Immunologic factors
The implantation process begins six or seven days after fertilization of the egg. At this time, specialized embryonic cells (i.e., trophoblast), which later becomes the placenta, begin growing into the uterine lining. When the trophoblast and the uterine lining meet, they, along with Immune cells in the lining, become involved in a "cross talk" through mutual exchange of hormone-like substances called cytokines. Because of this complex immunologic interplay, the uterus is able to foster the embryo’s successful growth. Thus, from the earliest stage, the trophoblast establishes the very foundation for the nutritional, hormonal and respiratory interchange between mother and baby. In this manner, the interactive process of implantation is not only central to survival in early pregnancy but also to the quality of life after birth.
Considering its importance, it is not surprising that failure of proper function of this immunologic interaction during implantation has been implicated as a cause of recurrent miscarriage, late pregnancy fetal loss, IVF failure, and infertility. A partial list of immunologic factors that may be involved in these situations includes anti-phospholipid antibodies (APA), antithyroid antibodies (ATA), and, perhaps most importantly, activated natural killer cells (NKa). Presently, these immunologic markers can be adequately measured by only a few (less than a half dozen) highly specialized reproductive immunology laboratories in the United States, from patient blood samples. 1)Antiphospholipid Antibodies (APA)
A large body of literature has confirmed that patients who experience repeat IVF failures often have increased levels of circulating APAs. Compelling evidence has also demonstrated that up to 50% of women with pelvic endometriosis and unexplained infertility harbor APAs in their blood. Despite this information, the role of APAs in reproductive outcome is still controversial. In 1995, we proposed that in cases of non-male factor infertility, women who test positive for APAs be treated with a mini-dose heparin and low-dose aspirin to improve IVF implantation and thus birth rates. This approach was based upon research that suggested that heparin repels APAs from the surface of trophoblast cells, thus enhancing their development and aspirin, by inhibiting platelets from adhering to the early trophoblast, might prevent clot formation in the early uteroplacental vasculature. We subsequently demonstrated that heparin/aspirin therapy improved IVF outcome only for women whose APA testing was positive for antibodies other than those directed against two specific phospholipids, i.e., phosphatidylethanolamine (PE) and phosphatidylserine (PS), and that only women who had IgG/IgM-related anti-PE or anti-PS antibodies experienced a significant improvement in IVF implantation and birth rates when IVIg therapy, instead of heparin/aspirin, was initiated more than 1 week prior to embryo transfer.
Our recent observations suggest that the use of heparin alone is just as effective as combining it with aspirin. Accordingly we no longer prescribe aspirin at all. Notwithstanding the above, the following recent observations suggest that APAs rather than being causally linked to implantation failure, might serve to identify a population at inordinate risk of implantation failure and that NKa, through the unregulated release of embryotoxins, are in fact the real culprits.
- The presence of APAs in male factor cases appears to bear no relationship to IVF outcome;
- Only APA positive women who also test positive for abnormal NK activity appear to benefit from selective immunotherapy with IVIg
- More than 75% of APA+ women who have increased NK cell activity also harbor a PE and/or a PS antibodies
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