This past summer, I had the opportunity to travel to Amsterdam, Holland for the annual meeting of the European Society for Human Reproduction and Embryology (ESHRE). Though largely attended by Europeans, this scientific meeting draws physicians, embryologists and scientists from around the world to discuss their research, attend courses and lectures, and discuss the latest topics in our field. Although I don’t think this year’s meeting was as quite as good as last year’s ESHRE in Barcelona, there were still some good learning opportunities. Here are some of the highlights of the meeting:

“From Gamete to Heartbeat: The Missing Link”

This was a post-graduate course offered in conjunction with the meeting. The course covered sperm and egg evaluation,

expression of genes in the early embryo and in the endometrium (uterine lining) and some of the latest research into basic embryo implantation mechanisms.

One of the interesting talks was on gene expression in the early embryo. We have come to believe that the differences in pregnancy rates between younger and older women is mainly due to an increase in the number of abnormal chromosomes in embryos from women as they age (such as increased risk for Down Syndrome). However, this only explains part of the differences in successful pregnancy in younger compared to older mothers. New research into expression of proteins from embryonic genes is showing that in both chromosomally normal and abnormal embryos, there are differences in the number and types of genes encoding proteins in younger and older women. This suggests that it is not just changes in the number of chromosomes but subtler differences in the way individual genes are being expressed that affect the developmental competence of their embryos. Determining which genes and proteins are involved, and what the mechanisms are for regulating the expression of these genes in early embryos, will be an area of focused research in the coming years.

“Hyaluronic Acid (HA) favors selection of spermatozoa with intact DNA and normal nucleus, resulting in improvement of embryo quality” (Bologna, Italy)

This presentation (Parmegiani, et al.) looked at the percentage of sperm showing DNA fragmentation based on several methods of sperm preparation for IVF-ICSI (in vitro fertilization with intracellular sperm injection). They compared sperm in the fresh specimen 30 minutes after ejaculation, sperm that had been processed with a standard “swim-up” technique, and sperm that were placed in PVP (polyvinyl propylene), a substance used to slow sperm down so they can be picked up from a culture dish just prior to injection into the eggs. Lastly, they looked at sperm that had been placed into dishes that contain a ring of hyaluronic acid at the bottom of the dish, a substance to which some sperm will automatically bind. They looked at the percentage of sperm showing total or partial fragmentation of the DNA with each of these steps in the sperm preparation process. In the freshly ejaculated sperm, the DNA fragmentation was 16.5% of tested sperm. In the “swim-up” sperm prep, 11% were fragmented and in the PVP-exposed sperm, it was also 11%. Sperm that had bound to hyaluronic acid showed the least amount of fragmentation, at 5.3%.

These findings suggest that using HA binding to select sperm for sperm injection may result in fewer abnormalities in embryos, and possibly higher pregnancy rates. PFC is currently investigating HA binding on our own to see if it is something we would wish to routinely incorporate into IVF. The downside (like everything else!) is that HA plates are expensive.

Stress and Fertility – an enlightening symposium

Jacky Boivin, PhD., a researcher from Cardiff University in Wales, presented some very interesting data about the stresses of infertility treatment. She discussed a new study from Alice Domar’s group in Boston that surveyed why women/couples discontinued IVF treatment before achieving pregnancy (Fertility and Sterility, in press 2009). In this study, 132 women who had insurance coverage for IVF were surveyed. The two main reasons given for dropping out of treatment were the toll that infertility took on the couples’ relationship and being too anxious or depressed to continue. Among the less common reasons for dropping out were medication-related issues (such as difficulty with injections) and feeling the need for a female doctor. Dr. Boivin also discussed results from her own study that was published in the journal Human Reproduction in 2008. In that study, she developed a copingstratagem for women awaiting results of their treatment (i.e. the time between embryo transfer and first beta hCG). It is known that this is a most anxious time for women and the stress of waiting can become overwhelming. She utilized something called the “positive reappraisal coping intervention” card, or “PRCI” card. This is a small printed card that a patient can carry around in his or her pocket and it is meant to be read 2 times per day, every day during the 9-11 days between embryo transfer and first pregnancy test. The card has several little sayings such as: “During this experience I will try …to do something that makes me feel positive” and “During this experience I feel that….I’m energized or I’m creative.” This is a way of programming thoughts towards the positive and away from the negative. She and her colleagues were able to show that patient felt less stressed and felt that the PRCI was helpful during this period.

Currently, at PFC, we have begun a task force to look into ways to better incorporate counseling and tools for stress management for our patients. Please also see this recent Patient Odyssey. Support groups are a wonderful way to diffuse stress and feel more positive.

Corifollitropin: a modification of Follistim to allow a once-a-week injection.

As most people know, the medication we most commonly use for fertility treatment, Follistim, is pure human FSH, manufactured using recombinant DNA technology. The company that makes Follistim, Schering Plough, is working towards FDA approval of a modified version of Follistim, called Corifollitropin, that will make the drug very long-acting.

For those interested in the details; Corifollitropin is the recombinant FSH molecule + 22 C-terminal peptides from betahCG. It does not bind to the LH receptor. This modification lengthens the half-life of Follistim from 22-34 hours to 60-74 hours for Corifollitropin. The recommended regimen will be one dose per week, starting at baseline, then switch to daily recombinant FSH after that. After injection, peak levels are reached in 2 days then they slowly level. It may be possible to only take one injection per week!

A symposium at ESHRE presented information from the ENGAGE trial with data from 14 European and 5 Asian IVF centers, using women with body mass indices (BMIs) between 18 and 32 (generally less than 60 kg -132 lb). The patients were randomized to receive either Corifollitropin or conventional daily recombinant FSH for oocyte recruitment. The number of days of stimulation was the same in both groups (9). The number of eggs retrieved was significantly higher in the Corifollitropin group (13.3) vs. the FSH group (10.6). The rates of ovarian hyperstimulation syndrome were the same in both groups (about 3%). The pregnancy rates were 25% in the Corifollitropin group and 34% in the FSH group, a difference that did not quite reach statistical significance.

Data were also presented on a second study of Corifollitropin from the U.S. and Europe, comparing two doses of the drug. In the study, 100 mcg/dose was given to women less than or equal to 60 kg and women greater than 60 kg were dosed at 150 mcg. Over 1500 patients were included in this large trial. In this study, the average number of eggs recovered was 13.7 for the Corifollitropin group and 12.5 for the Follistim group. The mature egg and fertilization rates were the same. The percentage of good quality embryos was the same.

The clinical pregnancy rate in the Cori group was 38.9% and was 38.1% in the Follistim group. These rates were statistically the same. We expect that Corifollitropin will likely be available in the U.S. in 2010 or 2011.

—Carolyn Givens, M.D.

Carolyn Givens, M.D. 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.

My husband and I have been riding the infertility roller coaster for almost 3 years now. The ups and downs have included invasive diagnostic testing, four failed intrauterine inseminations (IUIs) and most recently an unsuccessful in-vitro fertilization (IVF) attempt. Each wave of excitement over the hope brought on by the next treatment cycle would come crashing back down with the negative news. While I am confident I am receiving the best possible medical care with the team at PFC and am keeping “hope frozen in time” with my frozen embryos, it can still be a hard road to travel.

Considering my first attempt at IVF failed, you would think I would be at the lowest point of my journey towards parenthood. But, amazingly, I am not. I am sharing my story to tell you how I survived the ups and downs and was able to feel more grounded and

Lisa Wickham.

regained a sense of control in my life while continuing treatment.

This is what saved me: A powerful combination of group support and mind/body techniques.

My PFC acupuncturist (seeing tears stream down my face) recommended a Mind/Body class to help ease my obvious difficulty in coping with the emotional stress I was under. This was huge. This was the first step I would take in reclaiming my 0ormer self. What are Mind/ Body techniques? They are tools including deep breathing, meditation, guided imagery, progressive muscle relaxation, cognitive reframing, light yoga, tai chi and journaling exercises. My first thought was, “Will this be too ‘new age-y’ for me?” I could barely comprehend the fact that I was doing acupuncture regularly, let alone meditate.

The great thing about Mind/Body is that it is a tool box, so you pick what works for you. I never really did learn to meditate, but the regular use of relaxation CDs for deep breathing, muscle relaxation and guided imagery has given me profound peace of mind. Cognitive reframing (learning to recognize destructive thoughts and “reframe” them) was also powerful for me. I used to hear a tape playing in my head over and over, “I’ll never get pregnant, I’ll never get pregnant”. I learned to challenge the truth of that statement and rethink how it made me feel. A 10-week Mind/Body course I took was a key turning point. PFC offers a one-day workshop that offers an introduction to Mind/Body and is free for patients.

The other key component to my peace of mind has been meeting others who “get it”. It’s hard to explain to someone not experiencing infertility themselves just how this takes over your life. Well-meaning family and friends try to understand, but they truly cannot. Only my best friend, who also experienced difficulty in trying to conceive “got it”. That is, until I did my first IUI. Having to explain washed sperm to her and describe what it’s like to have your legs in stirrups as the washed sperm is inserted into you was beyond depressing. I knew I needed to meet others going through similar situations.

Lisa and Jonathan Wickham.

I attended my first Open Path group support meeting last year and had no idea what to expect. I only knew I needed to at least talk to someone else who knew what an IUI was. Open Path (fertilityandadoption.com) is a Bay Area organization that provides regular group support. There I met two amazing women and we are now a larger group of women who meet regularly and support each other over email, coffee and even cocktails in between cycling. We are a Sisterhood of Infertility. We all have different stories whether doing IUIs, IVF, using donor eggs, considering a gestational carrier or considering adoption. We have different personalities, some are quiet, some are loud, some blog their innermost thoughts to the online world (google “Stirrup Queens”), some are “closeted” with their infertility secret to all but a few. But our common thread is infertility. We all wear the red, pomegranate string around our wrists as a reminder that we are not alone (you can google “infertility’s common thread” to read more about this). We support each other when we are down and we celebrate our victories (small and large) together. While most of us could not find it in ourselves to feel happiness for friends we had known all our lives that got pregnant, we were able to give loud cheers of joy when one our IF Sisters did. This was healing beyond words. And this gives us hope.

I’ve heard the statistics about Mind/Body and group support increasing pregnancy success odds, but, for me, even more important than getting pregnant, was the peace of mind that came.

My hope is that my story can, in some way, help bring peace of mind to someone else as they navigate their own path. You are not alone. You do not have to do this alone. And there are concrete ways you can make yourself feel significantly better while undergoing treatment.

Try these resources for more information:

• Mind/Body @ PFC - pacificfertilitycenter.com/support/relax_workshop
• Open Path - fertilityandadoption.com
• Resolve - resolve.org
• Resolve support group listings: http://www.resolve.org/site/PageServer?pagename=npac_peer_groups

— Lisa Wickham, Current PFC Patient, San Francisco, CA

Special LGBT event happening tomorrow! We hope to see you there.

6:30 - 8:00 PM
LGBT Community Center
1800 Market St., San Francisco
Call 888-834-3095 or contact us for reservations

Attend an informative educational event on Wednesday, October 7th and hear firsthand from gay and lesbian parents about their family building experience. This is an opportunity to ask you specific questions and learn about advanced family building solutions.

Topics include:

* Selecting the right donor and/or surrogate
* Emotional & psychological aspects of gays & lesbians having children
* Hearing gay and lesbian parents accounts of their personal experience

Let Pacific Fertility Center be your guide on your journey to building a healthy family.

This summer, we are introducing a new procedure in our laboratory that will allow us to do genetic testing on embryos that have reached the blastocyst stage of development. Traditionally, embryos are biopsied when they are just 3 days old at which time they should have reached the 8-cell stage (see figure 1). The biopsied cell is sent to the genetics laboratory for testing while the remainder of the embryo continues to grow in our laboratory. The genetic testing results are received 48 hours later, when we hope that the embryo will have reached the blastocyst stage (see figure 2). Blastocysts that have passed genetic screening can be transferred or frozen for later use.

Performing the biopsy when the embryo has become a blastocyst is more technically challenging, and it allows less time for the genetics lab to do their testing. However, in a blastocyst, we are specifically able to biopsy from the part of the embryo that will become the placenta, and we can get more than 1 cell, which allows for greater accuracy in the genetic testing. Depending on how quickly the test is run, the embryo may have to be frozen while we wait for the results.

While freezing is inconvenient, it does allow time for more complex genetic testing, and for multiple tests if necessary. And, with the success of vitrification for preserving embryos (see Fertility Flash Vol. 7, Issue 3), we are confident that the frozen embryos will survive and implant at high rates when thawed.

In the next few years, we expect that the traditional methods for biopsy and genetic testing will disappear and that blastocyst biopsy will be the standard procedure. As genetic testing evolves, it will not be possible to rely on just a single cell from an embryo to get dependable results. We already know that there is genetic variability among cells in an individual embryo, a phenomenon known as mosaicism, and our new procedure will overcome this problem.

In the coming months, we will announce an exciting new partnership with a Bay Area genetic testing lab, and we will keep readers informed on our progress with genetic testing in embryos. This is an exciting field that continues to evolve.

Joe Conaghan, Ph.D., HCLD is PFC’s laboratory director. Dr. Conaghan is internationally recognized for his work on improving embryo culture conditions. His interests include developing programs for the treatment of severe male factor infertility; diagnosis of genetic disease in embryos; and improved embryo culture.

For patient(s) who need to use an egg donor to create or expand their family, medical scrutiny is performed on the chosen egg donor before she can proceed with the IVF cycle.

The medical screening of egg donors is an important process. Here at the PFC Egg Donor Agency, we proceed with an extensive screening process PRIOR to allowing the egg donor to become eligible for choosing by the intended parent(s). This extensive screening is performed to help determine and identify any medical factors which may disqualify the donor, or to identify information which may require additional testing prior to determining donor eligibility. At PFC, our philosophy is that we want to identify any issues prior to intended parents choosing the donor, so that the risk of identifying medical issues with the donor after the start of the IVF cycle is minimized, and the risk of canceling the cycle is much reduced.

Medical screening for the donor includes an extensive review of her personal and family medical history, physical exam and pelvic ultrasound, psychological evaluation (in-person visit with our MFT Peggy Orlin),

standardized personality assessment (PAI), and blood testing including ethnic appropriate genetic testing.

The PFC Egg Donor Agency complies with current recommendations by the American College of Obstetrics and Gynecology (ACOG), and the American College of Medical Genetics (ACMG). The donor identifies her ethnic background, and based on this information, appropriate testing is performed (see article by Lauri Black, Genetic Counselor, outlining current recommendations). This testing is done and results reviewed prior to approving the egg donor as eligible to be in the donor database. If the donor is a carrier for a genetic mutation, this may disqualify her from being an egg donor; some genetic mutations may not be disqualifying, but the sperm source may need to be screened for that mutation, prior to deciding to choose that egg donor. These tested mutations are for recessive disorders, so an embryo would only be at risk of having the disorder if BOTH the egg and sperm source were carriers for the identified mutation (see above noted article).

It is important to understand that new genetic mutations are identified almost every day; so recommendations for ethnic-based testing do potentially change year by year. While many genetic mutations have been identified on the human genome, many of these are very rare, and only mutations that are more frequently seen within one’s ethnic group are those that are recommended to be tested for. It is not appropriate, nor feasible, to check for all known possible mutations. The PFC Egg Donor Agency is kept apprised of current recommendation by our affiliated genetic counselors, so that our list of genetic screening tests may change over time. Rest assured that we keep informed of these changes, and comply with up-to-date recommendations.

While all this testing may seem cumbersome, it is to help assure that once you choose your egg donor, we can proceed with the IVF cycle with minimal risk of a cancellation, and start you on your way to achieve your dream of a healthy family.

Isabelle Ryan, M.D. is recognized by prestigious medical associations for her pioneering research leading to new insight into the important clinical problem of endometriosis related infertility. Dr. Ryan is medical director of PFC’s Third Party Parenting Program and Egg Donor Agency.

On May 15th, we were fortunate to have Dr. Daoshing Ni, D.O.M, L.AC., Ph.D., a Licensed Acupuncturist in the State of California, a Diplomat of Chinese Herbology, and a 76th generation acupuncturist come to speak at PFC about the benefits of combining acupuncture and ART.

Dr. Ni spoke about some of his own research studies on acupuncture and ART and also discussed some of the issues with the current protocols that are being used today. He emphasized that the Paulus protocol is a good guideline when doing embryo transfers, and he encouraged the addition of other supportive acupuncture points. He also strongly encouraged that patients be treated with Chinese medicine for at least 3 months before their ART cycle begins. Dr. Ni also spoke about how the use of Chinese herbs contribute to improving egg quality.

This outstanding program was attended by PFC’s acupuncturists, physicians, and staff. In addition, area wide acupuncturists were invited to hear Dr. Ni’s presentation, meet one another, and share ideas.

We are excited to introduce a new website FertilityWire, http://fertilitywire.com.  This site is separate from our current website www.pacificfertilitycenter.com.

FertilityWire will provide access to a wealth of fertility information, news, and social content. Please take a moment to check out this exciting new resource. You can let us know what you think in the comments section.

Enjoy!

-Robb Mayberry, Director of Development

Steve and I met and fell in love in our twenties. We both thought we would want children “some day.” Eleven years later we realized “some day” had finally arrived. I was thirty-six then, but I never thought we would have any problems conceiving. My mom had three children in her late thirties and into her forties.

After six months with no success, my doctor ran the usual tests and found nothing wrong, so my OB recommended going to PFC. We did one IUI, then decided to move on to IVF. My first IVF cycle failed. We were preparing for the second when we were delighted to findout I was pregnant naturally. I gave birth to a healthy baby boy.

We wanted more children, and as it had taken two and a half years to conceive Alan, we decided to start trying again straight away. We weren’t so lucky this time, so after 18 months we were back at PFC talking to Dr. Givens about doing IVF again. Then we discovered a new problem – my FSH was now elevated. So, now I also had decreased ovarian reserve in addition to unexplained infertility.

We tried four cycles of IVF with my own eggs. I did get pregnant on my third cycle, but sadly miscarried at eleven weeks. I was now forty-two and felt it was time to move on.

Now we faced decision time-do we give up, move on to donor egg, or move to adoption? We were both sure we wanted more children, and I felt that by carrying the child I would feel that it was truly mine, even if I didn’t have the biological connection. Oddly enough, it was harder for Steve to move on to an egg donor. But after lots of talking it through, he felt it was the best choice for our family too.

We met with Peggy the PFC counselor, who was very helpful. Dr. Givens thought an egg donor was a great option for us. She said that with a transfer of two blastocysts, our chances of conceiving were about 80%. We ended up with a short list of two potential donors. One was a perfect match on paper—my height, my hair color, my eye color, with the right ethnic background. The second wasn’t such a perfect match, but I just felt a really strong connection to her. I really felt that if we met in real life we would be friends. In my mind I kept going back to something Peggy had said “pick someone you really like”, it was great advice. We went with donor number two, and are very happy with our choice.

Initially everything went well, but then on day three we received a phone call asking us to come in. Our embryos were looking very stressed. Most were grade three with low cell count. We transferred the best three and prayed.

On the day of our beta pregnancy test, Ann (one of the nurses at PFC) called to give us the good news. I was pregnant! Once we saw the heartbeats, we told our son Alan, “Mommy has two babies growing in her tummy,” and he was thrilled. Feeling those babies kicking and squirming around inside, I had no doubt whose babies they were—I might not have provided the eggs, but my body turned those little seven or eight celled embryos into two beautiful children.

The first day Alan got to meet his new brother and sister the look on his face said it all. It was love at first sight. He has made a wonderful big brother, the twins adore him, and our family now feels complete. I feel truly lucky when I look at my three wonderful children. I am very grateful to Dr. Givens and all the wonderful staff at PFC, and especially to our donor.

Some people may wonder, if I love all of my children the same. They have three very different personalities, so I love them all differently; but I do love each one as much as the other. In the words of one of our favorite books, they are “all my favorites.”

—Submitted by Trisha (PFC patient)

Many populations of the world have specific genetic conditions that are prevalent within their ethnic group. Consequently, numerous medical organizations have recommended that genetic screening for these conditions should be offered when women are either planning for, or are currently pregnant. We are all carriers of genetic conditions: generally this is of little concern, as it is highly unlikely that we would have children with a partner who is a carrier for the same condition.

The genetic conditions listed in the table below are recessive. A recessive gene mutation is “carried” by someone who is unaffected by the disease, and thus unaware of their carrier status. Men and women have equal potential to be carriers for recessive conditions. Even if someone is a carrier, we would not expect to see a family history of the disease. If there is a family history, the likelihood of being a carrier of that condition is generally greater than in the general population. Being a carrier for a genetic condition typically has no impact on the carrier’s health and development. However, if a carrier has a child with another carrier of the same genetic disease, the chance that the child will be affected with the disease is 1 in 4 (25%).

If only one partner is a carrier, and the other tests negative, then the risk of an affected child is low, but not zero (a result of the limited ability to test for all defects that would make one a carrier; see table). These genetic screening tests are typically performed on a blood sample.

Below is a table listing the minimum number of tests for various ethnic groups recommended by the physicians at Pacific Fertility Center prior to starting assisted reproduction treatment. Additional genetic tests may be considered after a discussion with your physician.

If you know that both you and your partner are carriers of the same genetic defect, you may be able to have embryos created in an IVF cycle and tested for their status. Preimplantation genetic diagnosis (PGD) is a technology that allows embryos to be tested for specific disease causing mutations. PGD can identify unaffected embryos for transfer back to the uterus or freezing.

—Guest Contributor – Certified Genetic Counselor Lauri Black, M.S., C.G.C

*See lab specific accuracies on test result

Assisted reproductive technology (ART) has been a part of modern medicine now for over 30 years and in the US alone over 132,000 IVF cycles were performed in 2007. All birth outcomes are reported to the Centers for Diseases Control but there is no mechanism for long-term follow-up of IVF births.

Well over a million babies have been born world wide through IVF and new data are emerging about reproductive birth outcomes after conception. Some countries, particularly the Scandinavian countries, do an excellent job on gathering data for all births, including IVF-conceived births. One of the greatest risks of ART is prematurity from multiple gestation. From several of these databases, it has become apparent that even singleton IVF births are statistically associated with poorer birth outcomes. Lower birth weights, pre-term delivery and infants small for gestational age (i.e. lower weight than expected for number of weeks in utero) are some of the findings from follow up of IVF babies.

These findings beg the question: is it something about IVF, namely the culture of the early embryo in a lab for the first three to five days of life, that results in these poorer outcomes, or is it something about the couples that need IVF to conceive that is associated with them? This can be a difficult issue to sort out because relatively few people undergo IVF who are not infertile.

A recent study from Norway was published in the British medical journal Lancet that tried to address this question by comparing IVF babies with their spontaneously-conceived siblings. The study compared 1,200,922 spontaneously-conceived live births and compared them with 8,229 live births after ART between January 1984 and June 2006. Of those women who had given birth to a singleton infant after ART, 2,456 also delivered a singleton infant after spontaneous conception. In 56% of the cases, the ART baby was born first and in 44% the ART baby was conceived after the birth of the spontaneously-conceived infant. The researchers looked at birth weight, gestational age as well as a number of other factors.

Compared with women in the general population that delivered a spontaneously-conceived birth, the women that delivered after IVF were older, less likely to smoke and had fewer previous births. Induced labor and cesarean section were more common in the IVF moms. The difference in birth weight between ART and non-ART babies was 131 grams (4.6 ounces). That is, the ART babies weighed, on average, 4.6 ounces, or about 3/4 pound less than the spontaneously-conceived babies. After statistical adjustment for gestational age, maternal age, prior births, year of birth, the difference in birth weight between ART and non-ART babies was 25 grams (0.88 ounces). The ART babies were born, on average, 3.7 days earlier than the controls. After statistical adjustment, the number of days of total gestation was 2 fewer days. Because of the large sample size, these were statistically significant differences but realistically, they were probably not clinically significant.

In comparing the sibling relationship ART vs. non-ART births, the differences were even smaller. The difference in birth weight was only 87 grams (about 3 ounces) for the ART babies as compared to their spontaneously-conceived siblings. The gestational age differences at birth were 1.3 days less for ART. After adjustment, these differences were only 9 grams and 0.6 days. These differences were not even statistically significant.

From these data, we can see that ART births do show statistical differences in some birth outcomes as compared to spontaneously conceived births. However, none of the differences seem are to an extent that would have any real clinical meaning. These differences tend to disappear to a large extent when comparing siblings from both spontaneous and IVF conception, suggesting that it is something about the families that utilize ART, rather than the technique itself that may be associated with the outcome differences.