IMMUNOLOGIC IMPLANTATION FAILURE & ENDOMETRIOSIS
Endometriosis is defined as the presence of endometrial cells outside of the uterus that can result in pain, distortion of pelvic structures and infertility. Various reports in the medical literature suggest that endometriosis is related to a deficiency in the immune system. Impaired immune response in some women may result in ineffective removal of the endometrial cells from the pelvic area that may result in endometriosis. A number of substances are involves in the pathophysiology of the disease including cytokines and natural killer cells. Although a number of theories have been proposed in the development of endometriosis, the exact pathophysiology is still to be determined.
The natural conception rate for healthy ovulating women in their early 30s (without endometriosis) is approximately 15-20% per month and 75-85% per year of actively attempting to conceive. Conversely, the conception rate for women of a comparable age who have minimal or mild pelvic endometriosis (Stage I or II disease) is about 3-5% per month and 20-30% after 2 years of trying. The reduced conception rate in women with endometriosis may be explained by either decreased egg reserve (resulting in chromosomally abnormal embryos) or one of the following additional factors:
Altered Peritoneal Environment
Women with endometriosis may have an inflammatory reaction in the pelvis that may result in the release of toxic substances and activation of specific white cells. These toxins may reduce the natural fertilization potential of the sperm as well as the egg. In vitro fertilization (IVF) treatment involves aspirating the eggs before they are released from the ovary during the process of ovulation and prevents exposure to endometriosis related toxins. It is possible that once the eggs are released into the pelvis they are exposed to various toxins and inflammatory cells and this may be the case for sperm as well.
Immunologic Implantation Failure
Some women with endometriosis have anti-phospholipid antibodies (APA) in their circulation. Also, approximately one third of women who have endometriosis (regardless of severity) show evidence of increased Natural Killer Cell activity (NKa) in the peripheral blood and potentially in their endometrial linings. In such cases there is a higher likelihood of early or later immunologic implantation failure. In the case of early immunologic implantation failure, it is possible that rejection occurs at the time that the embryo attaches to the uterine wall. These patients may have been pregnant before, but in most instances the pregnancies may have been undetected. In the case of the latter (late implantation failure), poor implantation may result in a miscarriage. It is not certain whether APA themselves cause implantation failure, although it’s plausible. They could be markers pointing to those women who are at increased risk of immunologic implantation failure. Having said that, a recent large study did not find any difference in pregnancy and miscarriage rates in APA positive and APA negative women. Additionally, early miscarriages may be due to chromosomally abnormal embryos, whereas late miscarriages (more than 7 weeks gestation) may be due to the presence of APA.
Selective immunomodulation with steroids along with heparin and aspirin and/or Intravenous Immunoglobulin G (IVIG) or Intralipid may effectively counter immunologic implantation failure and may lead to successful pregnancies in women who have APA and/or increased NK cell cytotoxicity. Oral steroid treatment along with aspirin and heparin use may be helpful in women with anti-phospholipid syndrome and decrease the risk of having a miscarriage. In cases of increased NKa a new treatment modality appears to be promising. Intralipid treatment prior to and after embryo transfer in cases of increased NKa may be helpful, although it should be regarded as experimental approach. In the past, IVIG was used in women with a history of recurrent pregnancy loss, but the outcome was mostly similar whether women used IVIG or not. Intralipid appears to be a promising intervention, but more medical information is needed to offer it on a regular basis in cases of implantation failure.
It appears that historically emphasis has been on the uterine lining without paying too much attention to the most important and determining variable in pregnancy outcome, which is the chromosomal make up of the embryo. Based on the most recent genetic test available for chromosome testing of embryos called CGH, pregnancy rates are significantly increased and the risk of miscarriage is significantly decreased when CGH-normal (chromosomally normal) embryos are transferred into the uterus.