ASRM 2011 Updates

In addition to the magical wonders of Disney, Orlando welcomed reproductive endocrinologists from around the world this October to attend the annual meeting of The American Society for Reproductive Medicine (ASRM).  Several members of Pacific Fertility Center were among the participants. 

Preimplantation Genetic Screening (PGS)

PGS was again a hot topic of discussion.  Multiple presentations showcased the recent technological advances in this field.  The ability to perform comprehensive chromosome analysis using microarray technology instead of the first generation method of FISH (fluorescent in situ hydridization), which could only test a selected number of chromosomes at a time, has increased the accuracy and the detection rate of embryonic aneuploidy (abnormal number of chromosomes).  Laboratory advances such as biopsy of the trophectoderm (the outer cell layer of a day 5 embryo) and vitrification (a method of rapid cooling of embryos that minimizes ice crystal formation) have further improved success.  As the result of the above-mentioned technical breakthroughs, we have seen a measurable increase in the pregnancy rate and a decrease in the miscarriage rate from IVF using PGS.  Additionally, two respected groups independently presented data supporting the use of PGS as a successful embryo selection tool to promote elective single embryo transfer (the process of transferring one embryo at a time into the uterus to reduce the risks of multiple gestation).  The pregnancy rates from a single PGS-selected euploid embryo were 58% and 60.7% compared to 42% and 40.7%, respectively, from a morphologically comparable but non-PGS-selected embryo.  Moreover, the miscarriage rates decreased to 6% and 6.3% from 12% and 12.5%, respectively.  The risk of multiple gestation was essentially eliminated (1-2% monozygotic twining).

We were excited to note the parallels between the data presented and our own work at PFC.  Several years ago, we made the commitment towards decreasing our multiple pregnancy rates by adopting a policy of encouraging elective single embryo transfer in qualified patients.  We have found that 24-chromosome aneuploidy screening (via informatics-based single nucleotide polymorphism microarray technology by Gene Security Network) of trophectoderm biopsy has significantly enhanced our ability to select the embryo with the best implantation potential.  Our improved vitrification program has also allowed us to reassure our patients that their unused embryos can be safely stored for future use, thus removing the pressure to transfer more embryos at one setting.  We are very proud of our success so far in achieving our goal as we are currently the number one ranked program in the nation of the fewest number of embryos transferred in donor cycles (1.4 embryos per fresh cycle) while maintaining a high pregnancy rate of 57% (of all programs with more than 20 donor cycles per year, 2009 SART).  For more details on our experience with single embryo transfer and its pregnancy rates, please read “What are my chances of having a baby from a single IVF cycle” by our embryologist, Erin Fischer, and laboratory director, Dr. Joe Conaghan, in this issue of Fertility Flash.

Fertility Preservation

Another interesting topic that deserves attention is fertility preservation using oocyte cryopreservation. Two centers with extensive experience in this area shared their outcome data from both methods of cryopreservation, slow freeze and vitrification.  A center in Atlanta vitrified over 2000 oocytes from donors with an average age of 26 years.  Of the 1772 oocytes rewarmed, 88% survived, 75% fertilized, and 51% resulted in viable cleavage stage (day 3) embryos.  Live birth rate per cryopreserved oocyte was 11%.  The other presentation by a group in New York reported their experience of rewarming 536 cryopreserved oocytes using both slow freeze and vitrification from non-donors with an average age of 32 years.  The overall live birth rate per rewarmed oocyte was 5.5%.  Study is ongoing to compare the efficacies of slow freeze and vitrification.     

PFC’s own data with vitrification of oocytes is comparable to, if not better than, the results presented at our national meeting by various groups across the US.  A 5-10% live birth rate per oocyte in women under the age of 35 years translates to a respectable chance of having a baby in the future from one to two treatment cycles in the present (10-20 oocytes can be expected to be cryopreserved per cycle).   As we further perfect our own techniques of vitrification, we will be increasingly more confident in our ability to offer young women with a viable option for future family planning in addition to embryo freezing and donor gametes.  Future research is needed to achieve the same type of success rates in older women.   

Participating at ASRM is always an educational experience.  We enjoyed sharing our own clinical and research endeavors with our colleagues across the US and all over the world.  Our position as the nation’s leader in many of the most cutting-edge technologies in our field is a validation of our commitment to excellence and to provide our patients with the highest quality care available.

Infertility & Reproductive News featured Pacific Fertility Center and interviewed Dr. Herbert for their August newsletter issue. 

Click here to read the article in Infertility & Reproductive News.

PCRS Meeting Review

Pacific Fertility Center’s team directed the Pacific Coast Reproductive Society’s annual meeting in April this year.  Dr. Carolyn Givens was President of the Society and Dr. Joe Conaghan was Program Co-Chair at the meeting this year.  And what a meeting it was!

Optimizing success rates for patients was the focus, with presentations on “Improving Live Birth Rates”, videos on the importance of early embryo development, optimizing treatment protocols, and early embryo testing.  There were sessions on stress reduction, discussions on single embryo transfer, healthy debates between experts, and conversations about new advances that will improve patient care.

Alice Domar, Richard Tucker, Michael Alper and Richard Scott were among the luminaries presenting at the meeting.  Right alongside them was Joe Conaghan, Carolyn Givens, Lauri Black, and Paul Turek with matching skills and knowledge.  All were directed at improving care for our patients.

Pacific Coast Reproductive Society is one of the important professional organizations supporting fertility care.  Although they are a West Coast organization by title, Pacific Coast has developed national and international status in our field by focusing on the patients. As described on their website, “PCRS provides an outstanding forum for the exchange of information, and the advancement of the ideologies of reproductive medicine in a relaxed and collegial setting building relationships that foster the integration of current knowledge to ensure quality medical care for patients.”

Pacific Fertility Center is pleased to support Pacific Coast Reproductive Society.  We are looking forward to applying these advances, and already working on the new advances we will be talking about next year!

-Philip Chenette, M.D.

Pacific Coast Reproductive Society Highlights

One of the highlights of this year’s meeting was a talk by Sheryl Kingsberg, Ph.D., a Professor in the Dept. of Reproductive Biology and the Chief of the Division of Behavioral Medicine at Case Western University. Dr. Kingsberg’s area of expertise is in Human Sexuality and sexual disorders in women. She gave an excellent synopsis of “normal” sexuality in our culture and how we have come to view and define that norm. She also provided background on the physiology of sexual excitement and sexual response in women. She spoke about the different classifications of sexual disorders, which includes Hypo-active Sexual Desire Disorder (what we know as low libido), Sexual Aversion Disorder, Female Sexual Arousal Disorder, Female Orgasmic Disorder, and the Pain Disorders: Dyspareunia (painful intercourse) and Vaginismus (localized vaginal and vulvar pain).

Dr Kingsberg also covered the topic of sexual dysfunction and sexual function. One of the most valuable things she discussed was that doctors should use a sexual function checklist. Here is the checklist she presented:

Please answer the following questions about your overall sexual function in the past 3 months or more:

Please answer the following questions about your overall sexual function in the past 3 months or more:

1. Are you satisfied with your sexual function?
   • Yes
   • No              If no, please continue.
2. How long have you been dissatisfied with your sexual function?
3. The problem(s) with your sexual function is: (mark one or more):
   1. Problems with little or no interest in sex
   2. Problems with decreased genital sensation (feeling)
   3. Problems with decreased vaginal lubrication (dryness)
   4. Problems reaching orgasm
   5. Problems with pain during sex
   6. Other
4. Which problem is most bothersome?  Circle one: 1  2  3  4  5  6 
5. Would you like to talk about it with your doctor?
   • Yes
   • No

Many of us at the conference realized there is a need to identify and assist our fertility patients that also may be suffering from sexual dysfunction. We need to spend a few moments covering this topic with our patients. We will be considering how to add these types of questions to our current patient history forms. We want to identify the patients with sexual dysfunction in addition to fertility problems so we may assist them in finding the appropriate resources for treatment.

-Carolyn Givens, M.D.

Genetic Testing Breakthrough

Genetic screening techniques are a prime topic of research and dialogue in the IVF community.  We continue to seek techniques that are 1) accurate, 2) have quick turnaround times for results, and are 3) versatile enough to be able to give a breadth of testing results on one embryo, as well as 4) cost effective.

One of the exciting presentations at PCRS was by a firm called Gene Security Network (GSN), whose laboratory is in Redwood City, CA. GSN has been on the forefront of providing pre-implantation embryo genetic testing which is accurate, covers all 23 pairs of chromosomes including the sex chromosomes, and provides results within 24-48 hours post embryo biopsy (therefore negating the need to freeze embryos while waiting for the genetic results, as with the CGH technique). This technique, developed by GSN, is called Parental Support.

Parental Support is a new technology for Preimplantation Genetic Diagnosis (PGD) that tests all 24 chromosomes in a single cell from an embryo (called a blastomere) for a variety of genetic abnormalities. The test reliability typically exceeds 99% and results are returned within 24 hours in time for Day 5 embryo transfer.

Single gene mutations (such as cystic fibrosis) have been traditionally tested for as one genetic test only.  Dual testing, the ability to test for both single gene mutation and aneuploidy screening was not able to be done accurately or easily.  GSN has been working on this challenge of dual testing, and had just announced the birth of the first baby born after such dual screening—a healthy baby girl.

This announcement was also exciting for us, since the patient who is now a proud parent of a healthy baby, was a PFC patient.

We continue to collaborate with GSN on current and upcoming clinical trials, pushing the frontiers of genetic testing of embryos, and of diagnostic testing that promotes the creation of healthiest babies possible.

-Isabelle Ryan, M.D.

Advances in research & development bring a deeper understanding of infertility:

Modern fertility science is changing treatment, enabling better pregnancy rates.  A healthy child for every person suffering from fertility problems remains Pacific Fertility Center’s goal.  Through a better understanding of the egg and embryo we are  closer to delivering on that promise of one healthy baby at a time.

The problem of the aging egg:

The aging egg remains a very basic problem in fertility.  As a woman ages, her eggs do not work as well, resulting in embryos that do not develop or implant.  Mistakes in early cell division, chromosomes, and development become common.  With an aging egg, pregnancy rates are lower and miscarriage risk higher.

Finding that healthy egg can be a problem.  For a twenty year old, roughly 1 in 3 of her eggs will be healthy.  For a woman over forty, less than 1 in 20.  This continues to be a real and ongoing challenge for our patients.

One way to work around this problem is to increase the number of eggs.  Starting with more eggs gives a better chance of finding at least one that is healthy.  Once we have a batch of eggs, the problem emerges of trying to choose the best out of the group.  Which egg is most likely to achieve pregnancy?

Research of early egg and embryo development:

We are excited to share that we are currently working with a privately held medical technology company, along with several other centers in the Bay Area, on a new investigational imaging device in the early stages of development.  We can now observe, using a video microscope, the early stages of embryo development.

Knowledge of the way an embryo develops, the early cell division, when and how, promises to improve selection of embryos.  Over a several year period at Stanford Institute for Stem Cell Biology & Regenerative Medicine, Dr. Renee Pera, in collaboration with Stanford colleagues, Dr. Barry Behr (Associate Professor and IVF Lab Director), Dr. Thomas Baer (Executive Director of the Stanford Photonics Research Center), and post-doctoral fellows Dr. Connie Wong and Dr. Kevin Loewke, conducted ground-breaking research into early human embryo development.  Looking at embryos in their first few days of development, the team identified an elegant set of imaging parameters by day 2 that accurately identified embryos that develop to the blastocyst stage.

Through the use of precision imaging technology coupled with novel measurements, embryologists may be able to choose the best embryos more accurately and consistently.  Published last year in Nature Biotechnology, Time magazine named the discovery one of the 10 medical breakthroughs of 2010.

Dr. Renee Reijo Pera, Ph.D.

Dr. Renee Reijo Pera, a leader of the team that published this study, understands these problems, working with them in a research lab for the last twenty years.  She is now bringing that knowledge to clinical medicine.

Dr. Pera received her PhD from Cornell University, and later worked in David Page’s lab at the Whitehead Institute.  While working with Dr. Page, she discovered a gene on the Y chromosome that was involved in male fertility called the DAZ (Deleted in AZospermia) gene.  As it turns out, the gene accounts for a significant proportion of male infertility and tests for this gene are now routine for men with low sperm counts.

Now, as Director of Stanford University’s Center for Human Embryonic Stem Cell Research and Education, Dr. Pera’s focus is on understanding issues related to human reproductive failure.  The questions she and her team are addressing encompass issues such as Egg formation and development, as well as what triggers cell division and formation of a healthy embryo

Fertility care will change based on Dr. Pera’s research on early development of eggs and embryos.  This work has vast implications for the future of treatment and prevention of infertility.  In her exploration, she is finding new ways of thinking about old fertility problems.  Dr. Pera’s work will strongly influence medicine and clinical realm for years to come.

At Pacific Fertility Center we are committed to bringing advanced science to the clinic.  We are finding major changes in our understanding of early egg and embryo development and anticipate continuing to lead the way in bringing these advances to help our patients have one healthy baby at a time.

-Philip Chenette, M.D.

Andy and I married in June of 2008.  I was just turning 39 and we tried to conceive a child “the old fashioned way” for a year  before working with PFC. We didn’t expect it to be so difficult as all signs indicated that we would get pregnant.  Andy’s sperm was normal and my FSH was good.  When we moved to the IUI and IVF processes, I responded well to the drugs, produced lots of follicles and eggs, we had nice looking embryos, and we were able to do day 5 transfers.  The doctors seemed confident.  But over the course of about 15 months we experienced 2 rounds of IUI, 4 rounds of IVF, and 2 miscarriages. 

Now it is December 2010 and we’re nearing the end of a blissfully uneventful pregnancy.  Our baby boy is due to arrive on New Year’s Eve!  It looks like our story will have a happy ending, but I don’t need to tell you how difficult the journey has been.  Instead, I’m going to try to share a little bit about how we got through it all, in the hopes that it might give you some ideas or a new perspective for your own experience.

First, Andy and I knew we wanted to be parents. We absolutely knew it would happen for us, one way or another.  Although our first preference was to have “our own” child, it was only a preference.  We both knew that if IVF did not work out for us with my own eggs, we would go the route of an egg donor.  If necessary, we knew we would move to adoption.  Starting a family was our priority and our dream.  We believed that whatever baby came into our lives, that baby would undoubtedly be the baby we were meant to parent, and we would love our baby no matter what.  Have you ever heard the Buddhist saying, “Don’t be attached to any particular outcome”?  It became one of our mantras and allowed us to stay focused on the big picture plan, as opposed to the various routes or paths that might be part of that overall plan.

Teamwork was another essential element of our journey.  I’m lucky because Andy is very detail-oriented, patient, and he was completely on board with the program.  I’m more emotional. I have a short attention span, I like information in summary format, and I can manage a calendar like nobody’s business.  We make a great team because I could endure the shots and stay on top of all those doctor appointments, but keeping track of the drugs, the dosages, the ordering—that was all Andy.  At first, I worried that we would run out of a drug that we’d need, and we wouldn’t realize it until it was too late.  However, thinking like that made me nuts.  Soon we developed a system where Andy managed all the prescriptions and ordering, he prepped my needles with the right dosages, and he tracked what we were supposed to do each day.  I did my own injections and dealt with the side effects.  Those were our roles.  I didn’t want to have to think about the details.  By relying on Andy to “manage the minutia,” I was able to stay more relaxed and less stressed.

Finally, I had an epiphany that, in order for this process to be successful, I’d have to stop expecting infertility to somehow fit into my life.  I don’t know about you, but I was pretty overwhelmed by all we had on our plates.  At first, I was trying to squeeze in my appointments with PFC and with my fertility acupuncturist, while maintaining a calendar filled with dinners with friends, a busy work schedule, and a significant amount of travel. It’s no surprise that I was tired and stressed out, but I also became very resentful.  I was seeing a fertility acupuncturist on a weekly basis, yet I was annoyed that she recommended I take herbs and make changes to my diet.  I was frustrated as I tried to find time for all the appointments at PFC. Then, one night I was crying and sharing my frustrations with Andy, and he helped me see things differently.  He said that none of this was going to work if I didn’t fully embrace what we were doing.  I had to take the herbs with a positive attitude and whole-heartedly believe in the power of both eastern and western medicines.  Otherwise, what was the point in going through it all?  I realized that my bad attitude could have the power to neutralize all we were doing and I had to shift my mindset, accept that this was our path, and surrender to the process.  I created a big opening in my life so that there would be space for the infertility and all the energy it would take to tackle it.  I stopped traveling, dramatically reduced my social commitments, and spent much more time resting and “nesting” at home.  This was really difficult for me as an extrovert, but it became so much easier to make the right decisions and to more graciously accept what was required of me.

The last thing I would like to mention is that we were not secretive or private about our challenges with infertility.  I’m used to being pretty open with my friends, and I think it helped us to reach out to people for support during our ups and downs. One friend in particular, who had gone through her own IVF process, was reading some message boards online and found out about a new form of preimplantation genetic testing that she thought might be helpful to us.  We brought it up to Dr. Chenette and he was happy to give it a try since our prior IVF rounds produced seemingly good embryos, but failed to result in a viable pregnancy. So, on our 3^rd round of IVF, on day 3 we had 12 great looking embryos.  PFC biopsied all 12 and Gene Security Network ran a full analysis of all 23 sets of chromosomes.  On day 5 we showed up to transfer the best ones.  We were excited because we would know which embryos were genetically viable and which were not.  As we waited to see Dr. Givens, we wondered whether we would have 2 or 3 embryos to transfer.  But when Dr. Givens entered the procedure room, we could tell something was wrong.  We were told that all 12 of our embryos were genetically defective and none were viable for transfer.  Worse yet, because all of them possessed defects from the maternal chromosomes, it was recommended that we stop trying to conceive with my eggs and to think about alternative paths.  It seemed that this path had come to an end.  None of our embryos were good and there was no point in trying to make any more.  The news was devastating for us.

Andy and I went to a dark place for a few weeks.  But I’m happy to say that after talking and crying and praying about our situation, we came out of the darkness fully ready to embrace the process with an egg donor as soon as possible.  But first, we wanted to do the same preimplantation genetic testing on the 4 frozen embryos we had saved from our 2^nd round of IVF.  As expected, 3 of those embryos were genetically defective, just like the 12 from our 3^rd round of IVF.  But, we also experienced a miracle: one of those embryos was a genetically perfect boy.  He was my last hope to have a baby with my own genetic make-up.  Amazingly, he survived the freeze and the thaw, and survived the biopsy for the testing.  We transferred him in April and today I hit 37 weeks of pregnancy.  He is now considered full term and we are excited to meet him soon!

So, that’s our story.  I know we all have one.  Andy and I wish you the very best as you pursue parenthood and aim to build your family in whatever way makes sense for you. 

~Andy and Susan Nelson

Update:

“Our son was born on 12/30/10 at 12:20 am.  His name is Boden, he weighed 6 lbs. 15 oz. at birth, was 20” long, and is completely healthy.”

The field of Assisted Reproduction has always been one of rapidly evolving technologies, but nowhere more so than in the area of screening embryos. Screening is possible for not only genetic disease (PGD) and but also abnormal numbers of chromosomes (PGS). Along with the revolution in human DNA biotechnology, new companies such as Gene Security Network of Redwood City, California have emerged.  They are able to apply information from the Human Genome Project to the analysis of DNA from single human embryonic cells.

It is now possible to accurately diagnose most any human genetic disease in a pre-implantation human embryo. We do not even need to know the mutated sequence as long as there is DNA available from the parents that carry the mutation. By using what are called “linked markers”, we can make an analysis from the amplified DNA from a single embryonic cell and compare it to the parental DNA to determine the likelihood that any one embryo received mutated copies from either parent. This analysis is done at the time of an IVF cycle when the embryos are in the IVF laboratory. Affected embryos carrying mutations that may cause the disease, such as cystic fibrosis or muscular dystrophy, are not transplanted back into the mother’s uterus.

Until recently, a single embryonic cell could only be analyzed for either a mutated gene sequence using a limited number of markers (usually about 10) or for chromosome copy number (karyotype), but not both at the same time. In the last year, Gene Security Network has offered testing of DNA for BOTH genetic mutations (when parents are at risk for having affected offspring) AND for chromosome copy number to rule out Down Syndrome, Trisomy 18, or any other “aneuploidies” that can cause implantation failure or miscarriage. Both tests can be done on the amplified DNA from a single cell. Pacific Fertility Center has been participating in their pilot studies on this project and, due to the success of the initial group of patients PFC is now offering this type of testing routinely to couples that need this service. We welcome this change because it means we can now not only select unaffected embryos, but also have a fairly high confidence that the embryos we select for embryo transfer have normal chromosome copy numbers and will have a good chance of establishing a normal pregnancy.

Another area in which this DNA micro-array technology has found application is in the area of testing miscarriages for chromosome copy number. In the past, if we wanted to know if the reason a miscarriage had occurred was due to abnormal chromosomes, we had to do a D&C procedure, obtain placental DNA and send it to a cytogenetics lab. At the cytogenetics lab, the placental tissue had to be put into cell culture to try to capture dividing cells, which is the only way a karyotyping analysis could be performed. If the placental tissue contained no viable, living cells, the culture would fail and there would be no results. If the analysis revealed a 46 XX karyotype, we could not be sure that this was a normal female miscarried or if the cell culture was contaminated with maternal DNA. Now we can send the placental tissue with a sample of the mother’s blood, and the lab can tell if the DNA is maternal or not and the tissue does not need to be viable to get a result. This then allows us to determine if a pregnancy loss was due to abnormal fetal chromosomes, one of the most common causes of miscarriage.

There is no doubt that all of these new genetic technologies will continue to evolve over time, becoming even more rapid and accurate than they are today. It is exciting to be involved with applying the latest science and biotech has to offer to help solve clinical problems for our fertility patients.

-Carolyn Givens, M.D.

Since March of 2007, PFC has been vitrifying embryos.  We have now completed over 600 warming cycles, utilizing those embryos.  Vitrification is proving to be a very reliable technology to preserve any unused embryos that remain after a fresh transfer. We continue to adjust our technique and thus increase the successful results of vitrification.  Last year, we introduced a modification to the procedure that allows us to remove the fluid from the cavity in a blastocyst before we begin vitrifying.  As with any freezing procedure, cell water must be substantially removed and replaced with cryoprotectants to avoid ice formation in the cells.  Five and 6 day old embryos, or blastocysts, can have a large fluid filled cavity that slows dehydration and passage of cryoprotectant into the cells.  Since vitrification is an ultra-rapid freezing procedure, any delays caused by the fluid in the cavity may affect the ability of the embryo to survive the procedure.  By making a small breach between two of the outer cells in the embryo, we are now allowing the cavity to collapse prior to beginning the vitrification procedure.  This artificial collapsing has further enhanced results.  We are seeing implantation rates with warmed embryos that are very similar to those achieved with fresh embryos.

Overall, from 636 warming cycles, we have achieved 284 clinical pregnancies (45%) in all age groups combined.  In younger patients (maternal age under 35), there were 103 successful clinical pregnancies from 190 transfers (54%) with an average of just 1.7 embryos transferred.  This pregnancy rate drops to 42% (41/97) in 36-37-year-old patients with an average transfer of 1.8 embryos.  In the 38-40 age group there were 31 pregnancies achieved successful from 79 transfers (39%). For patients over age 40, 8 of the 23 transfers were successful (35%).  In the donated oocytes group, 101 pregnancies resulted from 247 transfers (41% with an average of 1.7 embryos transferred).  For patients that had their embryos artificially collapsed, the results were better.  However, since this is a new technique, the number of cycles is small.

Overall, we are very pleased with the outcomes achieved with vitrified embryos.  We are optimistic that results will continue to improve.  The table above shows results for all cycles completed since the beginning of the vitrification program.  As our experience grows, so do our success rates.  Reviewing cycles of patients that had embryos warmed and transferred from just this year (Jan-Oct 2010), we see that the outcomes are exceptionally good, particularly  for patients whose embryos  were collapsed prior to vitrification.

At PFC we are continuing to vitrify all embryos by day 5 or 6 after oocyte retrieval if they are good or reasonable quality blastocysts.  We now routinely collapse any blastocyst with an expanding cavity.  These procedures have worked well.  Consequently, it has become necessary to reduce the number of embryos being transferred to avoid generating too many multiple pregnancies.  Our goal is to achieve a healthy singleton pregnancy in all patients; vitrification has allowed us to reduce the incidence of multiples by transferring just a single embryo most of the time.  For our 2009 fresh cycles, in patients under 35, 40% of the time we transferred just one embryo, and in patients using donor oocytes 60% of the transfers were a single embryo.  Vitrification has proved to be so successful that many patients have elected for a fresh single embryo transfer; virtually eliminating their risk of twins and knowing that their frozen embryos will be available should they be needed.

A 42 year old woman has given birth to a healthy baby boy by using embryos which had been cryopreserved (frozen and stored) for nearly 20 years.  Dr. Sergio Oehninger, Director of the Jones Institute for Reproductive Medicine at the Eastern Virginia Medical School, treated the woman who had been unable to conceive due to problems with egg production.  She had undergone almost ten years of fertility treatments without success when she was given five frozen embryos anonymously donated by another couple.  The donating couple had delivered a child in 1990 using an IVF treatment and had stored these additional embryos for over 19 years.  Of the five embryos, two survived after thawing and were grown in the laboratory for two additional days. Both embryos were transferred into the woman’s uterus but ultimately only one attached and grew.  In May 2010 a healthy baby boy weighing 6lb 15ozs was born.   

It is exciting to hear of cases like this one as it provides hope for other couples who might be able to use donated frozen embryos. The success of freezing and thawing embryos continues to improve with such new techniques as vitrification, embryo collapse before freezing or embryo assisted-hatching after thawing. Fortunately, there is also significant research data confirming the health of babies born after embryo cryopreservation. However, the majority of the cases used in the research to date have been frozen for less than five years. Therefore, we will need to gather more information on cases such as this one where the embryo storage has been for an extended time period. Happily, at least so far, there does not seem to be any “freezer burn” for embryos stored in liquid nitrogen.

-Carl M. Herbert, M.D.

The award of the 2010 Nobel Prize for Medicine to Robert Edwards was a mark of recognition for development of the first successful in vitro fertilization.  The award, though, goes far beyond a mark of personal accomplishment.  The real significance of the Nobel Prize is the immense impact of Dr. Edwards’ work on medicine.

The growth of research, education, and clinical care that emerged from this work continues to echo to this day, and the pace of this advancement shows no signs of slowing.  Pacific Fertility Center exists as a result of these efforts; however reproduction is not the only field that has been affected by Dr. Edwards work. All fields of medicine have benefitted from the outgrowths of technology that show their origins in Dr. Edwards’ work.

His work arose during a time of sparse knowledge concerning reproduction.  Little was known about the early steps of egg, sperm, and embryo development, and even less about the implantation of an embryo into the uterus that establishes pregnancy.  Dr. Edwards worked through many of the early details of IVF technology, such as ovulation induction, sperm capacitation, and embryo culture. Each stage of egg development and maturation, sperm management and fertilization, and embryo transfer, had to be studied, modeled, and attempted in the clinic.  When a technique did not work, it was back to the drawing board to try again.

The work was never easy.  In the beginning, success was difficult to achieve and the worries were high.  One of the earliest in vitro fertilization pregnancies ended in miscarriage.  A second ended in the fallopian tube, as an ectopic pregnancy.  Professional associates often, and loudly, doubted that in vitro fertilization was possible or safe. 

In the midst of these doubts, a normal child, Louise Brown, was born in 1978 after in vitro fertilization.  It was a pregnancy much like any other, except born after conception assisted by technology.  Concern and worry were replaced with the simple beauty of a newborn child in its mother’s arms.

All of us clearly remember the day we heard of Dr. Edwards’ work.  The ideas were startling at first, but soon created a newly opened door to a vast area of possibilities.  New techniques for fertility treatment, avenues for treatment of genetic illness, and new ways of thinking about medicine became possible.  For me, a young man in college, deciding on a career path, it was a call to learn and resulted in medical school and fellowship.  For researchers, educators, and clinicians already in the field, suddenly there was a new way to help patients, and an array of interesting pathways for research.

There began a massive change in medicine, with the development of a network of research, education, and clinical care.  Educational programs were established at most major medical institutions for training new practitioners and researchers.  Funding, mostly private, was established for research into fertility.  Professional journals, like Fertility and Sterility, and Human Reproduction, emerged to document the research findings.  A network of clinical care grew applying research findings.

Pacific Fertility Center was established in the midst of this development, in the late 1980s, as a center of excellence in fertility care, by a group of doctors at Pacific Presbyterian Hospital (now California Pacific Medical Center) in San Francisco.  A small program in the midst of a very busy medical care system, the Pacific Fertility rapidly established success as a leading private practice for in vitro fertilization and ovulation induction.   The five doctors that run the program today were true innovators in the field of IVF.

Pacific Fertility Center sought to improve a high standard of care from its early days, seeking the best proven technologies for patient-focused fertility care.  Early innovations included the move from laparoscopic to ultrasound-guided procedures, requiring less anesthesia and less risk to patients.  Intracytoplasmic Sperm Injection (ICSI) for male factor introduced in the mid 1990s, and methods to reduce multiple pregnancy rates and chromosomal testing of embryos (preimplantation genetic diagnosis and screening) were all mastered and introduced to Pacific Fertility Center within the last decade.  We continue these efforts today with innovations in fertility medications, vitrification, and fertility preservation.

Today, some 4 million children have been born worldwide through in vitro fertilization technology.  Pregnancy rates have steadily improved, while the risk of multiple pregnancy has declined.  Treatments have emerged for specific problems such as male factor infertility, and diminished ovarian reserve.  Fertility preservation, oocyte donation, and the prevention of genetic illness all are growing areas of reproductive medicine.  All of this came from the birth of one child three decades ago.

We are pleased at the recognition of Dr. Edwards’ work by the Nobel Prize committee. We are honored to have been able to participate in the development of these technologies, and we look forward to helping patients at Pacific Fertility Center benefit from this work, one healthy baby at a time.

-Philip E. Chenette, M.D.

Since Pacific Fertility Center came into existence in November of 1999, we have been offering genetic pre-screening of IVF embryos for couples with recurrent miscar- riage, repeated IVF implantation failure and sex selection for family balancing. For most of the last decade, a technology known as Fluorescent In-Situ Hybridization, or FISH has been used to screen embryos. FISH is employed to probe a cell removed from a Day 3 embryo to determine the chromosomal makeup for anywhere from three to twelve of the cell’s 23 pairs of chromosomes. With time, we, as well as everyone else in the reproductive genetic world, came to realize the serious limitations of this technology.

In the last 2-3 years, as the Human Genome Project has been completed and as more DNA-related biotechnologies have emerged to evaluate human genes, these methods are being utilized to analyze human embryos. The technology now available—the ability to analyze large numbers of genetic locations on each human chromosome, and quantify that genetic material, with the previously well-established techniques to amplify a single cell’s genetic material up to hundreds of thousands of copies—has allowed PGS to take a quantum leap forward. It is now possible to more accurately analyze all 23 chromosome pairs from a single embryo; not only to determine if the correct number of copies of each chromosome is present, but also to look at single gene mutations.

At the end of 2009, Pacific Fertility Center began working with a new biotech company called Gene Security Network, located in Redwood City (genesecurity.net). This company uses gene microarray technology to analyze amplified DNA from a single cell.

It then uses microchips to analyze 30,000 genetic loci in a quantitative manner. In addition, their unique technology allows us to compare the analysis of the embryos’ cells to the parent’s chromosomes to ensure that all the genes are being properly analyzed. It does appear that the error problems that plagued FISH technology have been overcome with this new, more sophisticated, method.

In October of 2009, Dr. Conaghan and I were invited to tour the GSN laboratory and see the technology in action. We met with David Johnson, the lead scientist at GSN, who explained the cell process; from the amplification of the DNA, to arranging the chromosomes on chips, to DNA analysis, to synthesizing the data generated with the parental genetic data to come up with a full analysis of that cell’s genome. In order to process the cells between the day of embryo biopsy (Day 3) and receive the results on the day of embryo transfer (Day 5), their technicians work around the clock in shifts. GSN has a very cold, clean room to replicate the single cells into multiple copies. They cannot allow any outside contamination, not even from a single cell. They videotape the cell duplicating process so if any errors subsequently arise, they have a video record of what the laboratory technician did. We found this to be very impressive. We also saw how the chips were coated with DNA and analyzed. We were shown the sophisticated software that generates the final report detailing the genetic makeup of each embryo from the cells in which they originated. All in all, the tour gave us great confidence in the quality control and scientific integrity at GSN.

Even with this 21st century technology, we continue to biopsy Day 3 embryos because it provides us with a 48 hours window to send the cells to the lab and complete the analysis in time for transfer. However, we have not yet found a way around the problem of mosa- icism. GSN and microarray technology appears to have largely solved the resolution error problem but it can only tell us what is in the chromosomal make-up of the single cell. It cannot tell us whether or not that cell represents what is truly going on with the rest of the embryo. We are currently looking at the possibility of biopsying Day 5 embryos. The set back would result in having to freeze these embryos due to the time constraint in analyzing the genetic material in time for fresh transfer. With all of the innovation occurring daily in the genetics field, we hope that this puzzle will be resolved.

— Carolyn Givens, M.D.

Previous Fertility Flash articles about PGS:
2 Methods of Gaining Info Prior to Implantation
PGD & PGS: Why Genetic Counseling is a Prerequisite
The Benefits and Pitfalls of PGS