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”

4 Comments

Anonymous

Dear Dr Sher, I hope all is well? We have been diagnosed with unexplained infertility and currently with Argc in London. We have had 6 transfers of pgs tested embryos and until a few days ago, never had successful implantation. On our 7th transfer we did achieve implantation but resulted in an early loss given low and low rising hcg (34 on test day).

We have pgs tested embryos -6/9 blastocysts were classed as pgs normal (we did ICSI) / HLA karotyping is normal/ we did ERA/EMMA/ ALICE / we did hidden c infection testing and took a course of antibiotics/ hsg test was normal/ thyroid normal/ have mild PCOS / amh is good and I am 34 years old /we have been tested via the Chicago test for immunes and they have all been normal apart from a very slight elevation of CD 19 – however after the infection testing and course of abx- even this went to normal levels / we have tried IVIG, Intralipids, Steroids (predisonone, dexamethasone), Clexane, baby aspirin and prontogest. I have also had 3 hysteroscopies- the 3rd one in Greece who thought they found some dead tissue which was removed and they also put in some implantation cuts. In this latest round we did a non medicated FET (Other than progesterone support post transfer) but added neupogen but didn’t do intralipids or ivig or steroids. so we don’t know whether implantation occurred because of the neupogen or recent hysteroscopy or another unknown variable. We have no idea what to test next or where to go from here and wondered if you might have any suggestions?

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Dr. Geoffrey Sher

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).
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
e. 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 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.
• 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?
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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.

Patients are encouraged to share the information I provide, with their treating Physicians and/or to avail themselves of my personal hands-on services, provided through batched IVF cycles that I conduct every 3 months at Los Angeles IVF (LAIVF) Clinic, Century City, Los Angeles, CA.

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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Dianne

Dr Sher
Could you please give me some information on whether it’s possible to have a baby . I have a 100 PC DQalpha gene match and activated TK cells

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Dr. Geoffrey Sher

Hi Diane,

Nothing is impossible and yes, I have seen a normal pregnancy occur under such circumstances but if the NK activation test was done correctly and at a laboratory that can test this correctly, then with a total match it would not be very likely that you would conceive of a viable pregnancy. You might want to consider gestational surrogacy!

Geoff Sher

Geoff Sher

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