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:
- Age: The chance of a woman under age 35 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 have been present in the ovaries from birth.
- Embryo Quality (“competency”): As stated, the woman’s age plays a big role in determining egg/embryo quality. 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 essential to customize and individualize the ovarian stimulation protocol.
- The uterine environment: We used to believe that the uterine environment is more beneficial to embryo development than is the incubator/petri dish. Accordingly, we thought the earlier on in development that embryos were transferred to the uterus, the better. To achieve this goal, we used to select embryos for transfer based upon their day two or three 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 15 years ago of Preimplantation Genetic Screening (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).
- 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 stimulation 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 can unpredictably result in twins or triplets which increase the incidence of maternal pregnancy-induced complications including preterm delivery with its serious risks to the newborn. It is for this reason that I strongly recommend single embryo transfers …especially when it comes to transferring embryos derived through the fertilization of eggs from young women. In addition, recent studies suggest that, when working with chromosomally normal embryos, the transfer of more than one embryo only seems to increase the twin pregnancy rate without actually changing the percentage of women who get pregnant at all.
- Implantation Dysfunction (ID): Implantation dysfunction is an 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 thin uterine lining (< 8mm) in which the lining itself does not contain enough tissue substrate for an embryo to latch onto and develop.
- A non-receptive lining in which the window of implantation has shifted pathologically to a time point before or after what is perceived to be the correct time for embryo transfer.
- A uterus with surface lesions in the cavity (polyps, fibroids, scar tissue)
- Immunologic implantation dysfunction (IID)
- Occult Infection of cervical mucus and the endometrial lining of the uterus, which 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.
- Sperm issues: embryos emanating from men whose sperm is shown to be overall high in DNA breakage often fail to thrive, and can do so even if PGT tested as normal. This would raise the notion of using more stringent sperm selection techniques in future IVF cycles.
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).