Background: 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 two 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 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, a regular uterine cavity and a normal uterus as well as patent Fallopian tubes.
CJ and RJ had previously gone through four intrauterine insemination (IUI) treatment cycles. 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 NGS chromosome analysis being performed on all embryos, followed by the transfer of one or more euploid (“competent”) embryos.
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 for antiphospholipid antibodies (APA) that are prevalent in cases of endometriosis (regardless of severity) as well as for natural killer cell activity (NKa) using K-562 target cell test. The results came back positive for NKa as well as for APA.
Treatment and Outcome: CJ and RJ underwent IVF with me. Twenty percent ( 20%) intralipid (IL) was infused intravenously, 12 days prior to ET. This was combined with daily injections of Lovenox (low-molecular-weight heparin) as well as oral Dexamethasone. We harvested 12 eggs, 9 of which were mature (MII) and all were fertilized by ICSI, resulting in nine embryos, four of which developed into expanded, good quality blastocysts. Two blastocysts were transferred fresh to CJ’s uterus and the remainder both vitrified and banked for future dispensation. She conceived, subsequently another gave birth to a healthy baby girl at term. The Lovenox and oral Dexamethasone were continued to the 10th week of pregnancy.
About 15 months later, CJ returned for a frozen embryo transfer (FET), using her remaining frozen blastocysts. She conceived of a viable pregnancy and subsequently went on to deliver another full term female baby.
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 CJ 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 a 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.