Science Pulse    The Controversy of Immunology

The majority of reproductive endocrinologists in the U.S. and Europe do not recommend an extensive battery of immunological tests nor is there “immune system” specific treatment after repeated and/or unexplained IVF failures. To clarify, IVF failure is defined as IVF that does not result in a pregnancy.

Because it is frustrating to patients to experience repeated conception failures with no apparent explanation, it is only natural for them to continue seeking answers.

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. 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.
Eldon Schriock, MD
Dr. Eldon Schriock along with PFC's medical team is continually evaluating the latest research. Our patients' welfare is PFC's first priority. With this in mind, be assured we do not include new technologies and treatments unless they are backed with solid, evidenced-based research.

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.

Conception Health    Sperm Count and Laptops

It is well known that healthy sperm are produced ideally at a testicular temperature of 2 – 4 ºC below body temperature. Established studies have revealed a considerable decline in healthy sperm production - up to 40 % - resulting from scrotal or testicular temperature increases as small as 1 ºC. A long-term decline in sperm quality over several decades has also been identified by at least seven research studies, although definitive causes have yet to be determined. Given this, it was only a matter of time before the connection between laptops and infertility would be examined.

As reported in Human Reproduction, Vol.2, 2005, a group of scientists at State University of New York, Stony Brook embarked upon a research study monitoring the scrotal temperature change in 29 healthy male volunteers, median age 24, from laptop computer use. The researchers used two different types of laptop computers and randomly measured their thermal effect on the scrotum by using right and left scrotal temperature gauges in two separate 60 minute sessions.

They recorded scrotal temperature increases averaging 2.6 – 2.8 ºC.

The heat emitted by the laptops appears to be a factor, but curiously not the solo factor. The researchers also directed the study participants to sit upright without the laptop, but with their knees tightly pressed together. After sitting this way for an hour, researchers recorded their scrotal temperature, which increased on average 2.1 ºC.

This initial study may prompt further research seeking a more definitive link between laptop use and infertility, or it simply may be added to the myriad considerations of exogenous scrotal heat exposure related to lifestyle. In this same category are prolonged driving and sedentary sitting. Naturally this study calls for prudent use of laptops by men trying to become fathers while weighing in on how modern life in all of its ramifications might be boosting scrotal temperature and causing an overall decline in sperm count.
Philip Chenette, MD

Ask the Experts    Fibroids: To Keep or Remove?

A few women who desire pregnancy may need to have their fibroids removed (myomectomy) prior to conceiving if the fibroids are very large (greater than 6 cm) and/or if they impinge upon and distort the uterine cavity.

Various surgical approaches to removal are further described on PFC's web site at ../treat/surgical.php, along with a more in depth summary of the factors that our physicians consider when counseling a patient to undergo a myomectomy.

You probably received different opinions because the impact of fibroids as related to pregnancy chances depends on the size and location of the fibroids. Other issues to consider are that fibroids are dependent on estrogen to grow, and high levels of estrogen produced during pregnancy can lead to rapid growth of the fibroid(s). If the fibroid is on the outer surface of the uterus, this may present little problem. If the fibroid is located within the uterus muscle wall or nearer the uterine cavity where the fetus is growing, a patient may be at higher risk for various pregnancy complications (miscarriage, preterm labor...).

In rare cases, the fibroid may grow so rapidly during pregnancy that it outgrows its blood supply and starts degenerating, which can be painful and sometimes lead to pregnancy complications. Also uncommon but of significance is the fact that some fibroids may block the lower portion of the uterus, prohibiting the baby's head to descend into the birth canal, making cesarean delivery necessary. However, it is important to keep in mind that the majority of patients with fibroids experience no problems during pregnancy.

What is the impact of fibroids on pregnancy chances? It is unclear that there is any negative impact, if the fibroids are small and not growing within or distorting the uterine cavity.
Isabelle Ryan, MD

From Us to You    New Clinical Study: NuvaRing

First, we want to make sure the donor cannot get pregnant in the month prior to IVF at the time she needs to start Lupron. Also, hormonal contraceptives will usually prevent ovulation so that when the donor starts Lupron, there is less of a chance of inducing a cyst from the ovulation follicle. We also use birth control pills to get the donor's and the recipient's cycles in sync. Donors must remember to take one pill every day for anywhere from 14 to 35 days (usually 21 days).

A new contraceptive device manufactured by Organon is called NuvaRing. It is already FDA approved for contraception but to our knowledge, has not yet been used in ovum donors prior to IVF. This is a soft silastic ring containing estrogen and progesterone analogs. The patient places the ring in the vagina and removes it after 21 days. The potential advantage is that the donors will not have to remember to take a pill every day and therefore, help avoid any errors in a cycle.

We will be assessing by questionnaire whether or not the donor found the ring to be easy to use and whether or not they would consider using this method for future contraception. Because this is a randomized clinical trial, 15 donors will be randomly assigned to use the ring and 15 will be on our usual birth control pills. Organon will provide the pills or rings free of charge for donors in the study. For more information on NuvaRing and an interactive example of the ring's flexibility go to www.nuvaring.com
Carolyn Givens, MD

Patient Odyssey    Frozen Embryos: My Journey

Surgery after surgery, specialist after specialist, my quality of life was slowly going down the drain. Initially, I told doctors that I didn't want to have a hysterectomy but later, something had changed. I was eight surgeries into my journey and I asked my doctor if I could have just my uterus removed so I could still try and have a biological child. He said yes and I was quite relieved. After the surgery, I felt better for a while, but the pain still continued. I had to evaluate my life and decide what was important to me. I knew I wanted to live, but the pain had me in and out of the hospital and often times feeling suicidal. I had no other choice but to have my ovaries removed.

Luckily, I thought about freezing embryos and called Pacific Fertility Center. I met with Dr. Isabelle Ryan and she changed my life. My boyfriend and I knew we wanted to get married and I was on a limited time line until I had my ovaries removed. We only had one chance to do this and we were determined to do it right. We underwent one cycle of In Vitro Fertilization and froze all of our embryos. We froze our embryos at a 2PN stage* per Dr. Conaghan and Dr. Ryan's request. This would help our chances of having them thaw better but we don't know how they will turn out. We were willing to take that chance.

Two weeks later, I had my ovaries removed and then felt I was ready to move on with my life. My boyfriend and I got engaged and together dealt with the loss of having me carry our child. In our counseling session with Peggy Orlin, MFT at Pacific Fertility Center, we talked about what if a gestational cycle didn't work. We knew that we would be parents no matter what and if it wasn't our biological child we could be ok with that.

From time to time, I still grieve the loss of being pregnant, but know that I did everything that I could. Since then we have gotten married and have been offered the opportunity of a lifetime. A dear friend has said that she would like to carry our child. She has restored our faith in humanity. What an offer!

As we are working out the details, we are thankful for her commitment to us and our journey. We will transfer some of our embryos into our gestational carrier and hope for the best. Dr. Ryan and all of the staff at Pacific Fertility Center have been so supportive of us that we can't wait to come back when we are ready to do our transfer.
Anonymous, San Francisco

* A note from Laboratory Director Joe Conaghan, PhD:
Embryos can be frozen at different stages of development, usually 1, 3 or 5 days after oocyte retrieval. In general, the earlier they are frozen, the better they tolerate the freezing process. Embryos frozen on day 1, or at the 2 pro-nuclei stage, survive freezing and thawing at a rate over 95%.

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-- Best regards from all of us at Pacific Fertility Center.