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Immunologic Implantation Dysfunction (IID) & Infertility (IID): PART 2-Making a Diagnosis

by Dr. Geoffrey Sher on November 17, 2015

Currently there are fewer than a dozen immunology reference laboratories in the U.S that are capable of analyzing the required elements with a sufficient degree of  sensitivity and specificity as to be reliable in my opinion. These elements include measuring blood levels of the eighteen to twenty IgA, IgG and IgM-related APA’s that are directed against six or seven specific phospholipids, as well as assessing Natural Killer (NK) cell activity (cytotoxicity) as measured by their killing effect on K-562 target cells.

Whether  alloimmune  or  autoimmune  in  origin, it is only when specialized immune cells in the uterine lining known as natural killer (NK) Cells and CTL become activated and TH-1 cytokine dominance is established that IID occurs. Thus a full evaluation of IID requires that DQ alpha, APA, ATA, as well as NK/CTL activation be evaluated. This requires highly specialized blood and possibly also endometrial tests that can only be adequately performed by a handful of specialized reproductive immunology laboratories in the United States.

The following conditions should always raise a suspicion of an IID, and prompt testing:

  • A diagnosis of endometriosis or the existence of symptoms suggestive of endometriosis (heavy/painful menstruation and/or pain with ovulation or with deep penetration during intercourse—even though this is suggestive of, but not in and of itself diagnostic of, endometriosis. Definitive diagnosis of endometriosis requires visualization of the lesions at laparoscopy or laparotomy –see later)
  • A personal family history of hypothyroidism or hyperthyroidism as well as those with abnormal TSH blood levels
  • Detection of elevated blood levels of antithyroid or anti-TSH antibodies.
  • Family or personal history of any disease believed to have an autoimmune cause (Lupus erythematosus, Rheumatoid arthritis, dermatomyositis, scleroderma)
  • “Unexplained” infertility
  • Recurrent pregnancy loss
  • A history of having miscarried a conceptus that, upon testing of products of conception, was found to be euploid (have a normal numerical chromosomal configuration.
  • Unexplained IVF failure
  • Secondary infertility (i.e. have had child(ren) in the past).
  • “Unexplained” intrauterine growth retardation due to placental insufficiency or late pregnancy loss of a chromosomally normal baby

Alloimmune implantation dysfunction usually presents with a history of unexplained (usually repeated) miscarriages, secondary infertility (where the woman conceived initially and thereupon was either unable to conceive started having repeated miscarriages). 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 will be early symptoms of pregnancy or even an early positive pregnancy test (chemical pregnancy) and perhaps even a few days of delay in the onset of menstruation…but no clear evidence of a good implantation. However, there is often no clear demarcation in the presentations of alloimmune versus autoimmune implantation dysfunction. In some cases the former will present as “presumed” primary infertility while the latter (autoimmune implantation dysfunction) will present as secondary infertility (especially in cases of endometriosis) and even as RPL.

Alloimmune Implantation 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.

Testing for IID can be expensive. In our 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 hallmark of testing for IID is through evaluating for NK cell activation. Since NK cell activation and CTL activation usually coexist, testing for both, in our opinion, is unnecessary.  Currently the gold standard NK cell activation is best tested for through a blood K-562 target cell test. And if desired, CTL activity can be evaluated by a blood immunophenotype test that assesses CD8, CD4 and CD3 lymphocytes and to do HLA-DR measurement. Some reproductive immunologists might also test the blood Treg cell concentration and/or recommend an endometrial biopsy to histochemically evaluate uterine NK cells or measure blood TH-1/ TH-2 cytokines. However, in our opinion, such testing is not essential.

In some cases where a primary autoimmune condition such as rheumatoid arthritis, Hashimoto’s autoimmune hypothyroidism or Lupus erythematosus is suspected, it is advisable to also test the female partner for antinuclear antibodies (ANA), for a full panel of antiphospholipid antibodies (all 21 subtypes), antithyroid antibodies and for a full  immunophenotype.

Since autoimmune implantation dysfunction is often genetically transmitted, it is not surprising that this condition is more likely to exist in women who have a family (or personal) history of primary auto- immune diseases such as lupus erythematosus, scleroderma, clinical or subclinical hypothyroidism, rheumatoid arthritis, etc. It also occurs in 30% of women who have endometriosis (regardless of its severity) and in 50% of women who harbor anti-TSH antibodies or antithyroglobulin /anti-microsomal/TPO antibodies, regardless of whether their thyroid hormone levels are abnormal or not.

As previously stated, autoimmune implantation dysfunction most commonly presents as infertility or unexplained repeated IVF failure. This is because NK cell activation is present from the very outset and is immediately lethal to the implanting embryo. As previously alluded to, alloimmune implantation dysfunction while often also presenting as primary infertility commonly presents as secondary infertility (where there has been a pregnancy before) or as RPL.

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  • Linda - November 22, 2016 reply

    Hi Dr Sher, I just have a question on HLA matching. Is it only classed as a ‘match’ if your husbands markers match yours? For instance if my DQ Alpha is 1.2 and 2.0 but my husbands is 3.0 and 3.0 is that a ‘match’ as his are the same? Also if his are 3.0 and 3.0 does that not mean his parents were at least a partial match or possibly a full match even though they had no problems conceiving him? I would love to hear from you! Thank you 🙂

    Dr. Geoffrey Sher

    Dr. Geoffrey Sher - November 22, 2016 reply

    Only relevant if he matches you in at least one value.

    I strongly recommend that you visit http://www.DrGeoffreySherIVF.com. Then go to my Blog and access the “search bar”. Type in the titles of any/all of the articles listed below, one by one. “Click” and you will immediately be taken to those you select. Please also take the time to post any questions or comments with the full expectation that I will (as always) respond promptly.
    • Controlled Ovarian Stimulation (COS) for IVF: Selecting the ideal protocol
    • IVF: Factors Affecting Egg/Embryo “competency” during Controlled Ovarian Stimulation(COS)
    • The Fundamental Requirements For Achieving Optimal IVF Success
    • Ovarian Stimulation for IVF using GnRH Antagonists: Comparing the Agonist/Antagonist Conversion Protocol.(A/ACP) With the “Conventional” Antagonist Approach
    • 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.
    • 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!

    Please call or email Julie Dahan, my patient concierge. She will guide you on how to set up an in-person or Skype consultation with me. You can reach Julie at on her cell phone or via email at any time:
    Julie Dahan
    • Email: Julied@sherivf.com
    • Phone: 702-533-2691
     800-780-7437

    Geoff Sher

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

    Geoff Sher

  • Belinda - August 31, 2016 reply

    Hi Dr Sher,
    Thanks for your blog and your time. I am in Australia and have had normal plasma levels of NK cells (however uncertain if tested for activation vs levels) and am due for laparoscopy to assess for endometriosis and for endometrial biopsy for NK cells at the same time.
    This is on a background of 4 failed IVF t/fs – 1 x fresh, 2 x FET (1 did achieve pregnancy but miscarried at 8/40, chromosomally normal POC), adenomyosis, +ANA (1:640) and strong fam and personal Hx of AI disease.
    I have read the articles you suggest and my concern is that given reproductive immunology is not widely pursued over here whether having tests done locally are still valid or will they not be sensitive/specific enough to appropriately guide management. The endometrial biopsies are taken to Douglas Hanley Moir lab in Sydney for lymph analysis.
    I would be grateful for your opinion. Thanks in advance.

    Dr. Geoffrey Sher

    Dr. Geoffrey Sher - August 31, 2016 reply

    Endometriosis is a complex condition where, the lack or relative absence of an overt anatomical barrier to fertility often belies the true extent of reproductive problem(s). All too often the view is expressed that the severity of related infertility is directly proportionate to the anatomical severity of the endometriosis itself, the implication being that the primary reason for endometriosis –related infertility is anatomical interference with egg transport to the Fallopian tube(s). This over-simplification and an erroneous view is often used to justify the performance of many unnecessary surgeries for the removal of small innocuous endometriotic lesions, on the basis of such “treatment” evoking an improvement in subsequent fertility.
    It is indeed indisputable that even the mildest form of endometriosis can compromise fertility. It is equally true that, mild to moderate endometriosis is by no means a cause of absolute “sterility”. Rather, when compared with normally ovulating women of a similar age who do not have endometriosis, women with mild to moderate endometriosis are about three to four times less likely to have a successful pregnancy. Two important reasons for such reduction in fertility potential are:
    a) Toxic Pelvic Environment: Endometriosis is associated with the presence of local pelvic toxins that significantly reduces the fertilization potential of eggs as they pass from the ovary to the fallopian tube via the pelvic cavity and,
    b) Immunologic Implantation Dysfunction (IID): Given that the pathogenesis of endometriosis almost certainly involves an abnormal immune response. In about one third of cases, activation of uterine natural killer cells (NKa) causes the uterus to reject the embryo (fertilized egg) as it attempts to gain attachment to the uterine lining (endometrium).
    The reported annual birth rate for normally ovulating women under 35 yrs who are free of endometriosis or any other pelvic disease, is about 70-80%. For women 35-40yrs of age, the comparable annual rate is about 40-50%, for women in their early 40’s, it is probably less than 20% and by the mid-forties, …around 10%. In contrast women in similar age categories who have even the mildest degree of endometriosis can expect a 3-4-fold reduction in the annual birth rate.
    Since, the reason for women with mild to moderate endometriosis having a much poorer reproductive performance has little to do with ovulation dysfunction or anatomical disease, it should come as no surprise that the use of fertility drugs, surgery to ablate small endometriotic deposits and minor adhesions, and/or intrauterine insemination is unlikely to any improvement in pregnancy rate over no treatment at all. Women under 35 years who fit this profile, and who conceive following fertility hormone therapy, intrauterine insemination (IUI) or surgery, should consider that they probably conceived in spite of (rather than due to), such treatment. Failure to recognize this reality carries with it the risk that when it comes to planning for another baby, the woman will erroneously belief that having conceived before means that there should be no difficulty in doing so again and be lulled into a false sense of complacency. In reality, the achievement of a viable pregnancy by a woman with mild/moderate endometriosis, whether it occurred spontaneously or following such treatment probably does not improve her subsequent ability to conceive.
    Younger women (under 30 yrs) with mild/moderate pelvic endometriosis (who have patent fallopian tubes, are ovulating normally and have fertile male partners), have about a 40% chance of having a baby within 3-4 years. Accordingly they justifiably can choose taking a “wait and see “approach, avoiding surgery, fertility drugs and intrauterine insemination (which in my opinion would be unlikely to improve the chance of a successful pregnancy over no treatment at all) and In Vitro Fertilization which by involving the direct extraction of eggs from the ovaries and initiating the fertilization process in the Petri dish/incubator, the IVF procedure facilitates fertilization, is much likely to be successful, but might have been avoided by a “wait and see approach”.
    Finally, I wish to point out that in addition to an inevitable toxic “peritoneal factor” present in all women with endometriosis, about 1/3 of women with endometriosis (regardless of its severity), also have an immunologic barrier to implantation involving NKa and possibly the action of antiphospholipid antibodies. This population of women are not likely to achieve a viable pregnancy conceive until/unless the IID is addressed through selective immunotherapy involving Intralipid, heparinoids (Lovenox/Clexane) and low dosage (short term) steroid therapy. It therefore behooves all women with endometriosis who are planning to have a family to be thoroughly tested which in my opinion should be performed in a reproductive immunology reference lab of which to my knowledge no more than a half dozen in the United States, capable of performing these tests with the required sensitivity. I preferentially use Reproductive Immunology Associates (RIA) in Van Nuys, CA.
    Given the effect of the accelerating biological clock, women over 35yrs who have endometriosis-related infertility, do not have time to waste and should, in my opinion do IVF as a first line approach, regardless of their immunologic status. In the absence of clear evidence of increased NK cell activity, I often recommend a conservative approach in women under 35years (who potentially can afford the time to wait). However, regardless of age, women who have increased NK cell activity, should in my opinion undergo IVF accompanied with immunotherapy with Intralipid (and sometimes heparin, Clexane or Lovenox) because without such treatment they are not likely to conceive regardless of the approach to treatment) undergo IVF.

    I strongly recommend that you visit http://www.DrGeoffreySherIVF.com. Then go to my Blog and access the “search bar”. Type in the titles of any/all of the articles listed below, one by one. “Click” and you will immediately be taken to those you select. Please also take the time to post any questions or comments with the full expectation that I will (as always) respond promptly.
    • Controlled Ovarian Stimulation (COS) for IVF: Selecting the ideal protocol
    • IVF: Factors Affecting Egg/Embryo “competency” during Controlled Ovarian Stimulation(COS)
    • The Fundamental Requirements For Achieving Optimal IVF Success
    • Ovarian Stimulation for IVF using GnRH Antagonists: Comparing the Agonist/Antagonist Conversion Protocol.(A/ACP) With the“Conventional” Antagonist Aproach
    • Ovarian Stimulation in Women Who have Diminished Ovarian Reserve (DOR): Introducing the Agonist/Antagonist Conversion protocol
    • Anti Mullerian Hormone (AMH) Measurement to Assess Ovarian Reserve and Design the Optimal Protocol for Controlled Ovarian Stimulation (COS) in IVF.
    • 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?
    • “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!
    • Traveling for IVF from Out of State/Country–
    • Endometriosis and Infertily
    • Endometriosis and Infertility: Why IVF Rather than IUI or Surgery Should be the Treatment of Choice.
    • Treating Ovarian Endometriomas with Sclerotherapy.

    Please call or email Julie Dahan, my patient concierge. She will guide you on how to set up an in-person or Skype consultation with me. You can reach Julie at on her cell phone or via email at any time:
    Julie Dahan
    • Email: Julied@sherivf.com
    • Phone: 702-533-2691
     800-780-7437

    Geoff Sher

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

  • Emma J - May 16, 2016 reply

    Dear Dr Sher, many thanks for your informative blog. I am 38 and have had 3 IUIs and 4 IVF (both fresh and FET) that failed (I never get a positive beta (<0)). I have an elevated ANA but tested negative for specific autoimmune and I suspect I have an autoimmune dysfunction. I've mentioned Intralipid during conversations with my RE but it seems that is not common in my country and they have never done it before. I would appreciate very much if you can share your thoughts on what my next best course of action – should I try prednisolone and baby aspirins as I heard this also helps..? Many thanks!

    Dr. Geoffrey Sher

    Dr. Geoffrey Sher - May 16, 2016 reply

    Not much I can say, except that perhaps we should talk. It does sound as if you could have an implantation dysfunction (anatomical or immunologic).

    I strongly recommend that you visit http://www.DrGeoffreySherIVF.com. Then go to my Blog and access the “search bar”. Type in the titles of any/all of the articles listed below, one by one. “Click” and you will immediately be taken to those you select. Please also take the time to post any questions or comments with the full expectation that I will (as always) respond promptly.

    • Controlled Ovarian Stimulation (COS) for IVF: Selecting the ideal protocol
    • IVF: Factors Affecting Egg/Embryo “competency” during Controlled Ovarian Stimulation(COS)
    • The Fundamental Requirements For Achieving Optimal IVF Success
    • 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)
    • Natural Killer Cell Activation (NKa) and Immunologic Implantation Dysfunction in IVF: The Controversy!
    • Endometrial Thickness, Uterine Pathology and Immunologic Factors
    • Vaginally Administered Viagra is Often a Highly Effective Treatment to Help Thicken a Thin Uterine Lining
    • Traveling for IVF from Out of State/Country–
    • A personalized, stepwise approach to IVF
    • How Many Embryos should be transferred: A Critical Decision in IVF.

    Please call or email Julie Dahan, my patient concierge. She will guide you on how to set up an in-person or Skype consultation with me. You can reach Julie at on her cell phone or via email at any time:
    Julie Dahan
    • Email: Julied@sherivf.com
    • Phone: 702-533-2691
     800-780-7437

    Geoff Sher

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

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