidy (numerical chromosomal integrity) is not the only determinant of its “competency, it is by far the most important and in fact is a rate-limiting factor in human reproduction. It is causal in the vast majority of cases of “failed nidation which in turn is responsible for most cases of a failed pregnancy (natural or assisted) and causes most sporadic early pregnancy losses (both chemical gestations and miscarriages) as well as  many chromosomal birth defects such as Turner syndrome (X-monosomy ) Down syndrome (trisomy 21) and Edward syndrome (trisomy 18) .

In most cases, embryos that develop too slowly as well as those that grow too fast (i.e. ones that by day 3 post-fertilization comprise fewer than 6 cells or more than 9 cells) and/or embryos that contain cell debris or “fragments” are usually aneuploid and are thus unable to propagate a healthy pregnancy (“incompetent”). Additionally, embryos that fail to survive in culture to the blastocyst stage are also almost always aneuploid/”incompetent”.

At a certain point in the later stage of a woman’s reproductive career, the number of remaining eggs in her ovaries falls below a certain threshold, upon which she is unable to respond optimally to fertility drugs. Often times this is signaled by a rising day 3 basal blood follicle stimulating hormone (FSH) level (>9.0MIU/ml) and a falling blood anti-Mullerian hormone (AMH) level (<2.0ng/ml or <15nmol/L). Such women who have  diminished ovarian reserve (DOR) produce fewer eggs in response to ovarian stimulation. While DOR is most commonly encountered in women over 40 years of age it can and indeed also can occur in much younger women.

A few important (but often overlooked concepts should be considered in this regard:

• Age: It is advancing chronologic age and NOT declining ovarian reserve (as evidenced by abnormal blood AMH or FSH that results in an increased incidence of egg/embryo “incompetence” due to aneuploidy
• The ovaries and developing eggs of women with DOR (regardless of age) are highly susceptible to the adverse effect of excessive Luteinizing Hormone (LH)-induced, ovarian overproduction of male hormones (e,g. testosterone and androstenedione). While a little testosterone produced by the ovary promotes normal follicle growth and orderly egg development excessive testosterone has a converse effect. That is why in older women and those who regardless of their age have DOR (and thus excessive LH bioavailability and increased ovarian testosterone production), the use of ovarian stimulation protocols that fail to down-regulate LH activity prior to initiating ovarian stimulation with gonadotropins, often prejudices egg/embryo quality and IVF outcome.
• Simply stated, while age is certainly the most important factor in determining the incidence of egg/embryo aneuploidy, women with DOR (regardless of their age), are less likely to propagate euploid (competent) eggs/embryos. While virtually nothing can be done to lower the incidence of age related aneuploidy, it is indeed possible to avoid a further decrease in egg/embryo “competency”  by individualizing the protocols of ovarian stimulation used.
• My preferred protocols for women who have relatively normal ovarian reserve:
• The conventional long pituitary down regulation protocol: BCP are commenced early in the cycle and continued for at least 10 days. Starting 3 days before the BCP is to be discontinued, it is overlapped with an agonist such as Lupron 10U daily for three (3) days and continued until menstruation begins (which should ensue within 5-7 days of stopping the BCP). At that point an US examination is done along with a baseline measurement of blood estradiol to exclude a functional ovarian cyst. Daily Lupron (10U) is continued and an FSH-dominant gonadotropin such as Follistim, Puregon or Gonal-f daily is administered daily falong with 37.5U of Menopur (an FSH/LH combination) for 2 days. On the 3^rd day the gonadotropin dosage is reduced by about one half and the dosage of Menopur is increased to 75U daily. Daily ultrasound and blood estradiol measurements are conducted starting on the 7^th or 8^th day of gonadotropin administration and continued until daily ultrasound follicle assessments indicate that most follicles have fully developed. At this point egg maturation is “triggered” using an intramuscular injection of a recombinant hCGr (Ovidrel) 500mcg or urinary derived hCGu (Pregnyl/Profasi/Novarel) 10,000U. And an egg retrieval is scheduled for 36h later.
• The agonist/antagonist conversion protocol (A/ACP): This is essentially the same as the conventional long down regulation protocol (see “a”-as above), except that with the onset of post-BCP menstruation, the agonist is supplanted by daily administration of a GnRH antagonist (e.g. Ganirelix, Cetrotide or Orgalutron) at a dosage of 125-250mcg daily until the day of the “trigger”. When it comes to women who have DOR I favor the use of the A/ACP, adding supplementary human growth hormone (HGH). In cases where the DOR is regarded as severe (AMH=<0.2), I often augment  the AACP protocol by using estrogen priming for 7-9 days prior to or with the commencement of gonadotropin therapy; For this I prescribe E2 skin patches  or intramuscular  estradiol valerate (Delestrogen), prior to or sometimes concurrent with, the  commencement of the GnRH antagonist administration.
• The following Ovarian stimulation protocols are in my opinion best avoided in stimulating olderf women and /or thosed who regardless of age , have  DOR :

1. Microdose agonist (e.g. Lupron) “flare” protocols which result in an out-pouring of pituitary-LH at the critical time that ovarian follicles and eggs start developing/growing.
2. High dosages of LH -containing fertility drugs (e.g. Menopur).
3. Supplementation with preparations that are testosterone-based
4. Supplementation with DHEA (which is converted to testosterone in the ovaries.
5. Clomiphene citrate or Letrozole which cause increased release of LH and thus increase ovarian male hormone (testosterone and androstenedione output.
6. “Triggering” egg maturation using too low a dosage of hCG (e.g. 5,000U rather than 10,000U) or Ovidrel (e.g. 250mcg of Ovidrel rather than 500mcg)
7. “Triggering” women who have DOR, with an agonist (alone)such as Lupron Superfact/ Buserelin/Aminopeptidyl/Decapeptyl.

• Preimplantation Genetic Screening (PGS):

The introduction of preimplantation genetic testing/screening (PGT/PGS) for e permits identification of all the chromosomes in the egg and embryo (full karyotyping) allowing for the  identification of the most “competent” (euploid) embryos for selective transfer to the uterus. This vastly improves the efficiency and success of the IVF process and renders us fare better equipped us to manage older women and those who regardless of their age, have DOR.

Please visit my new Blog on this very site, www. SherIVF.com, 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
• 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 Approach
• Anti Mullerian Hormone (AMH) Measurement to Assess Ovarian Reserve and Design the Optimal Protocol for Controlled Ovarian Stimulation (COS) in IVF.
• The “Biological Clock” and how it should Influence the Selection and Design of Ovarian Stimulation Protocols for IVF.
• A Rational Basis for selecting Controlled Ovarian Stimulation (COS) protocols in women with Diminished Ovarian Reserve (DOR)
• Diagnosing and Treating Infertility due to Diminished Ovarian Reserve (DOR)
• Controlled Ovarian Stimulation (COS) in Older women and Women who have Diminished Ovarian Reserve (DOR): A Rational Basis for Selecting a Stimulation Protocol
• 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
• Frozen Embryo Transfer (FET) versus “Fresh” ET: How to Make the Decision
• Frozen Embryo Transfer (FET): A Rational Approach to Hormonal Preparation and How new Methodology is Impacting IVF.
• Staggered IVF: An Excellent Option When. Advancing Age and Diminished Ovarian Reserve (DOR) Reduces IVF Success Rate
• Embryo Banking/Stockpiling: Slows the “Biological Clock” and offers a Selective Alternative to IVF-Egg Donation.
• Preimplantation Genetic Testing (PGS) in IVF: It Should be Used Selectively and NOT be Routine.
• Preimplantation Genetic Sampling (PGS) Using: Next Generation Gene Sequencing (NGS): Method of Choice.
• PGS in IVF: Are Some Chromosomally Abnormal Embryos Capable of Resulting in Normal Babies and Being Wrongly Discarded?
• PGS and Assessment of Egg/Embryo “competency”: How Method, Timing and Methodology Could Affect Reliability
• 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
• Premature Luteinization (“the premature LH surge): Why it happens and how it can be prevented.
• IVF Egg Donation: A Comprehensive Overview

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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

ADDITIONAL INFORMATION:

I am attaching online links to two E-books which I recently  co-authored with  my partner at SFS-NY  (Drew Tortoriello MD)……. for your reading pleasure:

1.From In Vitro Fertilization to Family: A Journey with Sher Fertility Solutions (SFS) “

http://sherfertilitysolutions.com/sher-fertility-solutions-ebook.pdf

1. “Recurrent Pregnancy Loss and Unexplained IVF Failure: The Immunologic Link

https://drive.google.com/file/d/1iYKz-EkAjMqwMa1ZcufIloRdxnAfDH8L/view

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