Science Pulse    Natural Killer Cells in Implantation and Pregnancy

Like all living species that gestate their young within the mother’s body, humans have evolved mechanisms to protect the baby from rejection by the host mother’s system. The last few years has seen an increased interest in the subject of the role of the immune system in implantation of embryos and maintenance of pregnancy. The clinical relevance of perceived abnormalities in the immune system of women with unexplained infertility, unexplained implantation failure and recurrent miscarriage is a controversial topic. Elaborate theories to explain these failures have been proposed but most have not yet stood up to the test of good science. One of the latest theories to lay blame is that of a class of immune cells (lymphocytes) known as "natural killer" cells. Natural killer (NK) cells are responsible for killing certain types of foreign cells. In the current theory, increased NK cell activity potentially leads to attack of placental cells and therefore rejection of the fetus. But NK cells will only kill lab-cultured placental cells in the presence of another protein, called interleukin-2. Yet interleukin-2 is not present in the uterine lining of the uterus at the time of implantation. NK cells are found in both the bloodstream and in the uterine lining. NK cells are present in the uterus only during the second half of the cycle and can be found concentrated at the site of implantation. In mice that have been genetically altered to no longer make NK cells, successful reproduction will only occur if NK cells are given back to these mice. This suggests that, at least for these mice, NK cells may be necessary for implantation. So are NK cells there to inhibit or promote embryo implantation? The answer is not clear. Further complicating the NK cell story is the fact that there are several kinds of specific NK cells. These types can be classified by the expression of specific receptor proteins on the surface of NK cells. As it turns out, NK cells in the uterus are different from the NK cells that circulate in the bloodstream. Therefore, using blood tests to determine if there are too many circulating NK cells would bear little reflection on what is going on within the population of uterine NK cells. Other blood tests have been devised to assess whether these uterine-specific NK cells are being over-produced, such as tests for Tumor Necrosis Factor a (TNF-a), and Interferon g (IFN-g). These are proteins secreted by a particular class of NK cells found in the uterus. Women identified by these blood tests as having elevated NK activity or increased levels of TNF-a or IFN-g have been told that they will never successfully conceive unless they receive treatment with various immune suppressing agents such as intravenous immunoglobulin infusions (IVIG), glucocorticoid (prednisone) medications or anti-TNFa medications. But these treatments are not free from risk. Anti-TNFa medications have been implicated in several serious diseases such as lymphomas and lupus-like syndromes. Glucocorticoids during pregnancy can be associated with an increased risk of pre-term rupture of the fetal membranes, increased risk of pre-eclampsia (high blood pressure during pregnancy) and gestational diabetes. Immunoglobulin infusion (IVIG) is the use of infusions of a pooled blood production (immune proteins) and can be associated with anaphylactic (shock) response, and a host of side effects. This is why the vast majority of reproductive endocrinologists do not support administration of these drugs to women, even if they have been told they have increased NK cell activity in their blood stream. Unfortunately, our understanding of the role of the immune system in implantation and pregnancy is very rudimentary at this point. Trying to take this limited knowledge and develop tests to predict who may or may not be experiencing abnormalities of the immune system is akin to going out on a long limb of unproven possibilities. Furthermore, determining that women with supposed abnormalities in their NK cell activity be treated with anti-TNFa medications, steroids or immunoglobulin infusions to globally suppress the immune system is akin to going out even further on a flimsy stem. These treatments can be expensive and potentially harmful. The good news in all of this is that there is extensive research under way to try to better understand the very complex nature of embryo implantation and the immune privilege of the fetus within the womb. The bad news is that we are still a long way from understanding whether or not there truly are immune system malfunctions that occur which could potentially block implantation or directly cause repeated miscarriage. To therefore say that we can run a clinical test on a woman or furthermore, develop a rational mode to safely treat a woman for such a syndrome is going way beyond the bounds of good clinical medicine. - Carolyn Givens, MD
Carolyn Givens, MD was the first in San Francisco to successfully initiate a pregnancy using intracytoplasmic sperm injection (ICSI). She currently co-directs the Bay Area Pre-Implantation Genetic Diagnosis Program (PGD) and is director of PFC's PGD program. Dr. Given's excellent care and over 12 years of experience is recognized by her peers who repeatedly single her out as a "Best Doctor" in national surveys.

From Us to You    Collaboration with International Fertility Center

This is where IFC, International Fertility Center, comes into the picture.

IFC has been working with PFC, Pacific Fertility Center, exclusively since 1997 to help Japanese couples become parents. IFC informs their clients about the services at PFC, prepares their medical history in English and provides transportation. IFC attends all patient appointments and provides translation and support throughout their entire IVF cycle with the ever-patient and efficient help of PFC’s Janet Debow, RN, IVF coordinator. IFC also works with donor/surrogate agencies, attorneys and Japanese-speaking infertility counselors to make the program happen even while the patients wait in Japan. Ever since we brought patients to Dr. Carl Herbert and his partner physicians, we have been impressed with their thoroughness of care, their generosity of time and understanding and their ability to deliver sometimes painful, but much needed, straightforward diagnoses. Unfortunately, we have discovered that many of our clients, prior to coming to IFC and Pacific Fertility Center, have undergone numerous IVF cycles- as many as 20 or more. Many of these patients would have benefited from egg donation, however egg donation does not exist in Japan. Using the only treatments available to them, these patients continue to hope that their next IVF cycle will be successful and do not have the heart to put an end to their infertility treatment. They stop only when their doctor tells them they are too old. The most wonderful thing about working with PFC is that the physicians, nurses, embryologists, and the rest of the support staff, are so understanding and hard-working. They bend over backwards to make the patients feel welcomed and relaxed, while providing the world’s top-level medical care. IFC had the option to select any infertility specialist’s practice in the Bay Area, and we have never regretted our choice to work with Pacific Fertility Center. The practice is state-of-the-art, ethical, honest, and warm. The PFC-IFC collaboration has been successful and is considered to be a good example when considering the future of reproductive medicine in Japan.

Kari Kwada speaking at the 6th Annual Japanese IVF Conference

As director of IFC, I have been invited to speak about our collaboration at various medical conferences in Japan, including the IVF Conference, Ethics Committee of Japan Fertilization and Implantation Society, Jichi-Medical School, and Tokyo Medical and Dental School. My work has been published in the Japanese OB/GYN periodicals and I have been interviewed for a variety of Japanese media. Our work with Pacific Fertility Center has resulted in many happy Japanese families that remember San Francisco as the place where they truly left their hearts. They all promise to come back with their children one day - to the place where their dreams came true and new life began.
- Kari Kawada, Director, International Fertility Center

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Infertility Care Outside the USA
Even though the United States continues to battle out issues related to abortion and stem cells, it would appear that advanced reproductive technologies are here to stay. Few other nations match the quality, number of clinics and the choice of treatment options that couples enjoy in the U.S. even with recent tightening of FDA regulations regarding donors and donated embryos. Without summarizing every nation’s policy, it is worth describing at least a handful to help put into perspective what American infertile couples may take for granted. Besides the Japanese regulations described in the article; New laws just passed by the government in Scotland have removed all donor anonymity. As a result, childless couples in Scotland needing either sperm or egg donation face a wait of up to five years because of a chronic shortage of both sperm and egg donors.

In general, European Union countries with egg donation programs do not allow the egg donors to be compensated for their oocytes – resulting in severe shortages of willing donors and delays in treatment of 2-5 years unless one has a friend/family willing to volunteer.

In Victoria, Australia, non-married people and same-sex couples are fighting to legally receive infertility treatment. Currently they must travel elsewhere.

This past June a voter referendum was unable to overturn one of the most prohibitive laws set in place by the Italian legislature in 2003. This law completely prohibits any donation of egg or sperm, as well as surrogacy arrangements. Only heterosexual couples that prove themselves to be in a stable relationship are eligible for infertility treatment. Also, only three embryos may be created at a time and all three must be implanted simultaneously. Freezing of embryos and sperm is prohibited and unused embryos must be kept until they perish.

In South Africa an organ smuggling scandal caused the country’s egg donor program to be shut down for 18 months even though the two were proven later to be unrelated.

Patient Odyssey    Life with Twins

Because both Patrick and I were fine with the possibility of having twins, the decision to implant more than one embryo in order to increase our chances was never an issue. Dr. Schriock was comfortable with me carrying twins, but in the small chance that more embryos did in fact attach, he strongly recommended reducing. The day of the transfer, we were told that we had seven viable fertilized eggs and the recommendation was to transfer up to three of them. I actually wanted to transfer four in the hopes of having an even greater chance of conceiving, but was overruled not only by the doctor but my husband who was terrified that all four may actually attach. A few weeks later, after having my blood drawn, my numbers were so high that I was sure I was carrying triplets. It was such a relief to finally have an ultra-sound and see two tiny heartbeats. We were both so happy to have finally been able to conceive and I was especially thankful to have avoided a decision on what to do if I was carrying three babies. My biggest concern throughout my pregnancy was to carry two babies to full term. There seemed to be a lot of "negative material" out there to be read. The biggest cause of concern seemed to be of multiples being born prematurely. After reading a lot of baby books, I finally found one that became the positive influence I was searching for: When You’re Expecting Twins, Triplets, or Quads. It shows that having multiples does not necessarily mean that you will have a difficult pregnancy or that your babies are destined to be born weighing only a few pounds. Rather it encourages you to think beyond the 35-37 week time frame that most twins are usually born and to try for the full 40 weeks if possible. One thing that I really liked about the book is that it encourages you to eat. The suggestions to eat double cheeseburgers and milk shakes definitely made my pregnancy a little more fun. I exercised 6 days a week just like I did pre-pregnancy but instead of running I used pregnancy exercise videos. I continued to exercise up until my 37th week, three weeks before I delivered. Ashley Jordan and Janelle Patrice were born on May 6, 2004, forty minutes past Cinco De Mayo. We went 40 weeks and one day before having to be induced. Because I wanted to have them vaginally and hadn’t experienced any complications, my doctor allowed me to carry them past the normal 37 weeks. In the end though, they were delivered by cesarean. Life with twins is wonderful. They actual help with entertaining each other and it is fascinating to watch them develop skills at different rates. They did start to crawl one day apart just after turning 6 months, but Janelle can already walk with a walker while Ashley has just learned how to pull herself up. For me, I sometimes wish I could have a little more one-on-one with each but I don’t think they notice. We all play together and they are used to being a twosome. There is nothing like watching them laugh hysterically with each other when playing and they seem to already have their own secret language. We are glad that at 36 years of age, we have two beautiful, healthy babies and they have each other to play and grow up with. We still have three frozen embryos and are considering trying to do it again down the road. I encourage everyone I know that is having difficulty in getting pregnant to go to PFC before any other clinic. There is no way we can thank Dr. Schriock and his team enough for giving us our beautiful girls. - Jana

Twin pregnancies are common in women undergoing IVF and we congratulate Jana on her very successful experience as a mother of twins. Most twin pregnancies have good outcomes, however, the chance of having a healthy baby is much higher in singleton pregnancies. At Pacific Fertility Center, a singleton pregnancy is our preferred outcome. Prior to transfer, the risks and benefits of transferring one or more embryos are discussed. The patients’ final decision is made in partnership with the physician. Multiple pregnancy is risky for both the mother and infant. Premature birth occurs in over 50% of twin pregnancies. A twin is seven times more likely to die in the first month of life. Preeclampsia occurs three to five times more frequently. Prolonged bed rest and hospitalization for preterm labor is common and cesarean section is often needed for delivery. Patients may wish to refer to Patient’s Fact Sheets from the American Society of Reproductive Medicine: "Complications of Multiple Gestation" and "Challenges of Parenting Multiples". It is very important for patients to realize that excellent pregnancy rates can be maintained while controlling the rate of multiple pregnancy. More than one study has shown that transferring one embryo at a time can be as effective and more economical than transferring two embryos. Embryo freezing is now very successful. As preimplantation genetic diagnosis improves, it may also be helpful in selecting which single embryo to transfer. With improvements in the laboratory such as embryo isolettes, refinement of medications, improved freezing techniques, and preimplantation genetic diagnosis, we are closer to our goal of all singleton births.
- Eldon Schriock, MD

Ask the Experts    Clomid vs. Letrozole

A.
Both clomiphene citrate (marketed as Clomid), and letrozole (marketed as Femara) are oral medications used to stimulate ovulation. Letrozole is emerging as a viable alternative to Clomid for women undergoing ovulation induction, although no broad scientific studies have yet established the drug’s efficacy as the first course standard treatment. Several preliminary studies have shown letrozole to be useful for anovulatory women, and provides few side effects, especially for women whose uterine lining may be thinned out by Clomid. As to its exact mechanism, letrozole falls in the category of drugs known as nonsteroidal aromatase inhibitors, meaning it is highly specific in suppressing estrogen synthesis. Aromatase is an important enzyme prompting the creation of estrogen. If the body makes less estrogen, FSH level increases and ovulation is stimulated. Letrozole was originally developed for breast cancer treatment, as certain types of breast cancer cells slow their growth in response to decreasing estrogen levels. Letrozole has shown to be particularly helpful for a subset of anovulatory women whose endometrial lining may be thinned out while taking Clomid. As an anti-estrogen, Clomid can limit the development of the endometrial lining, making it difficult for an embryo to implant. For reasons that aren’t quite yet clear, letrozole appears less likely to affect the uterine lining. Furthermore, letrozole has a short life span in the body whereas Clomid can last for 4-6 weeks following an oral dose. Overall, we're pleased with what we’ve seen so far with the medication and we look forward to seeing the outcome of studies that are underway to further assess its efficacy as standard treatment.
- Philip Chenette, MD

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