Case Report: The Diagnosis of “Unexplained” Recurrent IVF-Failure is Sometimes a Cop-out

Ingrid (37y) and Jesse 41y had been trying to conceive for 6 years. The couple was “thoroughly tested” and had been “labeled” as having “unexplained infertility”.

Ingrid had patent fallopian tubes, a normal (regular) uterine cavity, was experiencing regular and normal menstrual cycles and her ovulation was found to be normal with adequate supporting hormonal environment. Jesse had normal sperm parameters and had in fact initiated a pregnancy in a previous relationship, 8 years prior. He also been tested negative for sperm antibodies.

Ingrid and Jesse had experienced 4 failed attempts at ovulation induction with intrauterine insemination (IUI), followed by 4 IVF attempts where all blastocysts were subjected to preimplantation genetic screening (PGS). A total 6 PGS-normal (euploid) blastocysts were transferred in the course of 4 frozen-embryo transfers (FETs).

For about 10% of all infertile couples, the cause of the infertility cannot be readily determined using conventional diagnostic methods. Such cases are often referred to as “unexplained infertility.” The truth however is that in most such cases, the diagnosis of “unexplained infertility is in fact “presumptive” because a more in-depth evaluation would have revealed a cause. This having been said, people diagnosed with so called “unexplained infertility” fall into two broad groups: a) those couples who don’t have any biological problems interfering with pregnancy and, b)  those who do but the reason cannot be found due to insufficient medical information or technology. It is in this latter group that improved testing techniques have made infertility easier to diagnose and treat.

In the case of Ingrid and Jesse, PGS testing of their embryos all excluded embryo “incompetence” as a cause for IVF failure. In addition, hysteroscopy and hysterosalpingogram (HSG) as well ultrasound assessment of her uterine lining at the time of maximal estrogen stimulation, all but ruled out anatomical causes of implantation dysfunction. It only remained to evaluate Ingrid and Jesse for a possible underlying immunologic implantation dysfunction (IID).

Central to making a diagnosis of an immunologic implantation dysfunction is the appropriate interpretation of uterine 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, provided the testing is performed appropriately  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.

The parameters that require evaluation for IID, include: measurement include:

o          Testing 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 include:  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.

o          Testing for Alloimmune implantation Dysfunction:  While alloimmune Implantation dysfunction 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). Testing for Alloimmune implantation Dysfunction is much more expensive that testing for autoimmune causes. Thus, as a cost-saving measure, it is worthwhile to restrict testing for an alloimmune cause, to patients who test positive for ve for Nka.

Ingrid tested positive for activated NK cells (Nka+). She and Jesse were subsequently were also tested for DQ alpha/HLA matching and this came up negative.

Since the couple has no left-over frozen blastocysts, they plan to undergo another IVF cycle with PGS testing, followed by the selective transfer of 1-2 PGS-normal blastocyst at a subsequent FET. In that transfer cycle, Ingrid will receive selective immunotherapy in the form of intravenous intralipid (IL) and steroid therapy, starting 10 days prior to the anticipated FET. I am guardedly optimistic that they will be successful this time around.

“It is an indisputable fact that most causes of infertility can be diagnosed, and it is unfortunate that the diagnosis of “unexplained infertility” is often used as an excuse for not having performed a full and detailed evaluation of the problem.  Couples should not simply accept a diagnosis of “unexplained infertility” at face value since treatment is most likely to be successful when the specific cause of the problem can be fully identified”

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