Immunologic Implantation Dysfunction (IID) -Making the Diagnosis

Dr. Geoffrey Sher - February 23, 2022
Immunologic Implantation Dysfunction (IID) -Making the Diagnosis

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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