This is the 19th in a series of answers to common questions about failed IVF.
Early pregnancy loss – whether due to miscarriage or chemical pregnancy – is due to two major factors. In more than 70-80% of cases the cause is attributable to embryo abnormalities which are usually (but not invariably) related to chromosomal irregularities (aneuploidy). These most commonly result from the egg being abnormal, rather than the sperm. In the remaining 20-30% of cases, the cause is dysfunctional implantation which can result from anatomical (lining), immunologic, or molecular biochemical abnormalities.
Since egg and embryo aneuploidy occur so frequently as a component of normal reproductive performance, it follows that early pregnancy loss is likewise a part of normal reproductive performance. Moreover, since chromosomal irregularities of the egg increase with age, embryo aneuploidy will likewise increase correspondingly as the woman gets older. The fact is that even in young women, at least 20% of embryos are lost due to implantation dysfunction. Depending upon how early this occurs, it would manifest as either a chemical pregnancy (a positive pregnancy test without ultrasound evidence of a developing conceptus) or later as a miscarriage (loss of an established pregnancy).
Furthermore, the incidence of early pregnancy loss rises dramatically as women age beyond 40 years, such that by the mid 40’s it can be greater than 50%. Such chromosomal early pregnancy losses occur sporadically, so that a woman might have a baby, lose one or two, and then have another healthy pregnancy. In other words, they rarely occur repeatedly.
In contrast, early pregnancy loss due to implantation dysfunction (i.e., a non-receptive uterus) tends to be recurrent because unless treated successfully, the cause of the miscarriage remains ever present. In summary, while miscarriages most commonly occur as a result of chromosomal embryo abnormalities, these rarely present as recurrent losses (more than 2 in a row). Thus, when they do, it is important to rule out embryo implantation problems before proceeding to another IVF attempt.
Women who experience repeated IVF failures thus need to be evaluated thoroughly for both embryo competency and implantation dysfunction before and/or in the course of their next IVF attempt. Implantation problems should be evaluated before proceeding to the next IVF cycle. The tests needed include:
- Evaluation of the anatomical integrity of the uterus. This necessitates performance of a sonohysterogram (saline sonogram), a hysteroscopy or a pelvic MRI (rarely is it necessary to go this far). A hysterosalpingogram (HSG), also known as a Dye X-ray, is inadequate because it involves injecting a radio opaque substance into the uterine cavity which can obscure small lesions due to scarring, polyps or fibroids protruding into the uterine cavity.
- Assessment of endometrial thickness. This can be determined by ultrasound examination around the time of normal ovulation or can be determined based on endometrial thickness as measured in previous cycle. A lining of greater than 9mm in thickness is ideal. Less than 8mm is poor and between 8 – 9mm in thickness is intermediate. In my opinion, embryos should not be transferred into a uterus where the lining measures less than 8mm. The administration of vaginal Viagra (sildenafil) suppositories for at least 72 hours prior to the hCG trigger will often dramatically improve a “thin lining”.
- Autoimmune and alloimmune causes of immunologic implantation dysfunction should be assessed. Since both types are ultimately linked to Natural Killer Cell activation, you can start by doing a Natural Killer Cell activity (NKa) test using the K562 target cell test and only proceed to more detailed evaluations if this turns out to be abnormal. Read my prior post on immunologic factors that affect implantation and immunotherapy that can reverse such problems.
- Testing of molecular and biochemical factors in the endometrium. There has been a growing interest in measurement of various endometrial biochemical and molecular factors as a method to assess implantation potential. Frankly, I personally do not share enthusiasm for such tests because to my knowledge there is little concrete evidence of efficacy. Besides, treatment of suggested abnormalities remains obscure and unproven.
Recent advances in egg and embryo karyotyping (chromosome testing) using Comparative Genomic Hybridization (CGH) and related technologies have markedly improved our ability to identify “competent” chromosomally normal embryos for transfer. This requires biopsying the egg or the embryo and testing the DNA using CGH. When the embryo is tested, a biopsy can be done on either day 3 or day 5 (blastocyst stage). Whether it is done on day 3 or day 5, embryo transfer must be deferred until a subsequent treatment cycle (Staggered-IVF) so as to allow enough time for the results of the testing to become available. In such cases, the embryos can be frozen via vitrification (ultra rapid freezing) and stored for subsequent dispensation.
Aside from the above, there are other far less common causes of embryo incompetency (e.g., unbalanced embryo chromosomal translocations) and implantation dysfunction (bacterial and parasitic infections, etc.).
There is nothing more stressful to patients and to caring physicians than dealing with repeated early pregnancy losses following IVF. There is also no greater imperative than to carefully identify the underlying cause, without which successful treatment is far less likely.