SCIENCE PULSE    Highlights from 2008 ESHRE

This past summer, Dr. Herbert and I had the opportunity to travel to Barcelona, Spain 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.

Here are some of what I consider the highlights of the meeting:

Outcome of 1267 Children after Frozen Embryo Transfer – Study from Denmark

Control group: Fresh IVF pregnancies

Only 14% were twins

They compared 957 frozen embryo singletons with about 10,000 fresh IVF singletons

No increase in neurological problems or malignant diseases on FET babies.

No differences were seen when IVF or ICSI-derived frozen embryos were compared.

Results similar to prior Swedish study showing better outcomes for FET babies.

Why a better outcome? The authors postulated that patients conceiving with FET were more likely to be good prognosis patients.

Three years of clinical application in human oocyte vitrification (freezing): high survival rate and healthy deliveries (from Rome)

3138 unfertilized eggs were frozen between 10/04 – 10/07.

They reported on 295 cycles with planned embryo transfer – all patients were less than 40 years old. The patients underwent programmed endometrial preparation using a GnRH agonist (like Lupron) and oral estrogen and vaginal progesterone.

770 unfertilized eggs were thawed, 98.9% survived the thaw. The eggs were injected with sperm 2 hours after thawing and the embryos were transferred on Day 3.

Results: Avg. # embryos transferred = 2.3

Clinical pregnancy rate = 27.8%

Implantation rate = 13% per embryo, 11.3% per thawed egg. That is, about 11% of the eggs thawed resulted in a viable gestation.

58 deliveries of 63 babies, mean birth weight = 2930 grams

They experienced no congenital malformations at birth.

Then, the most controversial paper presented by Dr. Norbert Gleicher, an RE from New York.

The title: “In contrast to prevalent opinion, twin pregnancies after fertility treatments are medically, ethically and economically desirable outcomes.”

His arguments to support this opinion:

Most couples want to have more than one child. Therefore, they will need to undergo two pregnancies of two separate singletons vs. one pregnancy of twins to have two children. He argued that twins born after ART have much better pregnancy outcomes (by 30-50%) than spontaneously-conceived twins. He also argued that the accumulated costs and risks to mother and babies are higher with two singleton than one twin pregnancy.

Despite these intriguing arguments, this paper was hotly debated and essentially disavowed by the European ART community. Europe has led the way in legislating for avoidance of twins. In fact, in Denmark, if a woman has twins after the transfer of more than one embryo using IVF, she incurs any neonatal costs out of pocket.

Corifollitropin: a modification of Follistim to make it 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. It may be possible to only take one injection per week!

A symposium at ESHRE presented information from studies underway in Europe and USA. Corifollitropin is not in clinical use yet, even in Europe, but will be very soon.

For those of you interested in the details, Corifollitropin is the recombinant FSH molecule + 22 C-terminal peptides from beta-hCG, It does not bind to the LH receptor.

This modification lengthens the half-life of Follistim from 22-34 hours to 60-74 hrs for Corifollitropin. After injection peak levels are reached in 2 days then slowly levels decline. The recommended regimen will be one dose per week, starting at baseline, switch to daily recombinant FSH after that.

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.

Carl Herbert, M.D. was instrumental in the development of one of the first assisted reproductive technology programs in the United States and has been performing IVF longer than any physician in the Bay Area.

ASRM ROUNDUP    Highlights from ASRM 2008

   Pacific Fertility Center Team: Left to Right: Front: Philip Chenette, MD, Isabelle Ryan, MD, Carolyn Givens, MD, Back: Joe Conaghan, PhD, Carl Herbert, MD, Eldon Schriock, MD

The American Society of Reproductive Medicine (ASRM) held it’s Annual Meeting in San Francisco at the Moscone Convention Center on November 8 th – 12 th, 2008. Many of PFC’s physicians had the opportunity to attend some the sessions and have shared some of the highlights from the conference.

Progesterone Supplementation Into Early Pregnancy

One of the prize papers at this year’s ASRM meeting was a paper from The University of Minnesota entitled “Duration of progesterone-in-oil support following in vitro fertilization and embryo transfer (IVF-ET): A randomized, controlled trial.” In this study, IVF patients were all treated with 11 days of progesterone supplementation after IVF egg retrieval. The patients were then randomized to discontinuing progesterone with a positive pregnancy test result, or continuing progesterone for 8 more weeks in early pregnancy. There were 52 patients that stopped the progesterone and 46 patients that continued the progesterone. There were no differences in miscarriage rates in the two groups. This study is yet another study questioning the standard practice of most IVF programs to continue progesterone supplementation into early pregnancy. Carolyn Givens, MD

Microfluidics

Microfluidics is an exciting new laboratory culture technique that may improve IVF success rates. Small amounts of culture media continuously flow through a very small chamber. The flow can be pulsatile, similar to blood flow in the body. Microfluidics can be used to improve sperm isolation and processing, fertilization, and embryo culture. Currently embryos remain in a static environment in a dish. In a microfluidic chamber, embryos are constantly bathed by a very small stream of media resembling the environment in the fallopian tube. In mice, microfluidics improved in vitro pregnancy rates by 22%. Microfluidics may also be used for assessing embryo viability by analysis of embryo secretions. Small samples of media exiting the embryo chamber can be analyzed to assess embryo viability and to adjust nutrients entering the system. PFC will be one of the first IVF programs to test this exciting technology starting April 2009.Eldon Schriock , MD

Stem Cell Research Update

A significant hurdle to the advancement of human embryonic stem cell (ESC) research is the ethical dilemma presented by the fact that the derivation of human embryonic stem cell lines requires the destruction of embryos to obtain the tissue needed to derive these stem cell lines. The embryo is grown to the blastocyst stage (5-6 days of growth post fertilization). A blastocyst already shows differentiation into the cells which are destined to be the placenta (trophectoderm), and those destined to be the fetus (inner cell mass (ICM)). The ICM cells are isolated and cultured in the laboratory, to hopefully obtain undifferentiated colonies of ESCs. These undifferentiated ESCs can then hopefully be induced to differentiate into specific cell types for medical therapeutic interventions (pancreatic cell transplant for diabetes, cardiac muscle cell transplant for heart attacks, etc…). The medical community is still quite a ways from being able to use human ESCs for therapy, but once available, the potential for these therapies should be tremendous.

Scientists have been looking for alternate sources of cells to generate human ESCs, especially techniques which would not involve the destruction of embryos. Dr. Irina Klimanskaya reported a novel technique whereby one single cell (blastomere) is taken from an undifferentiated embryo (3 days post fertilization) to derive human ESCs. These embryos have 6-10 cells, and removing one cell will not impact its ability to continue growing and developing. Therefore this novel technique does not destroy the embryo. There is work to be done to make this technique efficient; but it’s an important scientific breakthrough, and removes the ethical dilemma which has held back speedy progress in this arena. Isabelle Ryan, MD

Vitrification - A Technique That Offers Improved Pregnancy Rates

Vitrification is a technique for storing eggs and embryos that offers improved pregnancy rates. Storing eggs in very small volumes, vitrification promises better quality eggs. Better quality eggs produce better implantation and pregnancy rates, so vitrification is quite attractive.

Freezing biological tissues carries a risk of formation of ice crystals. Ice can injure cells, since it expands when it cools, risking rupture of the cell. The very fragile elements responsible for cell division are easily disrupted by stresses such as freezing. Storage demands techniques that preserve the cell membrane and internal structural components.

Vitrification utilizes extremely small volumes and high concentrations of cryoprotectants to maximize the chance of a healthy cell. The techniques are complicated and demanding of the embryology team, but reward the effort with improved pregnancy rates. Traditional slow-freeze techniques utilizing higher volumes of fluid have been problematic for egg freezing.

A group from Valencia performed a randomized controlled study of vitrification and slow freezing of eggs, looking at the microscopic appearance of the oocytes after each technique¹. Vitrification showed a higher survival rate (89% vitrification versus 56% slow-freeze). No DNA fragmentation was observed with either technique. The spindle apparatus, important for cell division, was present after thawing in more vitrified oocytes (90% vitrified versus 75% slow-freeze).

For patients that do not cryopreserve embryos for ethical or religious reasons, oocyte vitrification is an option for the eggs that are not inseminated. Unfertilized eggs, rather than fertilized embryos, can be cryopreserved. A group from Brazil compared the outcomes of cryopreserved embryos and cryopreserved oocytes from young patients (<35yo) utilizing their own eggs. At thaw, there was no difference in the pregnancy rates or implantation rates between cryopreserved eggs and embryos².

A group in Chicago looked retrospectively at outcomes after vitrified embryo transfer³. In young patients (average age 34.3), 499 transfers of d5 embryos were performed. Clinical pregnancy rate in this group were 50.1% per transfer, excellent results.

Vitrification is an emerging technology that opens avenues for fertility preservation, extension of fertility, and maximizing pregnancy rates. Pacific Fertility Center is pleased to have been a leader in establishing this technology. Philip Chenette, MD

Interactive Session Draws Crowd at ASRM

On Monday, November 10 th, PFC physician Dr. Carolyn Givens and CPMC genetics counselor Lauri Black, MS, CGC were featured speakers at an ASRM Interactive Session entitled: Epigenetics and IVF: What are We Telling Our Patients?”

The session was attended by over 500 ASRM attendees. Ms. Black (who also works closely with PFC on our Pre-Implantation Genetics Program) started off the session discussing the background of genetic imprinting disorders such as Beckwith-Wiedeman Syndrome and Angelman Syndrome. Controversy has arisen as to whether the incidence of these very rare disorders is increased in IVF children.

Dr. Givens concluded the session by reviewing the current world literature on the topic, including some recent reassuring studies from Denmark that did not find a link between imprinting problems and IVF babies. A lively discussion with the audience followed. Afterwards, many participants remarked that they found the session to be very informative.

PFC Hosts International Visitors

From left to right: Kari Kawada, Dr. Atsushi Tanaka, Dr. Carl Herbert, and Dr. Katsuhiro Takahashi	From left to right: Dr. Junko Koriyama, Dr. Carl Herbert, and Dr. Shibahara

The Annual Meeting of the American Society of Reproductive Medicine (ASRM) provided an opportunity for PFC to meet with several international groups and discuss issues we share in common.

Friday, November 7 th, PFC hosted a luncheon and discussion with eight physicians and embryologists from Denmark and two physicians from Germany. The interchange regarding IVF stimulation protocols, laboratory procedures, and patient management regulations was interesting and informative for all who attended.

On Monday, November 10 th, PFC and our affiliate Japanese program, International Fertility Center (IFC), hosted a dinner/lecture in our educational center for thirty-eight Japanese physicians and medical personnel. This was a rare opportunity for us to personally meet several physicians who have been referring patients to PFC/IFC for over fifteen years. Dr. Carl Herbert presented a brief lecture on the safety and efficacy of egg donation as well as our excellent outcome data for Japanese egg donor recipients for 2008. Dr. Joe Conaghan gave a concise update on current laboratory techniques including our recent success with egg freezing. As egg donation is not yet an accepted practice in Japan, the presentations and discussion were meant to help our visitors in their efforts to change these attitudes back home.

Finally, on Wednesday November 12 th, the PFC physicians had lunch with several physicians and medical personnel from South Korea. This was followed by a tour of our facilities and a brief talk on the PFC approach to egg donation and egg freezing.

Without exception, participants in all of the cultural exchanges were quite impressed and most grateful for the time they spent at PFC. We felt the global aspect of our specialty and were happy to solidify friendships with our international colleagues.

1. [O-70] Vitrification vs. slow freezing of oocytes: effects on morphological appearance, meiotic spindle configuration and DNA damage. M. Martinez, L. Herrero, R. Salvanes, M. Montoya, A. Cobo, J.A. Garcia-Velasco. IVI Madrid, Madrid, Spain; CNIO, Madrid, Spain; IVI Valencia, Valencia, Spain

2. [P-482] Similar pregnancy rates from vitrified/warmed embryos and embryos derived from vitrified/warmed oocytes. J.R. Alegretti, J. Fioravanti, P.A. Hassun, P.C. Serafini, E.L.A. Motta, G.D. Smith. Huntington Medicina Reprodutiva, São Paulo, Brazil; Genesis Genetics Brazil, São Paulo, Brazil; Department of Ob/Gyn, Urology, Physiology, University of Michigan, Ann Arbor, MI

3. [O-77] 4-years of vitrifying blastocysts: what is the verdict? J. Liebermann, J.M. Matthews, Y. Wagner, R.L. Brohammer, S.R. Sanchez, E.J. Pelts. Fertility Centers of Illinois, Chicago, IL

FROM US TO YOU    PGD Training Course at PFC

Participants in a workgroup.	Practicing micromanipulation

On November 8 th and 9 th, 2008, PFC held a training course for embryologists interested in learning the techniques associated with Preimplantation Genetic Diagnosis (PGD).

The course was organized in conjunction with the Genetics and IVF Institute (GIVF) of Fairfax, Virginia and was originally scheduled to run on the Sunday only. However, due to the overwhelmingly positive response to attend the course, PFC decided to offer the course on Saturday as well. Forty seven individuals heard excellent lectures over the 2 day period.

Dr Dagan Wells from Oxford, UK and Dr Alan Thornhill from London, UK, gave talks on current and future technologies for genetic testing on embryos. Participants were then divided into 4 working groups that spent the rest of the day rotating between activities. The activities included embryo biopsy training, cell fixation training, media and solution making and PGD troubleshooting. Lauri Black, MS, CGC, a Certified Genetic Counselor at California Pacific Medical Center and Mary Sands of GIVF gave talks on genetic counseling. The course also allowed embryologists from all over the world to view the new state of the art laboratory at PFC. Joe Conaghan, Ph.D., HCLD

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.

CRITICAL REVIEW    Conception at 40 and Beyond – Does IVF Help?

We all know that fertility declines with female age, but what is not certain is how much in vitro fertilization (IVF) improves one’s chances of conception if a couple/woman is having problems conceiving on her own.

The table below is one I often use when counseling patients 40 and over about their chances of conception with in vitro fertilization.

This table represents pregnancy outcomes with PFC patients from January 2003 to March 2008, so most of the viable pregnancies tabulated here have been delivered.

One thing to note is that over half of the patients that get a positive beta-hCG result do not end up delivering a baby. This is consistent with the observation that most embryos from women 40 and over have abnormal numbers of chromosomes.

Another thing to be aware of is that pregnancies after age 43 are exceedingly rare, even with IVF. We encourage most women over age 43 to strongly consider ovum donation.

FROM US TO YOU    The Strategies of Coping with Stress

Stress is no stranger to most of our lives. The everyday, chronic strain of a demanding job, driving in traffic, dealing with relationships, taking care of the chores of life, all leave us feeling “stressed out.” “Does stress cause infertility?” No matter what the answer to the question, it is important to look at ourselves and determine just how stressed we are. We need to then take steps to attempt to reduce the stress. One undisputable fact is that it makes good sense to reduce our stress to the lowest levels possible. At the very least, you will feel better!

To provide you with the opportunity to assess your fertility stress, we have added a Stress Test domar© to our website at www.pacificfertilitycenter.com. Click on “for patients” then “support” then “infertility stress test.” The test is brief and it generates a stress level score with comments. You can take it as frequently as you would like.

The goal of stress reduction is to reach what Harvard physician, Herbert Benson calls the “relaxation response.” It’s like stress running backwards. We can calm our racing minds. We can soften our tense bodies. The relaxation response leads to a series of changes that take place in the body and mind as you calm down. Your heart rate, muscle tension, breathing rate, and oxygen consumption fall below resting levels. Your brain wave patterns become slower. There are many ways to elicit the relaxation response. The goal is to find the one that works for you, meaning that it reduces your stress and you will take the time to practice it!

One way to learn about all of these techniques is to participate in our Mind/Body class. We discuss and practice each of the following methods; progressive muscle relaxation, breathing techniques, yoga, visualization, mindfulness meditation, and journaling. It is a wonderful day where you get to meet others going through treatment, learn some new skills, eat some excellent food and de-stress.

In addition to learning specific techniques to reduce stress, it may also be helpful to consider the following suggestions:

-Give up any and all feelings of guilt for how you are feeling. There is no right or wrong way to experience infertility. Your feelings may run the gamut from indifference to intense anger and despair and everywhere in between.

-Choose the gatherings you attend carefully. If being around children or babies upsets you, gracefully decline invitations to events where they are likely to be present. Know your limits and stick with them.

-Continue to get moderate amounts of exercise. Eat healthy and get plenty of rest. You will feel better if you treat your body with care.

-Communicate with your partner to let him/her know of your feelings. Even if you and your partner are feeling differently it may help to share. If you are single, call a friend with whom you feel safe to share your feelings.

-Meet and talk with others who are experiencing similar feelings. Finding that you are not alone helps.

We offer these stress reduction workshops every quarter. There is no charge for PFC patients to attend. Join us! Peggy Orlin, MS, MFT

Peggy Orlin, M.S., M.F.T. is a Licensed Marriage and Family Therapist. She has been counseling couples and individuals at PFC for over 10 years.

PFC SPOTLIGHT    Brigett Brackett

PFC’s Egg Donor Recruiter, Brigett Brackett, spends most of her time bringing joy to others and that’s exactly the way she wants it. The Egg Donor Recruiter is a vital position within the Egg Donor Agency (EDA); Brigett has held this position for over 5 ½ years and was the EDA receptionist for 1 ½ years prior to her current position. Brigett always knew she wanted to help others, which is why she pursued a career in health care and became a Medical Assistant. She didn’t realize that this ambition would lead her to help others fulfill their dreams of having children. She has loved the direction her career path has taken and is building on her foundation by attending school to become a nurse.

Brigett gets true satisfaction from helping egg donors understand the process and from seeing the joy the donors experience in knowing they have helped others achieve their dreams. Brigett attributes her desire to help others from the fact that she comes from a large family. The fifth out of six girls and the aunt to ten nieces and nephews, her family continues to grow. While Brigett was born and raised in San Francisco, like many Americans her parents were immigrants. Her mother and father left Belize, in Central America, and came to the United States where they settled in California. Except for her immediate family, most of Brigett’s family still lives in Belize. While Brigett would like to visit relatives in Belize more often, the distance makes it difficult. Not to mention the people she spends most of her time with, her husband of 7 years and their two daughters live with her right here in San Francisco.

Brigett’s great aunt operated a bakery in Belize, and passed her skills onto Brigett’s father. In turn, he passed the baking skills onto his daughters--Brigett was one of the lucky ones to grasp his teachings. She continues to enjoy baking in her spare time and hopes to pass the skill onto her own daughters, since it has brought so much pleasure to her life. “I find baking to be a kind of art form,” she explains, “an expression of one’s self. It gives me a sense of satisfaction seeing others enjoy my creations.” Brigett would love to bake more often, but spare time is hard to come by these days. She knows that this is a field she will love and that the experience she has gained as an Egg Donor Recruiter will only complement her degree. “It pleases me that I am able to be a part of such an amazing process to help women get pregnant.” Brigett adds, “Seeing the pictures from all the success stories makes it worth coming to work everyday.”

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