Understanding The Antibodies of Autoimmune Implantation Dysfunction

There are many different autoimmune implantation dysfunction associated with a variety of antibodies. Those most commonly associated with reproductive failure are:

Antiphospholipid Antibodies (APA)

Antithyroid Antibodies (ATA/AMA)

Activated Natural Killer Cells (NKa)

Women who experience repeated IVF failures often have increased levels of circulating APAs-proteins that occur as small negatively charged structures on the outer surfaces of cells. Up to 50% of women with pelvic endometriosis and unexplained infertility have APAs in their blood. Yet for some reproductive endocrinologists, the role of APAs in reproductive outcome is still controversial. Beginning in 1995, we started treating APA positive women with mini-dose heparin and low-dose aspirin regime to improve IVF implantation and thus birth rates.

Contrary to what is often assumed, the dose of heparin used is not enough to thin the blood and cause bleeding problems. Instead, the heparin repels APAs from the surface of trophoblast cells, thus enhancing their development. Aspirin was included to inhibit blood cells called platelets from sticking to the embryo as well as prevent blood clots from forming in the placenta. After analyzing data from the women treated, we demonstrated that heparin/aspirin therapy improved IVF outcome only for some of the women that had APAs. However, women with two specific phospholipids – phosphatidylethanolamine (PE) and phosphatidylserine (PS) – needed additional treatment to prevent implantation failure. This subtle difference is the likely source of confusion amongst fertility specialists. More recent analysis has shown that the use of heparin alone is just as effective as combining it with aspirin. Accordingly, we no longer prescribe aspirin.

Activated Natural Killer (NKa) Cells

Natural Killer cells are large lymphocytes (a type of white blood cell ) that play a vital role in regulating the impanation of the embryo’s root system (trophoblast).They produce a variety of local growth factors known as cytokines, of which there are two varieties: TH-1 and TH-2 cytokines. The TH-2 cytokines promote growth and penetration of the trophoblast while TH-1 cytokines cull the trophoblast cells. TH-1 and TH-2 cytokines are in balance, such that penetration of the uterine wall is limited and the lifeline of the developing baby is secured. In situations where NK cells become “activated” (i.e. NKa) there occurs an over-production of TH-1 cytokines. This compromises the trophoblast cells, leading to dysfunctional implantation with the result being either total failure of the embryo to implant, miscarriage, or poor subsequent development of a surviving pregnancy. The situations most frequently associated with NKa are:

Antithyroid Antibodies (ATA)

About 50% of women who have autoantibodies to their own thyroid tissues have activated Natural Killer cells. The most common antibodies are antithyroglobulin and antimicrosomal antibodies and yet many of effected women don’t have clinical signs or symptoms of reduced thyroid hormone activity (hypothyroidism). Instead, these women are often diagnosed as a result of reproductive failure manifesting as infertility, recurrent IUI and IVF failure or repeated pregnancy loss.

The antithyroid antibodies (antimicrosomal and/or antithyroglobulin antibodies) do not cause the problem. They act as markers pointing to an underlying immunologic implantation problem that occurs when NKa or T-cell activation is present. The result is that as soon as the embryo starts to implant in the endometrium, “toxins” are produced (locally) that impair their ability to establish a good blood supply. In some cases, the pregnancy is lost before a blood test can detect it, while in other cases a miscarriage occurs. For unknown reasons, some pregnancies escape the “toxic gauntlet” and proceed without treatment contributing to the controversy of immunologic factors contributing to pregnancy loss and infertility.

Dr. Geoffrey Sher was among the first to demonstrate that women who have reproductive failure associated with antithyroid antibodies and NKa+/T-cell activation can have successful IVF outcomes following administration of intravenous gammaglobulin (IVIG). Women who are antithyroid antibody positive but do NOT have NKa+ and or T-cell activation do not require intralipid/IVIG therapy to have a successful pregnancy.

Intralipid/IVIg therapy should be initiated prior to initiation of treatment with fertility drugs, and should be administered one more time after pregnancy is diagnosed. About 50% of women who harbor ATAs also test NKa positive. The risk of implantation failure in ATA-positive women appears to be confined to cases where ATAs coexist with NKa. IVIg therapy should be limited to such cases.