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 we further describe the types of testing and treatment scenarios that, for the most part, are considered non-evidence-based medical practice.

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.

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.

When a woman is not able to conceive after one or more attempts at IVF with no apparent reason, she may feel heightened anguish. She may then broaden her research efforts with a determined resolve, even exploring unconventional treatments. She may end up considering immunological testing and treatment.

It is easy for patients to scapegoat the body’s immune system when apparently healthy looking embryos fail to implant, or a pregnancy is thwarted for unknown reasons. Autoimmune factors related to recurrent pregnancy loss (RPL) have been fairly well studied, resulting in treatment methods that are relatively standard.

On the other hand, implicating the immune system for repeated IVF failures represents an area of medicine that can be subject to abuse. Practitioners of reproductive endocrinology in the U.S. as well as Great Britain consider this one of the more controversial topics in their field.

There is no shortage of data analyzing the role of immunology in reproductive success or failure. A number of comprehensive studies in the mid- to late1990s were undertaken to identify a potential cause and effect relationship between abnormal immune test results associated with reproductive failure. Yet the tests reached the same conclusions; the most rigorous studies failed to provide a correlation.

Today many years after most reproductive endocrinologists might have thought the topic was put to rest, women with greater research capabilities on the internet who actively seek answers for their fertility problems continue to come across offers of clinical immunological investigations and treatments that lack true scientific basis. As pointed out by the Royal College of Obstetricians and Gynecologists, “Praying to Artemis of Ephesus, a goddess associated with fertility, might be as useful as undergoing some of the fertility tests offered on the Internet”.

The market for potential abuse is considerable, given that nearly 15% of American couples suffer from infertility, 10% of whom suffer from unexplained infertility. Additionally 2% of childbearing women may experience recurrent pregnancy loss or RPL, (generally defined as three or more consecutive pregnancy losses before 20 weeks gestation) and as many as 60% of such RPL will demonstrate no cause. Despite the costs, the lack of scientific evidence and the majority of skeptical practicing reproductive endocrinologists, people nevertheless seek treatment for purported immune imbalances.

Many such patients might be genuinely mixed up, finding it difficult to distinguish potential immunological causes of RPL from failed implantation following IVF procedures. Indeed, there is some evidence that RPL can occur as a result of an imbalance of some immune factors. But RPL is very different than a failed pregnancy at the implantation stage. If patients are given the impression that studies will support unproven treatments, it is understandable that frustrated patients may agree to experimental treatments.

What is clear, however, among the majority of practicing reproductive endocrinologists is the myriad of studies conducted in the 1990s demonstrated a sound scientific approach to the question, and no causal relationship was found. The American Society for Reproductive Medicine (ASRM) also summarized the literature and published an opinion paper concluded scientific evidence is not sufficient to suggest immune therapies are valuable for IVF. The Royal College concurs: “It is clear that the advice given on many sites is strongly influenced by the personal prejudices of doctors practicing non-evidence based medicine. Much of the data they provide has never been exposed to the rigorous scrutiny of peer review. The couples are emotionally vulnerable, and there is currently no scientific evidence to justify the use of these tests and treatments.” Nevertheless, a highly visible, albeit controversial industry exists, comprised of just a handful of practicing physicians and associated laboratories offering panels of immunological tests and subsequent treatment.

Patients are rarely informed that there is no standardized testing methodology among laboratories, so the interpretation of test results (normal, borderline, or abnormal) is frequently inconsistent. If and when therapies are administered, many are designed to modify the immune system (i.e. glucocorticoid treatment, intravenous immunoglobulin, and peripheral leukocyte immunization) or to compensate for the suspected effects of the immune defect (i.e. heparin or aspirin to reduce thrombophilia from thrombogenic autoantibodies).

Given the lack of strong scientific proof of meaningful associations between abnormal immune testing and adverse reproductive outcome, combined with the poor quality of the standards of such tests, PFC physicians maintain a packet of information for our patients who inquire about potential immunological causes to their infertility.

In the next issue of Fertility Flash, we will provide a follow-up article that will include more detailed descriptions of the tests that have been conducted as well as an introductory description of what is considered viable immunological tests and treatments for RPL, versus those that are considered more controversial for repeated IVF failure.

Photos provided by 3DbabyVu

A first glimpse of a baby in the womb, especially for women who have faced an arduous route to pregnancy, is perhaps as euphoric a moment as the “You’re Pregnant!” announcement. It is only natural for parents to want a visual connection with the infant as early as possible.

Seizing on this yearning, a new crop of commercial ultrasound studios has mushroomed all over the country, offering parents a chance to have a first look via an elaborate 3D and even 4D video ultrasound. At least three such businesses are in the Bay Area. Yet new parents contemplating a nonmedical 3D ultrasound simply for novelty or posterity should be fully aware of this technology in a rapidly evolving marketplace.

The safety of common medical ultrasounds is undisputed. For over 35 years, ob-gyns have used 2D ultrasound technology as standard practice to medically diagnose the health of a weeks-old fetus, enjoying an early glimpse of its emerging shape, major organ development, tissue and blood flow and when desired, the gender. The ultrasound repertoire is so common; over 80 million procedures are now performed in the US each year, reports one clinic.

Nevertheless, the Food and Drug Administration (FDA) and the primary medical association that oversees ultrasonography – the American Institute of Ultrasound Medicine (AIUM), have thus far refused to endorse 3D and 4D ultrasounds offered by commercial studios. The concern is less about the technology itself, and more about how it is applied. While the sound wave levels used for a 2D and a 3D/4D are reportedly of the same frequency, (it’s the computer diagnosis that creates the image differentiation), there is more built-in oversight in the medical community performing diagnostic ultrasounds.

For instance, is the person performing the commercial fetal portrait properly trained? Right now, it is up to the 3D studio to make sure that the person controlling the knobs and holding the transducer has undergone the same training standards required for ultrasonography at an ob-gyn office. Professional (non-physician) ultrasound practitioners undergo nearly three years of training, including 12-18 months for didactic and 12-18 months of clinical practice in order to gain the key certification from the American Registry of Diagnostic Medical Sonographers (ARDMS).

Moreover, there is concern that a commercial portrait ultrasound will reveal a developmental problem with the fetus that should be observed and discussed only through a physician/patient relationship. Another concern is that enthusiastic parents will forego a routine medical ultrasound after obtaining an elaborate portraiture one. In response, many commercial ultrasound studios are requiring patients to bring proof of a prior medical diagnostic ultrasound.

Finally, knowing a bit about the technology helps parents make an informed decision. In the medical community, the standard is to expose the fetus to the lowest possible exposure level for the shortest amount of time, usually 10 minutes or so. Because frequent ultrasonography at higher levels can produce a heating effect in bone and tissue, the aim is to minimize exposure. Yet some commercial fetal portrait studios offer deluxe packages involving a 45 minute video ultrasound.

A spokesperson from 3DBabyVu insists that the potential for physical damage to the fetus via a wrong decimal level setting is literally and virtually not possible, at least with the standard GE Voluson machines, which provide a cap to the frequency level. Yet he admitted that the same machines have two other settings for cardiac mode and vascular mode to examine more robust adult tissue. If patients choose to purchase a dynamic 3D or 4D image package offered by one of these enterprising studios, we strongly recommend that you learn as much as possible and even consult with your ob-gyn if you are at all confused. Also, it is best to confirm that the sonographer at the commercial studio is ARDM certified. Because the practice of fetal portraiture imaging is self-regulated, it is the patient’s responsibility to be aware of current research and be as informed as possible prior to using this new technology.

What might a mindful career-oriented 36-year-old woman have in common with a 22-year-old just diagnosed with an unusual cancer and scheduled for radiation or chemotherapy treatment?

• Both may want to carefully chart their course of family planning.
• Both face the loss of their ovarian egg reserves: one from the damaging chemotherapy, the other from age.
• Both may be considering oocyte (egg) freezing.

The idea that a woman can undergo a standard IVF procedure and then freeze individual eggs, instead of having her oocytes inseminated and then frozen as an embryo, is a notion that is capturing the imagination of grandmothers, women and doctors alike. So much so, dozens of infertility clinics are boasting egg cryopreservation as a new service even though most qualify it as “experimental”. Indeed, egg freezing is simply too new, and it has not shown the success rates necessary for widespread marketplace acceptance. This procedure is not a panacea or an insurance certificate for everybody. However, it can be a viable option for women who are aware of its limitations.

What is most important is a patient’s absolute understanding of the challenges of egg cryopreservation. To say women’s oocytes are much more difficult to freeze than male sperm is an understatement. A good quality female egg is essentially a pin head-sized globule of fluid plus the necessary DNA to carry new life into being. It is this sac of liquid that must be carefully drained and then filled with anti-freeze to help the egg freeze and thaw. Accomplishing this without damaging the microcosm of genetic material, as delicate as a spider web, is the main hurdle. When egg quality is compromised, a myriad of problems ensue: failure to fertilize or implant, miscarriage and birth defects.

The race to offer egg cryopreservation was initially fueled by favorable research results from a study that used subjects in their early 20s, and which resulted in >50% chance of a live birth. Yet with only 7 subjects, that study is not statistically significant. In subsequent studies that used women in their early 30s, the success rate dropped below 25%. Currently, most U.S. clinics pioneering this procedure predict only an 8-10% chance of live birth. Also, a side effect of freezing is the hardening of the egg’s outer membrane, known as the zona pellucida, making sperm penetration difficult. However, this is overcome by using ICSI (intracytoplasmic sperm injection).

Those requesting this service need to have all of the facts before making a choice. In particular women in their mid- to late-30s, who tend to be the most enthusiastic candidates, need to weigh other options with higher proven success rates. We at PFC share an understanding with much of the medical community that this procedure may be the right choice for the right person, but only with a full understanding of its limitations. This will be our approach when we start offering egg cryopreservation to our patients later in 2004.

Acupuncture, one of the world’s oldest and most established healing practices, is growing in popularity as a way to complement the modern procedures of ART – Assisted Reproductive Technologies. Although the scientific evidence behind acupuncture is scanty, belief in this technique is so strong, some patients having just undergone implantation after IVF will head straight to their TCM (Traditional Chinese Medicine) practitioner for an immediate acupuncture treatment.

Acupuncture is just one component of Traditional Chinese Medicine (TCM), which also involves herbs, pelvic massages and dietary adjustments to garner a “whole body” systems approach to health. Following a track record of over 4000 years, nearly one quarter of the world’s population turns to TCM for their primary heath care. In Western societies, acupuncture is frequently cited as providing almost instantaneous relief to debilitating ailments such as bad backs and sports injuries.

Tiny sterilized needles are inserted into key points of the body and left there for 20-30 minutes. Barely felt, the needles reportedly open up Qi (pronounced Chee), which is vital energy defined by increased blood flow and the benefits of the body’s systems working together to break down so-called blockages.

Only two scientific research studies have examined the benefits of acupuncture with IVF treatment. The most talked about was reported in the journal Fertility & Sterility, April 2002 (Vol. 77, No.4) involving 160 IVF patients in Germany. Half of them underwent acupuncture before and after embryo transfer and the other half served as the control group. 34 out of the 80 women who received acupuncture revealed clinical pregnancies (42.5 %), whereas, 21 out of 80 women in the control group became clinically pregnant (26.1%).

Although the physiological mechanisms are not fully understood, it is believed that acupuncture optimizes endometrial receptivity and enhances blood flow to the pelvic area. According to TCM principles, energy flows through the body along pathways, or meridians. Acupuncture is a means of enhancing this energy and coaxing the body’s responses to induce a desired physiological effect. Ideally, according to TCM practitioners, women should undergo acupuncture treatment 3-4 months prior to an IVF cycle instead of as a last minute flurry.

We at PFC encourage our patients who inquire about acupuncture to pursue it, and we provide a list of Bay Area TCM practitioners who are certified by the National Acupuncture and Oriental Medicine Alliance and licensed by the state of California. (UPDATE: PFC now provides in-house acupuncture services.) However, under no circumstance do we condone the use of herbal supplements that are sometimes provided with acupuncture for women undergoing infertility treatment at PFC. Most TCM practitioners agree with this approach, and will communicate your treatment protocol with our physicians here at PFC.

Each year Pacific Fertility Center® sends a delegation to the annual meeting of the ASRM the American Society for Reproductive Medicine. This prestigious conference draws researchers and practitioners from around the world, and this past event in San Antonio in October 2003 was no exception. Over 6,000 people attended from 32 different countries.

We have provided this summary of highlights to share with Fertility Flash readers. This tiny sampling by no means reflects the scope and depth of the 1800 scientific research papers that were presented. Human Nuclear Transfer From a popular press’s point of view, the most talked-about paper was Dr. Jamie Grifo’s research on human nuclear transfer. Each day of the conference, a new headline appeared with the world “clone” or “clone-like” even though Grifo and his Chinese colleagues, who reportedly tried the process unsuccessfully, insist that the process is not cloning. They fused the DNA from the oocyte of an infertile woman with a donor oocyte from which the DNA had been removed, and then fertilized the “reconstituted egg” with sperm. This experimental procedure has not yet produced a live birth, and the FDA prohibits this type of research in the U.S. It was recently banned in China as well. It is an incredibly complex procedure that is not likely to ever be commercialized due to the fact that so many embryos are rendered non-viable. OK to Go Patients who have just undergone Embryo Transfer after IVF are no less or more likely to conceive if they immediately go to the restroom. A study revealed that there was no difference in pregnancy rates between those women who had to go immediately and those who waited. Relax about SSRIs Women undergoing infertility treatment who take prescription medications in the category of Selective Serotonin Reuptake Inhibitors (Zoloft, Prozac, Paxil, etc.) have less to worry about. Children conceived by women on SSRI medication were no more or less likely to have problems. 911 Decline Infertility patients from New York treated in the midst of the September 11, 2001 tragedy suffered from a higher rate of pregnancy loss than those treated prior. The results of nearly 400 patients who underwent an IVF procedure before and after September 11 were examined. Individuals placed in the “before” or “after” groups showed no significant differences in age, number of eggs retrieved, or number of embryos transferred. Clinical pregnancy rates were also comparable between the two groups. However, there was a nearly 25% lower delivery rate for the patients with a pregnancy test after September 11. This study again points to the significance of psychological factors that impact outcomes of infertility therapy.

Telomeres Predict Poor Prognosis Scientists are noticing a correlation between short telomeres and egg quality. Telomeres are small pieces of DNA at the ends of chromosomes, that shorten naturally as we age. Telomere length could someday be used as a test of fertility potential.

Joe Conaghan, PhD	Eldon Schriock, MD

Drs. Joe Conaghan, PhD and Eldon Schriock, MD along with other PFC professionals attended the ASRM meeting and are committed to continually evaluating the latest research and using proven treatments to improve patient care.