To:       Medical Director Name
            Insurance Company Name

            Patient Name:
            Patient Policy & Group Numbers:
            Policy Holder Name:

Dear ______________________________,
            The ability to successfully host a pregnancy is largely dependent upon complex immunologic interactions designed to promote orderly accommodation of the invading trophoblast (developing embryo).  Peer-reviewed studies provide compelling evidence that functional failure of these intricate immunologic interactions during implantation lead to infertility, failure of IVF, recurrent miscarriage, and late pregnancy fetal loss, and pirimarily involve  immunologic factors including anti-phospholipid antibodies (APA), anti-thyroid antibodies (ATA), and activated Natural Killer Cells (NKa).  These immunologic markers are measured via blood tests analyzed by specialized reproductive immunology laboratories.
            An increased incidence of detectable APA’s has been reported in women with pelvic endometriosis, unexplained infertility and repeated IVF failure (1-5).  Recent evidence strongly suggests that the presence of APA’s in cases of non-male factor infertility resulting in immunologically-associated implantation failure is likely mediated by activation of a sub-population of lymphocytes known as Natural Killer (NK) cells, in particular, CD 56 lymphocytes, that comprise more than 80% of the lymphocyte population in the late secretory and early pregnancy endometrium (6).   NK cells contain / produce a variety of TH-1 cytokines [tumor necrosis factor alpha (TNFa), interferon gamma and interleukins (IL) 1&2] and TH-2 cytokines (IL 3,4,6,7,8,11,12). Excessive release of TH-1 cytokines, particularly TNFa, is cytotoxic to trophoblast and endometrial glandular cells, causing unregulated apoptosis and subsequent failed implantation. Orderly, controlled release of TH-1 cytokines, occurring in association with an appropriate production of TH-2 cytokines, is vital to proper placentation.  This TH1/TH2 homeostasis creates an environment fostering implantation and optimal intrauterine development.
Endometrial NK cells are normally predominantly of the CD56+ and CD16- variety. However, in some situations NK cells may become sensitized and express the cell surface marker CD16+. These include:  (1) inappropriate HLA signaling (possibly due to allogeneic compatibility between the conceptus and the maternal organism) and (2) occult or overt organic pelvic disease where the female tests positive for APA, particularly for anti-phosphoethanolamine (PE)/anti-phosposerine (PS) (e.g., endometriosis).  CD56+ and CD16+ NK cells are highly susceptible to activation by TH-1 cytokines such as IL2, transforming them into lymphokine activated killer cells (LAK) which in turn, release large amounts of TH-1 cytokines that threaten implantation.  Because these activated NK cells (NKa) can migrate into the peripheral blood their cytotoxicity can readily be assayed.
IVIG is thought to offset or counter the anti-implantation effects associated with APA positivity and NKa because:
(1) IVIG is a potent suppressor of NKa;
(2) IVIG contains anti-idiotypic antibodies which counter the effects of harmful APA’s; and
(3) IVIG also suppresses activated T-cells and polyclonal B-cells. Studies suggest that this may explain why IVIG therapy improves reproductive performance in females who test positive for antithyroid antibodies (ATA) (7).
IVIG has a profound ability to down-regulate and deactivate endometrial/decidual LAK cells over a period of one to two weeks, therefore, the assay used to measure NK cell activity–the administration of titrated dosages of IVIG to NK cells–determines the amount of IVIG necessary to neutralize NK cell activation.  It has been recently demonstrated that IgG or IgM antibodies to PE or PS in non-male factor infertility cases is often accompanied by increased peripheral NK activity and that IVIG therapy selectively benefits this group of patients (6,8) as well. This suggests that APA’s, rather than being causally related to IVF implantation failure, may act as markers of an underlying abnormality of cellular immunity and shows that appropriate IVIG dosing improves outcome in this patient population. Because the immunologic expression of the fetoplacental unit converts from an atypical Class I (i.e. HLAG) expression to a typical Class I type, it becomes much less susceptible to immunologic injury. This change in HLA antigenicity confers improved immunologic protection to the trophoblast.  Therefore, it is probably unnecessary to continue IVIG therapy beyond the 6th week of gestation, the time at which this conversion occurs.
In conclusion, patients undergoing assisted reproduction may experience failed IVF cycles, implantation failure, clinical miscarriages, or other pregnancy wastage on the basis of pathologic immune processes. Clear evidence now exists to support the fact that patients with serologically demonstrable levels of APA’s and NK’s may benefit from immunotherapy in selected cases.  Further, other perturbations of the immune system, including activation of T cells and polyclonal B cells, and ATA’s, if associated with NKa, may represent an additional indication for IVIG treatment (7).
            In pursuit of optimizing the outcome of IVF, we have a profound responsibility to make every effort to enhance implantation, and hence the chance of pregnancy.  We believe that it is appropriate for you, as the insurer, to recognize that IVIG therapy for this patient is medically prudent and cost-effective in light of the potential alternative need for repeat treatment and/or third-party assisted reproduction in the event of IVF failure, and to authorize benefits for this patient accordingly.


Physician and/or Patient

1.   Fisch B., Rikover Y., Shohat L., Zurgil N., Tadir Y., Ovadia J., Wik I., and Yron I.: The relationship between in vitro fertilization and naturally occurring antibodies; evidence for increased production of antiphospholipid antibodies. Fertil. Steril. 56(4), 718-724, 1991.
2.   Gleicher N., Liu H.L., Dudkievicz A., Rosenwaks Z., Kaberlien G., Pratt D., et al.: Autoantibody profiles and immunoglobulin levels as predictors of in vitro fertilization success. Am J Obstet. Gynecol. 170:1145-1149, 1994.
3.   Birkenfeld A., Mukaida T., Minichiello L.., Jackson M., Kase N.G., Yemini M.: Incidence of      autoimmune antibodies in failed embryo transfer cycles. Am. J Reprod. Immunol.  31:65-68, 1994
4.   Kaider B.D., Price D.E., Roussev R.G., Coulam C.B.: Antiphospholipid antibody prevalence in patients with IVF failure. Am. J Reprod. Immunol. 35:383-393, 1996.
5.   Bustillo M. Goodman C.: Assisted reproductive technologies and immune infertility. Am. J.      Reprod. Immunol., 35:205-289, 1996.
6.   Matzner W. Presentation at Pacific Coast Infertility Meeting, 1998.
7.   Sher G., Maassarani G., Zouves C., Feinman M., Sohn S., Matzner W., Chong P., Ching W. The Use of Combined Heparin/Aspirin and Immunoglobulin-G Therapy in the Treatment of In Vitro Fertilization Patients with Antithyroid Antibodies. Amer. J. of Reprod. Immunol. 39: 223-225, 1998.
8.   Sher G., Matzner W., Feinman M., Maassarani G., Zouves C., Chong P., Ching W.: The selective use of heparin/aspirin therapy, alone or in combination with intravenous immunoglobulin G, in the management of antiphospholipid antibody-positive women undergoing in vitro fertilization. Am. J of Reprod. Immunol., 40:74-82, 1998.

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