The Controversy of Immunology Part 2
In last month's ***Fertility Flash***, we introduced readers to the controversy of implicating the immune system in response to repeated IVF failure. In ***Immunology PART 2***
Unfortunately, patients find information on the Internet, which prompts them to seek various tests and treatments, despite the lack of scientific basis. In some cases, these treatment options have been shown to be of **no** benefit, but patients still seek these in the hope that they might be successful. It is important to understand that physicians have a limited number of **valid tests** to perform in these situations. As we continue to understand the biology of embryo development and implantation, we may be able to identify other "valid tests" in the future. Most of the tests that are included in a typical "immunology" work-up are listed in Table 1. It is important to note that of the battery of tests that purportedly determine immune deficiencies related to infertility, several are standardized for recurrent pregnancy loss (RPL). RPL is defined as three or more consecutive pregnancy losses before 20 weeks gestation. We have noted the tests that are valuable in assessing RPL.
Below are descriptions of the questionable tests and additional treatment options that are administered by a handful of practitioners at great expense to patients. These tests are controversial not only because of their poor predictive value, but also because these **laboratory assays are not standardized; the threshold between normal and abnormal/positive and negative differs from one laboratory to another.** The following research studies and medical association positions have negated further consideration of such treatments by the majority of reproductive endocrinologists worldwide.
**Antiphospholipid Antibodies (APAs)** Because antiphospholipid antibodies (APAs) have been tied to recurrent pregnancy loss (RPL), particularly anticardiolipin antibodies (ACAs) and the lupus anticoagulant (LAC), medical researchers have investigated the role these antibodies may play in unexplained infertility. This area has been the focus of several well-conducted studies. Infertile women do show an increased prevalence of phospholipid antibodies. Whether these autoantibodies cause infertility or IVF failure, or are present due to other issues related to infertility, has been the critical question studied. The controversy surrounding this topic has prompted professional organizations to convene committees to examine the research. The American Society for Reproductive Medicine (ASRM), the world's largest professional body of reproductive endocrinology and infertility specialists, issued a statement in October 1999 reaffirming that **the presence of APA does not affect IVF success.**
**Anti-sperm antibodies** Reproductive scientists continue to debate whether or not antibodies bound to sperm cause infertility. Fortunately, effective treatments for male factor infertility include intrauterine insemination, IVF, and ultimately intracytoplasmic sperm injection.
**Anti-thyroid antibodies** Currently no compelling research data supports the use of routine antithyroid antibody testing in women undergoing assisted reproduction. Data reveals that the prevalence of thyroid antibodies is similar in fertile women and women with unexplained infertility.
**Other autoantibodies** There is a lack of compelling evidence that testing for anti-nuclear and anti-smooth muscle antibodies in routine clinical practice is relevant to the diagnosis or treatment of unexplained infertility.
**Leukocyte testing (immunophenotyping) for NK Cells** Immunophenotyping for the diagnosis of unexplained infertility or failed IVF lacks strong scientific support. Treatments to correct any presumed leukocyte dysfunction have not demonstrated efficacy in the treatment of infertility, nor for RPL. Very simply, the clinical use of leukocyte testing in fertility practice is not supported by current data.
**Treatments** Treatment approaches following such immunology tests are similarly of unconfirmed benefit and some may cause harm.
**Lymphocyte immune therapy (LIT)** This is a broad-based yet very controversial treatment purporting to improve a woman's maternal immune tolerance towards her fetus, which necessarily carries dissimilar paternal proteins on the surface of fetal cells. Not only is this therapy expensive, it also has potential serious adverse effects including transfusion reaction, anaphylactic shock and transmission of infection. The US Food and Drug Administration has issued restrictions against transfusion of women with their partner's white blood cells or cellular products.
**Intravenous immune globulin (IVIG)** Intravenous immune globulin treatment has been the subject of several studies. Those by Coulam and DePlacido suggested that women receiving IVIG had improved implantation rates, yet they were too small to be conclusive. A later randomized, controlled study demonstrated that IVIG added no benefit in unexplained recurrent IVF failure.
**Steroids** This treatment based on steroids' immunosuppressive effects has been linked to significant maternal and fetal morbidity. Two randomized, controlled studies revealed that the routine use of steroids was of no benefit to women undergoing [IVF treatment](/treatment-care/in-vitro-fertilization). Two additional randomized, controlled studies concluded that steroid therapy in women with RPL did not improve the live birth rate when compared with aspirin or aspirin plus heparin
**Aspirin** Treating infertile women with aspirin continues to be debated due to conflicting studies. One randomized, controlled trial found that aspirin did not improve implantation and pregnancy rates in selected women undergoing IVF + ICSI. Yet another randomized, controlled study reported that aspirin significantly improved implantation and pregnancy rates in women undergoing IVF. Low-dose aspirin is frequently prescribed in IVF cycles to enhance blood flow to the uterus. This is not seen as an immunological issue. The use of low-dose aspirin during pregnancy in cases of RPL has also been shown to improve pregnancy outcome for women with hereditary or acquired blood clotting problems.
**Heparin** The therapeutic benefits of heparin are one of the most vociferously debated topics in ART. Some physicians believe that heparin facilitates implantation. Two prospective studies, one randomized and another non-randomized, both showed that combination treatment with aspirin and heparin significantly improved the live birth rate in women with antiphospholipid antibody (APL) syndrome. Antiphospholipid antibody syndrome is a specific entity where the patient has a clinical history with miscarriages (usually second trimester), abnormal clotting events (DVT), various pregnancy complications and various systemic disorders (lupus). A prospective cohort study concluded that aspirin and heparin therapy was of no benefit in APA-positive women undergoing IVF.
**Summary** Women suffering from the anguish of unexplained IVF failure may be compelled to take action, even turning to treatment that is not widely accepted in the medical community. These women continue to be presented with testing and treatment cycles by non-specialists as well as a handful of practicing reproductive endocrinologists who appear to be on a mission to defy sound science. The majority of reproductive endocrinologists worldwide believe the evidence confirms immunology treatments are not valid for unexplained and/or repeated IVF failures. Currently the FDA has issued statements indicating that IVIG and LIT treatment are invalid in the treatment of infertility, **unless** administered in the context of a randomized study, supervised by clinical researchers. We at PFC concur and do not recommend this form of testing or treatment, even if a woman's options are narrowing.
**Note:** This article presents a basic summation of controversial testing and treatment options related to the topic of reproductive failure and immunology. An extensive packet of information, which includes copies of scientific studies and position papers compiled by our team of physicians at Pacific Fertility Center is available upon request. Call 888-834-3095.