Recurrent Unexplained IVF Failure with “Good Quality” Embryos
The following is a case study of a recent patient that came to me for treatment.
CJ, a 34 year old, and her husband RJ (age 35) presented to me with a six-year history of infertility. Based on semen analysis, RJ, who had initiated two pregnancies in a prior relationship, was found to be perfectly fertile. CJ had been married before and in that relationship, had also experienced 2 years of infertility. Of interest is the fact that CJ’s first husband remarried, and he and his new partner had since parented two children….So clearly, this was a female fertility issue.
CJ had had undergone a fertility evaluation and had been found to be ovulating normally, to have patent Fallopian tubes, and to have normal ovarian reserve. She had undergone a laparoscopy and hysteroscopy which revealed stage 1 (early) endometriosis and a normal uterine cavity.
CJ and RJ had gone through four IUI’s. The first two were with clomiphene stimulation and the last two with gonadotropins. Ovulation had been confirmed in all four stimulation cycles, but no pregnancy resulted.
Subsequently, the couple went through three fresh IVF attempts and two frozen embryo transfers (FETs). In each of the five embryo transfers, 2 well expanded, cellular, high quality blastocysts were transferred but no pregnancy occurred.
Their prior RE suggested that the reason for the failures was likely due to an unexplained egg/embryo issue and recommended another cycle of IVF, this time with CGH chromosome analysis being performed on all embryos, followed by the transfer of one or more embryos deemed to be chromosomally “competent” (CGH-normal).
I saw the problem differently. Here was a young woman with a male partner of proven fertility. She had a total of 8 high-grade blastocysts (as determined by microscopic analysis) transferred to an anatomically normal uterus, with a good endometrial lining, and yet had not even conceived once. Since in general, one out of every two of her eggs/embryos should be chromosomally normal and each chromosomally normal embryo should propagate a live birth 60-70% of the time, I concluded that there had to be an underlying implantation dysfunction that was preventing these embryos from attaching to the uterine lining.
Moreover, since 30% of women who have endometriosis, regardless of its severity, will have activated uterine natural killer cells (NKa) that could thwart implantation, it seemed to me that immunologic implantation dysfunction (IID) was the most likely explanation for CJ’s hitherto “unexplained” IVF failures.
We tested CJ through Reproductive Immunology Associates (RIA), Van Nuys, CA. and the NKa test (K-562 target cell test) result came back positive for activated killer cells. She was also found to have antiphospholipid antibodies (APA).
Treatment and Outcome: CJ and RJ underwent IVF at SIRM. We harvested 12 eggs. Nine were mature and all were fertilized by ICSI, resulting in nine embryos, four of which developed into expanded, good quality blastocysts. Two blastocysts were vitrified and banked and 2 were transferred fresh to CJ’s uterus. She conceived and subsequently gave birth to a healthy baby girl at term.
About 15 months later, CJ returned for a frozen embryo transfer (FET), using her remaining frozen blastocysts. She conceived another baby girl and is due to deliver later this year.
Commentary: Whenever confronted with repeated “unexplained” IVF failures where morphologically good embryos were transferred, the question arises as to whether the problem is due to inherent egg/embryo “incompetence” (which usually equates with an irregular chromosomal configuration [aneuploidy]) or whether it is due to an implantation dysfunction. The younger the woman and the higher the quality of available embryos (preferably blastocysts), the less likely it is that the fault lies with embryo “incompetence” and the greater is the likelihood that it is due to underlying implantation dysfunction.
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) and c) immunologic implantation dysfunction (IID). It was detection of the underlying IID problem that enabled NJ and RJ to go from “infertility to family”
Implantation dysfunction is a common cause of repeated “unexplained” IVF failure with good embryos. 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.