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Infertility Cubby

Chances of Successful IVF With Elevated Antinuclear, AntiOvarian and Antiphospholipid Antibodies
by Geoffrey Sher, M.D.

Q.I have been diagnosed with immunological problems. I have been trying to have a baby for the past four years (after a tubal reversal). I have gotten pregnant four times but cannot carry past 7.5 weeks. I have elevated Antinuclear, AntiOvarian and Antiphospholipid antibodies.

My RE now has me taking prednisone, 5mg cd 3 till trigger shot then 60 mg for 4 days, then 10 mg's till pregnancy test, if positive then 20 mgs, if negative then stop. (This is along with my baby aspirin, folic acid, Follistim and IUI treatment).

My question is, does this really work? What kind of chances does a 32 year old, with children aged 12 and 14 who has lost her last 4 pregnancies have of carrying a healthy baby to term?

A. National statistics indicate that only one out of four women under the age of 40 achieves a live birth following treatment with in vitro fertilization IVF. While most IVF laboratories report a similar egg fertilization rate (i.e., 60-70%), program-to-program IVF birth rates still range from below 10% to greater than 50% per embryo transfer. To improve IVF success rates, the cause(s) of this discrepancy, must be recognized and addressed.

Compelling evidence suggests that an abnormally functioning maternal immune system often leads to poor reproductive performance (i.e., IVF failure, recurrent abortion, poor intrauterine growth and even fetal survival) and that identification and selective immunotherapy results in a significant improvement in IVF birth rates, intrauerine development and fetal survival.

Almost across the board physicians who provide services in the field of Assisted Reproductive Technology (ART) tend to attribute recurrent unexplained treatment failures to sub-optimal embryo quality and then advise such patients that the only way to improve their subsequent chance of a successful outcome, is by changing clinical and laboratory protocols involved in ovarian stimulation, gamete and embryo preparation and/or the transfer of gametes or embryos to the woman's reproductive tract. Such logic fails to take into account the fact that it is "implantation failure" rather than poor egg/embryo number or quality that is often the root of the problem. A rational approach to subsequent treatment requires that a clear distinction be made between those factors that cause "true infertility" (defined the absence of normal fertilization and/or embryogenesis), and those that lead to "failed implantation," (namely; immunologic rejection of the embryo, local inflammation and pathology involving the uterine cavity). Only treatment directed at an identifiable probable cause of prior ART failure, can justify providing patients with renewed hope of success in a subsequent cycle of ART treatment.

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.

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 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. Aspirin, by inhibiting platelets from adhering to the early trophoblast, might prevent clot formation in the early utero-placental 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 one week prior to embryo transfer.

Notwithstanding the above, the following recent observations suggest that APA's 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 embryo toxins, 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 aPE and/or aPS antibodies

Natural Killer Cell cytotoxicity

After ovulation and during early pregnancy, NK cells comprise more than 80% of the white blood cell population seen in the uterine lining. NK cells produce a variety of local hormones known as TH-1 cytokines. Uncontrolled, excessive release of TH-1 cytokines is highly toxic to the trophoblast and endometrial cells, leading to their programmed death (apoptosis) and, subsequently to failed implantation. In the following situations these NK cells (and also T-cells) can become abnormally activated

  • In female patients that have both pelvic disease (especially endometriosis--regardless of severity) and abnormal APA testing
  • In about half of the cases where the woman forms antibodies gainst her own thyroid gland (i.e., antithyroid antibodies.)
  • Activated NK cells (NKa) can spill over from the uterine lining into the peripheral blood where their toxicity can be measured.
IVIG therapy, initiated more than 1 week prior to embryo transfer, can subdue activated NK cells, thereby reducing the risk of implantation failure.

Antithyroid Antibodies (ATA)

A clear relationship has been established between ATA and reproductive failure (especially recurrent miscarriage and infertility). We have previously reported on the ability to double IVF birth rates through the administration of IVIG to ATA+ patients. 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+ women appears to be confined to cases where ATAs coexist with Nka. IVIG therapy should be confined to such cases.

TREATMENT OPTIONS:

Heparin/Aspirin
There is compelling evidence that subcutaneous heparin (administration at a dosage of 5000 U twice daily to women undergoing IVF for female causes of infertility who test positive for APAs, but negative for NK activation), significantly improves IVF birth rates. Heparin administration is withheld on the day of egg retrieval until immediately following embryo transfer, whereupon it is recommenced and continued until the 8th week of pregnancy. Heparin is thought to act by repelling APAs from the surface of the trophoblast (early "root system" of the embryo). Provided that platelet counts are normal, are checked on a regular basis and heparin is withheld on the day of egg retrieval, its administration is virtually risk-free.

The administration of aspirin in combination with heparin, offers no benefit over treatment with heparin alone, for the management IVF patients with immunologic implantation failure. As such, with the notable exceptions of women with primary APA-related autoimmune diseases (e.g., lupus erythematosis, rheumatoid arthritis, etc.) and cases associated with recurrent pregnancy loss, we no longer prescribe aspirin to women undergoing treatment for reproductive failure.

Intravenous Immunoglobulin G (IVIG)
IVIG is a sterile protein preparation derived from human blood. Every effort has been made to ensure that it is free of bacterial and viral contamination. There are basically three ways in which IVIG may offset or counter the anti-implantation effects associated with reproductive immunologic deficiencies.

First, it is a potent suppressor of activated (toxic) NK cells (see above). Second, it contains anti-idiotype antibodies that combat the effects of harmful antibodies, thereby protecting the embryo/fetus from rejection. Third, IVIG deactivates activated T-cells and polyclonal B-cells that may be involved in poor reproductive performance associated with the presence of antithyroid antibodies (Sher, et al, American Journal of Reproductive Immunology, 1998). Unfortunately, IVIG has had some undeserved bad press. Since it is a blood derivative, the thought of administering it in an era where HIV is rampant, is frightening to most; but consider the following: The IVIG products available in the United States and the United Kingdom, according to the manufacturers, have not resulted in a single HIV viral transmission in more than two million administrations. Moreover, IVIG is derived from the very same blood pool used for transfusion purposes, and since millions of units of blood have been administered in the United States over the last 7 years without any reports of HIV transmission, and since the product is thoroughly tested in this country, it is safe to say that US produced IVIG is untainted by viral contamination. IVIG therapy for increased NK activity/APA positivity is initiated at least 10 days prior to embryo transfer, and for ATA positivity is initiated 7 to 14 days prior to the initiation of gonadotropin therapy. The infusion is repeated once pregnancy is diagnosed. We do not recommend repeating IVIG administration subsequently during the pregnancy.

Corticosteroid Therapy (Prednisone, Prenisilone and Dexamethazone)
Steroid therapy is a mainstay of most IVF programs. Some programs use daily oral methyl prednisilone while others prescribe oral Dexamethazone commencing about ten days prior to initiating ovarian stimulation with gonadotropins, and continuing until the diagnosis of pregnancy, whereupon, in the event of a negative test (Beta HCG or ultrasound), the dosage is tapered over a period of seven to ten days, and then discontinued. Pregnant patients continue treatment through the first trimester. Steroids are believed to act by inhibiting the cellular immune response.

The selective use of immunotherapy as outlined above has, on numerous occasions, has enabled us to achieve successful pregnancies in-patients who had previously suffered repeated IVF failures (4 or more). Many such patients had previously been advised not to try again with their own eggs. We are able to report IVF births occurring in more than a dozen cases, after more than ten (10) prior IVF failures. One such case involved a 42-year-old woman who had a baby (using her own eggs) following 22 consecutive prior IVF failures. It is indisputable that such results would not have been achieved without access to selective immunotherapy. In a recent study, we were able to show that Nka+ women who do not receive IVIG/heparin therapy have a 10 times lower chance of successful IVF.

Because immunologic problems may lead to implantation failure, it is important to properly evaluate women with risk factors such as:

  • Unexplained or recurrent IVF failures
  • Endometriosis (about 30% of cases are associated with increased Nka+ activity requiring IVIG/heparin)
  • Unexplained infertility
  • Infertility following recurrent miscarriage
  • A positive personal or family history of autoimmune disorders such as Rheumatoid arthritis, Lupus erythematosis and hypothyroidism (Hashimoto's disease) which is rather common in women.
The controversy relating to the use of selective immunotherapy in IVF has been spawned by issues other than those related to science. Political one upmanship, the competitive nature of the ART field and lack of understanding with regard to the complex issue of reproductive immunology, has led a lot of misinformation. This issue will be laid to rest by a large randomized and controlled study we have been able to undertake due to a >1 million dollar grant given to us by a large pharmaceutical company.

CONCLUSION:

The immunologic contribution to successful reproduction is a complex puzzle that is still being assembled one piece at a time. Clear evidence now exists to support the view that women with non-male factor related infertility, who harbor IgG/IgM, APAs, can selectively benefit from immunotherapy with heparin or IVIG. Rather than being causally linked to implantation failure, APAs, probably serve as markers that point to a population at risk and that this risk is greatly increased when such antibodies are specifically directed against PE and/or PS are present and/or when Nka are detected. APA positve/Nka negative women should be treated with heparin, while all Nka positive women, regardless of their APA/ATA status should receive IVIG.

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