Case Report: “Unexplained” Recurrent IVF failure: Was the Underlying Cause Overlooked?

Mary, a 37y female had never conceived in spite of >6 years of trying. . She had undergone multiple (failed) cycles of IVF-with intracytoplasmic sperm injection (ICSI). Her husband, Brian, was originally diagnosed with oligospermia with a sperm count of 18-20 million/mL and 40% motility. Repeat semen analyses at different labs showed similar findings. However, several years later when the couple decided to try much to their surprise, a repeat semen analysis showed absence of sperm in the ejaculate (azoospermia. Four months later, the semen analysis amazingly bounced back to 20 million/mL with 40% motility. A few months later, a semen analysis again revealed azoospermia which did not revert again. Brian had normal endocrine parameters and testicular biopsies, thereby excluding end-organ testicular failure. The diagnosis of bilateral obstructive azoospermia was made. The couple proceeded with several cycles of IVF with testicular sperm extraction (TESE) and micro-epidydimal sperm aspiration (MESA) and finally a bilateral Epididymovasostomy was done in the hope of restoring fertility, and/or maximizing the yield of mature, viable sperm for future IVF cycles. Over the ensuing 4 years, the couple has transferred 7 expanded blastocysts (5 Fresh and 2 by frozen embryo transfer (FET) and more recently, 3, good quality, day-3 embryos. All have failed to propagate a pregnancy. Their RE has suggested value in using donor sperm, or even an donor egg- but the couple is reluctant to pursue either of those option at this time. MY OPINION: This couple’s story really touched me. They have been through so many disappointments. Sometimes it is hard to understand the why? My concern is that hitherto most of the emphasis has been placed on Brian’s sperm dysfunction, which clearly is linked intermittent vaso-epidydimal obstruction. Sometimes when confronted with such an apparently clearly defined cause, one can overlook other contributing factors, even when they are staring you in the face. In this case, when considering that 7 blastocysts and 3 cleaved embryos were transferred without a single success, I cannot help but suspect that an implantation dysfunction (anatomical and/or immunologic) has been overlooked. Considering that a thin uterine lining, as well as an anatomical lesion encroaching on or protruding into the uterine cavity has been ruled out, I strongly suspect that a hitherto unrecognized immunologic implantation dysfunction has been overlooked. The Immunologic causes of implantation dysfunction that need assessment, include: o          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          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). 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.   Unless tests for immunologic implantation dysfunction (IID) are performed correctly and conducted by a one of the few reliable reproductive immunology reference laboratories 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. I personally recommend Reprosource Reproductive Immunology Laboratory in Boston, MA to my patients. 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 sub-optimal laboratories. Finally, for treatment to have the best chance of being successful, it is vital that the underlying type of IID (autoimmune versus alloimmune) be identified correctly and that the type, dosage, concentration and timing of treatments be carefully devised and implemented. Treatment is dependent on the cause of the IID. In this day and age, we no longer need to use intravenous gamma globulin (IVIG). It is very expensive, associated with too many side effects and is a blood product. 20% intralipid in combination with low-dosage steroids, works just as well, is relatively inexpensive and virtually free of significant side effect. Also, it is not a blood product. ___________________________________________________________ ADDENDUM: INTRODUCING SHER FRERTILITY SOLUTIONS (SFS) Hitherto I have personally performed the actual hands-on treatment of all patients who, seeking my involvement, elected to travel to Las Vegas for my care. However, with the launching of Sher-Fertility Solutions (SFS),in April,2019, I now fulfil a new and expanded consultation role. Rather than having hands-on involvement with IVF procedures I will, through SFS, instead provide fertility consultations (via SKYPE) to the growing number of patients (from >40 countries) with complex Reproductive Dysfunction (RD) who seek access to my input, advice and guidance. In this way I will be able to be involved in overseeing the care, of numerous patients who previously, because they were unable to travel long distances to be treated by me, were unable to gain access to my input.