Immunologic Implantation Dysfunction (IID) & Infertility (IID) & Infertility: PART 3-Treatment

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

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

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

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

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

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

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

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

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

Gestational Surrogacye For Alloimmune Implantation Dysfunction

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

Use of a Sperm Donor in Cases of Alloimmune Implantation Dysfunction

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

Use of Medications in the Treatment of IID

1. Intralipid (IL) Therapy:

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

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

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

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

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

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

Treatment of Alloimmune NKa Using Intralipid:

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

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

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

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

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

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

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

2. Corticosteroid Therapy (Prednisone, Prednisilone, and Dexamethasone)

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

3. Heparinoid Therapy

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

4. What About Baby Aspirin?

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

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

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

6. Leukocyte Immunization Therapy (LIT)

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

20 Comments

vikki

Dear Dr Sher, Hello from a desperate South African in need of some urgent advice 🙂 I am currently day 4 of my first immune protocol donor cycle.
Please can you let me know what dosage of Prednisone (along with IL therapy 12 days before Donor Egg transfer) Clexane 40, baby asprin, estropause and progesterone injections.) would you prescribe for autoimmune implantation disfunction. In review – At age 38 I have now had 8 fresh failed ICSI cycles with good quality embryos including some blasts. This year I moved to double donor sperm and egg and had 1 failed fresh blast transfer. My results are the same most times – faintly positive home pregnancy tests which get darker for a few days and then suddenly negative HPT and negative blood tests and period starts on time.. This has happened in 7 out of the 9 cycles I have done. The other two were completely negative no implantation. I have had stage 3 ‘silent’ endometriosis removed in 2016 after choc cyst was seen on ultrasound, I have tested positive for activated natural killer cells at an independent lab, but my dr at the time did not believe that was an issue. I have eczema occasionally, I have family history of rheumatoid arthritis both sides as well as thyroid issues both sides of the family yet none of them are ‘infertile’. I have low AMH and am a poor responder to IVF stims. From what I can tell I ovulate every month and have extremely regular periods even when on IVF treatment. I have recently been diagnosed with very high thyroid antibodies and Hashimotos Thyroiditis but my TSH is now below 2 after treatment. (It was over 5 for all of these past IVF cycles) All other blood testing has not shown any other factors with me. My current doctor has agreed to follow your information I gave him.. However we cannot find Dex in this country as they apparently no longer make it here… So he prescribed 15mg prednisone. Do you think this is adequate. I am tempted to up my dose as I have read most ladies go on 30-40mg. We plan to transfer 2 blasts on 1 August. I start my steroids today (12 July) Talk about late timing in trying to get advice, but after a sleepless night and utter desperation to have this cycle work, I am once again turning to the internet for help as my doctors (4 I have seen) really do not seem to believe to much in immune implantation issues. Thank you for any input you can add! Vikki x

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Dr. Geoffrey Sher

Firstly, it is in my opinion essential that you, in addition, have you and your partner tested for an alloimmune component (a DQ alpha/HLA match between you and your partner because that would significantly alter the IL/steroid treatment regime employed. Second. There are to my knowledge no labs in SA that can test NK cell activation (note: it is NOT the concentration of NK cells that matters but rather the activation as measured by the K-562 target cell test),or alloimmune implantation dysfunction adequately.

Unless tests for immunologic implantation dysfunction (IID) are performed correctly and conducted by a one of the few reliable reproductive immunology reference laboratory in the United States, treatment will likely be unsuccessful. . In this regard it is most important that the right tests be ordered and that these be performed by a competent laboratory. There are in my opinion only a handful of reliable Reproductive Immunology Laboratories in the world and most are in the U.S.A. Also, it is my opinion that far too often, testing is inappropriate with the many redundant and incorrect tests being requested from and conducted by suboptimal laboratories. Finally for treatment to have the best chance of being successful, it is vital that the underlying type of IID (autoimmune IID versus alloimmune) be identified correctly and that the type, dosage, concentration and timing of treatments be carefully devised and implemented.
Who Should Undergo IID testing?
When it comes to who should be evaluated, the following conditions should in always raise a suspicion of an underlying IID, and trigger prompt testing:
• A diagnosis of endometriosis or the existence of symptoms suggestive of endometriosis (heavy/painful menstruation and pain with ovulation or with deep penetration during intercourse) I would however emphasize that a definitive diagnosis of endometriosis requires visualization of the lesions at laparoscopy or laparotomy)
• A personal or family history of autoimmune disease such as hyper/hypothyroidism (as those with elevated or depressed TSH blood levels, regardless of thyroid hormonal dysfunction), Lupus erythematosus, Rheumatoid arthritis, dermatomyositis, scleroderma etc.)
• “Unexplained” infertility
• Recurrent pregnancy loss (RPL)
• A history of having miscarried a conceptus that, upon testing of products of conception, was found to have a normal numerical chromosomal configuration (euploid).
• Unexplained IVF failure
• “Unexplained” intrauterine growth retardation due to placental insufficiency or late pregnancy loss of a chromosomally normal baby
What Parameters should be tested?
In my opinion, too many Reproductive Immunologists unnecessarily unload a barrage of costly IID tests on unsuspecting patients. In most cases the initial test should be for NK cell activation, and only if this is positive, is it necessary to expand the testing.
The parameters that require measurement include:
o For Autoimmune Implantation Dysfunction: Autoimmune implantation dysfunction, most commonly presents with presumed “infertility” due to such early pregnancy losses that the woman did not even know she was pregnant in the first place. Sometimes there as an early miscarriage. Tests required are: a) blood levels of all IgA, IgG and IgM-related antiphospholipid antibodies (APA’s) directed against six or seven specific phospholipids, b) both antithyroid antibodies (antithyroid and antimicrosomal antibodies), c) a comprehensive reproductive immunophenotype (RIP) and, c) most importantly, assessment of Natural Killer (NK) cell activity (rather than concentration) by measuring by their killing, using the K-562 target cell test and/or uterine cytokine measurement. As far as the ideal environment for performing such tests, it is important to recognize that currently there are only about 5 or 6, Reproductive Immunology Reference Laboratories in the U.S capable of reliably analyzing the required elements with a sufficient degree of sensitivity and specificity (in my opinion).
o For Alloimmune implantation Dysfunction: While alloimmune Implantation usually presents with a history of unexplained (usually repeated) miscarriages or secondary infertility (where the woman conceived initially and thereupon was either unable to conceive started having repeated miscarriages it can also present as “presumed” primary infertility. Alloimmune dysfunction is diagnosed by testing the blood of both the male and female partners for matching DQ alpha genes and NK/CTL activation. It is important to note that any DQ alpha match (partial or complete) will only result in IID when there is concomitant NK/CTL activation (see elsewhere on this blog).
How should results be interpreted?
Central to making a diagnosis of an immunologic implantation dysfunction is the appropriate interpretation of natural killer cell activity (NKa) .In this regard, one of the commonest and most serious errors, is to regard the blood concentration of natural killer cells as being significant. Rather it is the activity (toxicity) of NK cells that matters as mentioned. Then there is the interpretation of reported results. The most important consideration is the percentage of target cells “killed” in the “native state”. In most cases a level of >10% killing should be regarded with suspicion and >12% overtly abnormal. In my opinion, trying to interpret the effect of adding IVIG or Intralipid to the sample in order assess whether and to what degree the use of these products would have a therapeutic benefit is seriously flawed and of little benefit. Clinically relevant NK cell deactivation can only be significantly effected in vivo and takes more than a week following infusion to occur. Thus what happens in the laboratory by adding these products to the sample prior to K-562 target cell testing is in my opinion likely irrelevant.
There exists a pervasive but blatant misconception on the part of many, that the addition of Intralipid (IL) /immunoglobulin-G IVIG) can have an immediate down-regulatory effect on NK cell activity. This has established a demand that Reproductive Immunology Reference Laboratories report on NK cell activity before and following exposure to IVIG and/or IL. However, the fact is that activated “functional” NK cells (NKa) cannot be deactivated in the laboratory. Effective down-regulation of activated NK cells can only be adequately accomplished if their activated “progenitor/parental” NK cells are first down-regulated. Thereupon once these down-regulated “precursor” NK cells are exposed to progesterone, they will begin spawning normal and functional NK cells, which takes about 10-14 days. It follows that to assess for a therapeutic response to IVIG/IL therapy would require that the patient first be treated (10-14 days prior to embryo transfer) and thereupon, about 2 weeks later, be retested. While at 1st glance this might seem to be a reasonable approach, in reality it would be of little clinical benefit because even if blood were to be drawn 10 -14 days after IL/IVIG treatment it would require an additional 10 days to receive results from the laboratory, by which time it would be far too late to be of practical advantage.
Neither IVIG nor IL is capable of significantly suppressing already activated “functional NK cells”. For this to happen, the IL/IVIG would have to down-regulate progenitor (parent) NK cell” activity. Thus, it should be infused 10-14 several prior to ovulation or progesterone administration so that the down-regulated “progenitor/precursor” NK cells” can propagate a sufficient number of normally regulated “functional NK cell” to be present at the implantation site 7 days later. In addition, to be effective, IL/IVIG therapy needs to be combined with steroid (dexamethasone/prednisone/prednisolone) therapy to down-regulates (often) concomitantly activated T-cells.
I strongly recommend that you visit http://www.DrGeoffreySherIVF.com. Then go to my Blog and access the “search bar”. Type in the titles of any/all of the articles listed below, one by one. “Click” and you will immediately be taken to those you select. Please also take the time to post any questions or comments with the full expectation that I will (as always) respond promptly.

• The IVF Journey: The importance of “Planning the Trip” Before Taking the Ride”
• Controlled Ovarian Stimulation (COS) for IVF: Selecting the ideal protocol
• IVF: Factors Affecting Egg/Embryo “competency” during Controlled Ovarian Stimulation (COS)
• The Fundamental Requirements for Achieving Optimal IVF Success
• Use of GnRH Antagonists (Ganirelix/Cetrotide/Orgalutron) in IVF-Ovarian Stimulation Protocols.
• 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!

If you are interested in seeking my advice or services, I urge you to contact my concierge, Julie Dahan ASAP to set up a Skype or an in-person consultation with me. You can also contact Julie by phone or via email at 702-533-2691/ Julied@sherivf.com You can also apply online at http://www.SherIVF.com .

*FYI
The 4th edition of my newest book ,”In Vitro Fertilization, the ART of Making Babies” is available as a down-load through http://www.Amazon.com or from most bookstores and public libraries.

Geoffrey Sher MD

PS: Prednisone 15mg daily is quite adequate in my opinion.

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vikki

Thank you so much for the reply Dr Sher.
Since we are now using double donor embryos we cannot do alloiumune testing as the donor was anonymous. My husbands sperm has gone from critically low (childhood mumps) to zero in the last 4 years, so there really is no hope for us having a biological child and we’ve had to accept that. Financially but more so emotionally I am at the end of the road and the 3 donor embryos we have on ice are our final try. I would LOVE to be able to consult & test with your clinic, but unfortunately we have to work with what we have left at this late stage for us. I wish I had contacted you after the 2nd failed cycle, as it was way back then that I started strongly suspecting I had an immune issue. It was a pity that none of my doctors picked up the thyroid issues that have been there all along and only just now corrected 🙁 I will have to hope for the best with the new protocol we are on. Thank you so much for putting all this information out there for us desperate ladies.

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vikki

Dr Sher I do have another questions and I know it is difficult for you to advise me over the internet without you having proper testing as you’ve suggested. Just something I did not mention is I have also done 2 IUIs with 2 completely different sperm bank donors and in those instances have ALSO gotten faint positive home pregnancy tests for a few days before period starting. In all these instances of getting faint positive tests, I am not confusing it with any trigger shots, as each cycle I have tested the trigger shot out and had negative tests for a good few days before they started turning faint positive again.. So we have had failure with my husbands sperm (we tried fresh and biopsy sperm) and we had failure with 3 different sperm donors. 2 IUI’s and 1 fresh egg donor cycle. So with my limited knowledge of these things, it is for this reason that I am guessing I do not have an alloimmune issue .. I believe the problem lies with me and not the sperm.
So having added the above info, would it make any more sense to you – that my problem could be immune issue – whether it be thyroid antibodies, activated killer cells – I am asking for your best guess here 🙂

So would upping the dose of prednisone to maximum dosage used on your immune protocols be an option – just as like a safeguard

Or can you over suppress the immune in this instance – and better to go cautiously?
I keep reading other women on much higher doses of steroids.

Final question and I will try leave you in peace 🙂 if this August transfer of 2 AA blasts fails, then we have 1 AA blast remaining. That would without a double be my final treatment as I have decided to stop after that. What medication would you do differently besides the 15mg prednisone, 40mg clexane, 20% / 100ml IL therapy, estropause, progesterone injections. Once again, THANK YOU !

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Dr. Geoffrey Sher

Sorry, but if you already have NK cell activity, changing the sperm provider will not remedy the implantation dysfunction.

Geoff Sher

vikki

Hi Dr Sher, I hope you remember me – you advised me last month.
I need your advice please 🙂 I am 6 days past my transfer of 2 expanding double donor blasts (FET) and yesterday evening I got an immediate very obvious positive home pregnancy test. I was & still am SHOCKED as I have never seen this so early and so clearly positive. You may remember this is my 10th transfer. I had intralipids once near beginning of FET cycle then again 2 days before transfer. I am on 20mg prednisone. This combination has finally worked for me it would seem. I am very hopeful but cautiously optimistic of course. My question… I am experiencing very thick woozy head / flu like symptoms since yesterday, lightheaded and dizzy at times. My cheeks are also flushing quite red in the evening & someone (not a Dr) has suggested to me that the flushing cheeks which gets quite hot and obvious at times – could be an immune flare up my body is having to the implantation. They have suggested I increase my prednisoe to 25mg and see if it helps calm this. Is there any harm in increasing my dose just for a few days? Thank you for all your help before!

Dr. Geoffrey Sher

In my opinion you are on an adequate dosage of Prednisone at 20mg. I personally do not believe that in]creasing it will add anything. Discuss with your RE.

Looks promising!

Good luck!

Geoff Sher

Chisa

Prednisone increased my NK cells and TNF-a cells. Everything! What would you suggest next if Prednisone is not an option?

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Dr. Geoffrey Sher

I really do not buy this and would need to know how/where the NKa was tested.

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”, “unexplained IVF failure” and “recurrent pregnancy loss (RPL)”. Although many factors that contribute to such implantation dysfunction, in the final analysis it is activated “functional” uterine natural killer cells (NKa) in association with cytotoxic-T cells (CTL), which through the production of cytotoxic cytokines (see below) damage the “root system” (trophoblast) of the embryo causing the pregnancy either to be immediately rejected, or so compromising placentation that early pregnancy loss occurs. Both immunoglobulin-G (IVIG) and intralipid (IL) therapy given in combination with corticosteroids (e.g. dexamethasone, prednisone, and prednisolone) are used to effectively reduce/down-regulate activated NK cells.

NK cells” reach the uterus from the woman’s bone marrow, early in the menstrual cycle, as so called “parental” or “progenitor” cells. There these early NK cells proliferate under the effect of estrogens. Only upon being exposed to progesterone do they begin to propagate “functional” NK cells that release cytokines and promote implantation. The concentration of functional NK cells in the endometrium is maximal about 7 days after exposure to natural(endogenous), or synthetic (exogenous) progesterone ….i.e. corresponding to the time the time when the embryo implants into the uterine lining (endometrium).

Functional uterine natural killer (NK) cells as well as T-helper cells are immune cells that frequent the uterine lining. They produce growth factors known as cytokines that regulate orderly implantation of the embryo and facilitate placentation (development of a functional placenta……the baby’s life line).There are of two varieties of uterine cytokines: a) TH-2 (humoral) cytokines that promote permeation of the uterine wall by the embryo’s trophoblast (“root system and, b) TH-1 (cellular) cytokines that oppose trophoblastic proliferation and permeation of the uterine wall by culling interstitial trophoblastic cells. Orderly implantation and formation of a functional placenta (lifeline of the baby) requires that TH-1 and TH2 activity be in equilibrium

There are two categories of immunologic implantation dysfunction (IID) linked to NK cell activation (NKa).
• Autoimmune IID. Here, there is often a personal or family history of autoimmune conditions such as Rheumatoid arthritis, Lupus Erythematosus, and thyroid autoimmune activity (e.g. Hashimoto’s hypothyroidism) etc. Autoimmune IID also occurs in about one third of cases of endometriosis (regardless of its severity).
• Alloimmune IID. Here uterine NK cell activation results from uterine exposure to an embryo derived through fertilization of an egg by a spermatozoon which shares certain genetic (HLA/DQ alpha)characteristics with that of the mother or embryo recipient.

In both autoimmune and alloimmune IID, the end point is excessive NKa/CTL, TH-1 release that damages the embryos trophoblast, resulting in failed implantation or early pregnancy loss.

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 degree of NK cell activation (cytotoxicity) that matters. In fact there are certain conditions (such as with endometriosis) where the NK cell blood concentrations is normal or well below normal and 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 TH-1 and TH-2 cytokines have been used with some success. However, use of the K-562 target cell test remains the gold standard. With this test, NK cells are isolated from the woman’s blood using Flow Cytometry and are incubated in the presence of specific “target cells”. These are then incubated together. The percentage (%) of “target cells” killed through exposure to NKa/CTL-TH1 cytokines is then quantified.

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. I have for 20 + years been working with Reproductive Immunology Associates (RIA) in Van Nuys, CA and preferentially recommend them to my patients.

There exist a pervasive but blatant misconception on the part of many, that the addition of IL/IVIG can have an immediate down-regulatory effect on NK cell activity. This has established a demand that Reproductive Immunology Reference Laboratories report on NK cell activity before and following exposure to IVIG and/or IL. However, the fact is that activated “functional” NK cells (NKa) cannot be deactivated in the laboratory. Effective down-regulation of activated NK cells can only be adequately accomplished if their activated “progenitor/parental” NK cells are first down-regulated. Thereupon once these down-regulated “precursor” NK cells are exposed to progesterone, they will begin spawning normal and functional NK cells. This process takes about 10-14 days. It follows that to assess for a therapeutic response to IVIG/IL therapy would require that the patient first be treated (10-14 days prior to embryo transfer) and thereupon, about 2 weeks later, be retested. While at 1st glance this might seem to be a reasonable approach, it is in reality would be of little clinical benefit because even if blood were to be drawn 10 -14 days after IL/IVIG treatment it would require an additional 10 days to receive results from the laboratory and by that time it would be far too late to be of practical advantage.

Neither IVIG nor IL is capable of significantly suppressing already activated “functional NK cells”. For this to happen, the IL/IVIG would have to down-regulate progenitor (parent) NK cell” activity. Thus it should be infused several days prior to ovulation or progesterone administration so that the down-regulated “progenitor/precursor” NK cells” can propagate a sufficient number of normally regulated “functional NK cell” to be present at the implantation site 7 days later.

It is very regrettable 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.

Geoff Sher

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Chisa

Rosalind Franklin in Chicago. Elevated TNF and NK cells with Prednisone. All levels normalized with Humira round 2. It’s just SO expensive! I was hoping there was a cheaper way of treating the elevated TNF-a. My NK cells are normal without treatment. One more question, my last D&C was due to an empty gestational sac. This was round 2 IVF treated with Humira which normalized my immune issues. The tissue showed a 46 chromosome boy. What is your hypothesis on this? We are prepared to move to donor eggs but I’m struggling to figure outfit we may have a chance still. Was the last miscarriage just an unfortunate loss since we know the egg was healthy? I have DOR. TSH is 0.915. LH is 5.3. FSH is 14.4. AMH 0.39. No end. Normal progesterone and estrogen levels. Uterine cavity is good to go. I’m so confused.

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Jana

I am having a frozen embryo transfer next month and am wondering when you would start the Prednisone for a FET and what dose? Thank you!

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Dr. Geoffrey Sher

I do not prescribe Prednisone for most cases. i prescribe Dexamethasone 0.75mg daily from the start of the cycle to the 8th week of pregnancy and then I tail it down over 2 weeks.

Geoff sher

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Michelle Jacobs

Dr Sher, my genetic normal donor embryo didn’t implant. I tested positive for NK cells and was treated with IV lipids and took dexamethasone. Is one treatment of IV lipids not enough sometimes?

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Dr. Geoffrey Sher

The immunologic treatment is described below in the attachments on my blog…please read the articles.

Whenever a patient fails to achieve a viable pregnancy following embryo transfer (ET), the first question asked is why! Was it simply due to, bad luck?, How likely is the failure to recur in future attempts and what can be done differently, to avoid it happening next time?.
It is an indisputable fact that any IVF procedure is at least as likely to fail as it is to succeed. Thus when it comes to outcome, luck is an undeniable factor. Notwithstanding, it is incumbent upon the treating physician to carefully consider and address the causes of IVF failure before proceeding to another attempt:
1. Age: The chance of a woman under 35Y of age having a baby per embryo transfer is about 35-40%. From there it declines progressively to under 5% by the time she reaches her mid-forties. This is largely due to declining chromosomal integrity of the eggs with advancing age…”a wear and tear effect” on eggs that are in the ovaries from birth.
2. Embryo Quality/”competency (capable of propagating a viable pregnancy)”. As stated, the woman’s age plays a big role in determining egg/embryo quality/”competency”. This having been said, aside from age the protocol used for controlled ovarian stimulation (COS) is the next most important factor. It is especially important when it comes to older women, and women with diminished ovarian reserve (DOR) where it becomes essential to be aggressive, and to customize and individualize the ovarian stimulation protocol.
We used to believe that the uterine environment is more beneficial to embryo development than is the incubator/petri dish and that accordingly, the earlier on in development that embryos are transferred to the uterus, the better. To achieve this goal, we used to select embryos for transfer based upon their day two or microscopic appearance (“grade”). But we have since learned that the further an embryo has advanced in its development, the more likely it is to be “competent” and that embryos failing to reach the expanded blastocyst stage within 5-6 days of being fertilized are almost invariably “incompetent” and are unworthy of being transferred. Moreover, the introduction into clinical practice about a decade ago, (by Levent Keskintepe PhD and myself) of Preimplantation Genetic Sampling (PGS), which assesses for the presence of all the embryos chromosomes (complete chromosomal karyotyping), provides another tool by which to select the most “competent” embryos for transfer. This methodology has selective benefit when it comes to older women, women with DOR, cases of unexplained repeated IVF failure and women who experience recurrent pregnancy loss (RPL).
3. The number of the embryos transferred: Most patients believe that the more embryos transferred the greater the chance of success. To some extent this might be true, but if the problem lies with the use of a suboptimal COS protocol, transferring more embryos at a time won’t improve the chance of success. Nor will the transfer of a greater number of embryos solve an underlying embryo implantation dysfunction (anatomical molecular or immunologic).Moreover, the transfer of multiple embryos, should they implant, can and all too often does result in triplets or greater (high order multiples) which increases the incidence of maternal pregnancy-induced complications and of premature delivery with its serious risks to the newborn. It is for this reason that I rarely recommend the transfer of more than 2 embryos at a time and am moving in the direction of advising single embryo transfers …especially when it comes to transferring embryos derived through the fertilization of eggs from young women.
4. Implantation Dysfunction (ID): Implantation dysfunction is a very common (often overlooked) cause of “unexplained” IVF failure. This is especially the case in young ovulating women who have normal ovarian reserve and have fertile partners. Failure to identify, typify, and address such issues is, in my opinion, an unfortunate and relatively common cause of repeated IVF failure in such women. Common sense dictates that if ultrasound guided embryo transfer is performed competently and yet repeated IVF attempts fail to propagate a viable pregnancy, implantation dysfunction must be seriously considered. Yet ID is probably the most overlooked factor. The most common causes of implantation dysfunction are:
a. A“ thin uterine lining”
b. A uterus with surface lesions in the cavity (polyps, fibroids, scar tissue)
c. Immunologic implantation dysfunction (IID)
d. Endocrine/molecular endometrial receptivity issues
Certain causes of infertility are repetitive and thus cannot readily be reversed. Examples include advanced age of the woman; severe male infertility; immunologic infertility associated with alloimmune implantation dysfunction (especially if it is a “complete DQ alpha genetic match between partners plus uterine natural killer cell activation (NKa).

Please visit my new Blog on this very site, http://www.DrGeoffreySherIVF.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

• 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)
• Natural Killer Cell Activation (NKa) and Immunologic Implantation Dysfunction in IVF: The Controversy!
• Uterine Fibroids and Fertility
• 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
• The Fundamental Requirements For Achieving Optimal IVF Success

I invite you to arrange to have a Skype or an in-person consultation with me to discuss your case in detail. If you are interested, please contact Julie Dahan, at:

Email: Julied@sherivf.com

OR

Phone: 702-533-2691

I also suggest that you access the 4th edition of my book ,”In Vitro Fertilization, the ART of Making Babies”. It is available as a down-load through http://www.Amazon.com or from most bookstores and public libraries.

Geoff Sher

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