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.

Engaging in well designed and executed research in the world of fertility treatment can be very difficult.  However, in order to advance in our field, and to counsel patients about expeditious and cost-effective plans for success, we need to conduct research.  When patients are diagnosed with Unexplained Infertility, it is both frustrating for the patient (why can’t my doctor figure out what’s wrong with me?), and for the treating physician (we like to be able to “show” where the problems are).  We have known for 10 years now, from a well designed study by Guzick and his team, that for patients with Unexplained Infertility the chances of success with “low tech” treatment options are still in a low range of 5-12% per cycle.  This range is dependent on the female’s age and use of Clomid or gonadotropins (1) (Ryan, I; A Most Frustrating Diagnosis (2)).  Now we have insight into comparing cost effectiveness of low-tech options (Clomid or gonadotropin therapy) versus IVF treatment (3).

The FASTT study started in September 2001 with 503 women between the ages of 21-39,   the average age was 33, and continued until April 2006.  A few months ago the final results were published, after a nine-year process.  The study took place at Boston IVF Center in Massachusetts, a state where fertility treatment is a covered health insurance benefit, including up to six IVF cycles.  After a full fertility evaluation confirmed that the couples had Unexplained Infertility, the patients were enrolled in the study.  Patients were randomly assigned to one of two treatment plans: 1) Three cycles of Clomid plus intra-uterine insemination (IUI), followed by 3 cycles of gonadotropin/IUI, then up to 6 IVF embryo transfer cycles (Conventional treatment), or 2) Three cycles of Clomid/IUI followed by up to 6 IVF embryo transfer cycles (Accelerated treatment).  All treatment protocols, medication dosing, and number of embryos transferred were practiced similarly among the patients.  In addition, the patients kept a diary of additional time and money spent in each treatment cycle.  This cost included time away from work, medication co-pays, and payment for additional care (e.g. emotional counseling). A financial analysis of the total charges incurred for each patient from the time of entry into the study until the patient had a delivery (including pregnancy and newborn care); the patient stopped treatment; or the study was closed.  The study’s two primary endpoints were comparing: 1) time to pregnancy, and 2) health care costs associated with that pregnancy/delivery.  Secondary endpoints were per-cycle pregnancy rates, per-couple pregnancy rates, and adverse outcomes.

Sixty-four percent of couples delivered at least one live-born baby by the close of the study in 2006 (150 conventional and 171 accelerated). The time-to-pregnancy was statistically shorter for the accelerated group compared to the conventional group.  The estimated time-to-pregnancy was 8 months in the accelerated arm and 11 months in the conventional arm.  This 3-month difference between the two groups would suggest that the additional 3 months doing gonadotropin/IUI cycles did not contribute to a shorter time-to-pregnancy than the 3 Clomid/IUI cycles alone.

Per-cycle pregnancy rates for Clomid/IUI, gonadotropin/IUI and IVF were 7.6%, 9.8% and 30% respectively.  The very slight increase seen in the gonadotropin/IUI rates did not have any impact on the “time-to-pregnancy rates” (as noted above), and yet are much more costly cycles than a Clomid/IUI cycle (average $500/cycle vs. $2500/cycle).

In the Guzick study, the greatest number of High Order Multiple (HOM) pregnancies (triplets or greater) was in the gonadotropin/IUI cycles.  This finding has been echoed by a number of other studies.  In the FASTT report, there were an equal number of HOM pregnancies in each group.  In the conventional group, there were two sets of triplets, both from gonadotropin cycles.  In the accelerated group, there were 3 sets of triplets, one from Clomid, and two from IVF.  The average number of embryos transferred in the IVF group was 2.3.  With the improvement in IVF laboratory techniques, many IVF centers currently advocate for transfers of only one embryo in women with an average age of 33.  This practice trend will likely decrease the number of HOM in IVF, and would most likely present further benefit (safety and financial) to the accelerated strategy.

A cost effective analysis shows the total charges per delivery to be $9,846 lower for the accelerated group ($61,553 per delivery) than the conventional group ($71,399 per delivery).  If the analysis is limited to charges of infertility treatment per delivery, the difference was $5,802 in favor of the accelerated arm.  The observed incremental difference in charges per couple was a savings of $2,624 for the accelerated treatment, and an increase in the proportion of couples with deliveries of 0.06.  In the parlance of cost-effectiveness analysis, accelerated treatment dominates conventional treatment.  This analysis holds true as long as the charges of an IVF cycle are <$17,749 (which, even in today’s dollar, is a realistic expectation for patients in their early 30s).

In summary, for patients with Unexplained Infertility, doing 3 cycles of gonadotropin/IUI after 3 cycles of Clomid/IUI was of no added benefit.  Accelerated treatment to IVF saves money and results in a greater proportion of couples with delivery of a live-born baby.  In terms of the financial benefit, the charges for treatment, pregnancy and delivery were less for couples in the accelerated arm compared to the conventional arm. 

Pacific Fertility Center strives to provide patients with treatment recommendations and protocols based on sound science.  We appreciate and are thankful to our IVF colleagues who have the tenacity and ability to proceed with studies such as this FASTT study.  We all benefit from their efforts!

Isabelle Ryan, MD

(1)   Guzick et al.  Efficacy of superovulation and intrauterine insemination in the treatment of infertility, N Engl J Med 1999;340:177-83

(2)     Ryan, I; A Most Frustrating Diagnosis; June 2009, Fertility Flash Science Pulse, Vol 7, issue 4; http://www.pacificfertilitycenter.com/fertilityflash/vol7_issue4.htm#Article1

(3)   Reindollar et al.  A randomized clinical trial to evaluate optimal treatment for unexplained infertility: the fast track and standard treatment (FASTT) trial, Fert Ster 2010; 94:3,888-898

Born into a musical family, some of my earliest memories are of visiting musicians and musical instrument makers.  I was fortunate to meet Carl Geyer in Chicago, who built some of the world’s finest French horns.  His shop was full of raw materials, the valves, tubes, and bells associated with a French horn.  I watched as Mr. Geyer shaped them into beautiful instruments, ones that professional musicians from all over the world came to play.  For me, these visits became early lessons in craftsmanship, quality and personal responsibility.

My father, a conductor and horn player, expected each of his five children to play an instrument.  I turned to Oboe.  There are many stories about oboe players, mostly revolving around the fact that playing the oboe is a real challenge; the oboe being “an ill wind that nobody blows good”. 

However, I pursued the art and craft of the oboe and learned from some of the top master oboists and conductors of the day.  My instructors came from major symphony orchestras in Indianapolis, Cleveland and Chicago.  I met and was influenced by world renowned conductors and composers;  Leonard Bernstein, Aaron Copland, Dika Newlin, and Peter Shickele.  Working with masters you learn that, while there are many ways to accomplish a task, the path chosen must be done correctly and pursued with passion.

Many years have passed since I played in an orchestra, but those early experiences are still with me each day I practice medicine.  The symphony is a wonderful analogy to describe the work in our practice.   In an orchestra there are nearly a hundred individuals of diverse backgrounds, origins, and personalities. There’s a conductor at the helm, working the notes placed on paper by a master of composition.  The mastery and craftsmanship, performed by a unified team devoted to a single goal, using all the skills available to them, creates a performance of great beauty and power.

Similarly, at Pacific Fertility Center, the doctors compose a treatment plan and direct the team.  We give our staff the best of class tools.  Our staff orchestrates the performance; a highly talented group of people applying their best skills to the unique problems of each individual patient.  It is an honor to work with the patients that entrust us with their care. We continue to pursue the best in fertility technology and pregnancy rates.

On reflection, perhaps I became interested in fertility medicine because it gave me the same sense of structure, purpose and wonder as playing the oboe as a young student.  I was inspired by the announcement of the first pregnancy from in vitro fertilization. The application of medical technology to help a family achieve their dreams was a landmark event.  Controversy and hoopla ensued, but the truth stood clear, that a small baby – a new child – was held in its parents’ arms as a result.   For me, this was a momentous event that inspired me to attend medical school at Indiana University, residency in obstetrics and gynecology at the University of Pittsburgh’s Magee-Womens’ Hospital, and ultimately a fellowship in reproductive endocrinology and infertility at USC.

USC was a crucible of fertility technology.  Roger Lobo was performing extraordinary work on ovulation induction and PCOS.  Some of the pioneers of IVF and oocyte donation were rewriting the book on fertility care.  Lobo, Rick Paulson and Mark Sauer published the first report of oocyte donation in women over 40 years of age (New England Journal of Medicine, 1990).  The protocol diagram in that paper is my design.

After completing fellowship, I returned to Chicago to join Anne Wentz in developing the program for in vitro fertilization at Northwestern University.  Anne came from the Gerogeanna and Howard Jones Institute tradition, and was a real master of the embryo transfer.  We established a successful program synthesizing the best of East and West coast protocols, advancing the theory and practice of embryo transfer, developing new techniques for male fertility problems, and developing fertility preservation for endangered species. 

California called me back, and I joined Pacific Fertility Center (PFC) in San Francisco in 1991.  At PFC, I was fortunate to meet Dr. Herbert who later established The San Francisco Center for Reproductive Medicine.  Dr. Herbert’s vision of patient-centric fertility care was pioneering and contemplated my own interests in quality care.  In 1999, we carried this vision forward joining with Drs. Schriock, Givens, and Ryan from the University of California to form Pacific Fertility Center as we know it today.

Being an early member of the profession, I have been blessed with many opportunities to apply technology to patient care.  I developed an embryo transfer system with Danforth Biomedical and was awarded a patent, “Methods for endometrial implantation of embryos”.  We were early adopters of networking technologies in the early 1990s and developed one of the first fertility support websites, PacificFertilityCenter.com (at that time sfivf.com) in 1993.  My wife was responsible for the early work leading to FertilityWire.com, which continues today as an educational resource for patients.  Ongoing interests in genetics, fertility preservation, and imaging are leading to new developments that we will apply to clinical care in the near future.

Today I am a husband to a remarkable wife and three wonderful girls.  I have many outside interests in skiing, music, bicycling, and aviation.  I was pleased to receive a “Best Doctors in America” award and recognition in “America’s Guide to Top Obstetricians and Gynecologists”. Our entire family went to New York for the American Fertility Association’s Kokopelli Ball, where I received the AFA’s Family Building Award. 

One of my interests includes teaching young doctors that are contemplating their roles in the field, and I was asked to join the faculty at UCSF where I teach these bright young minds.  I am reminded of how unique our profession really is, seeing  it again through their eyes.  Reproductive Medicine has grown much since that first IVF pregnancy and I am proud to be part of its continuance into the future.

-Philip Chenette, M.D.