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

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.

This past July, I had the opportunity to attend the 23^rd Annual In Vitro Fertilization and Embryo Transfer meeting in Santa Barbara, CA. This is an IVF meeting sponsored by UCLA.  It’s hard to believe that a meeting devoted solely to IVF has been presented annually for 23 years now.  I used to think of IVF as a brand new field, but it really has matured as a specialized area of medicine. This meeting is not considered a scientific meeting because it has more of a lecture/didactic course format rather than one of   presentations of new research by physicians and scientists.  However, this meeting is devoted to bringing various experts together with clinicians providing IVF care to discuss the latest theories and clinical practices. I had not attended this meeting in several years as it had not appeared to present much new information.  However, this years’ meeting was surprisingly thoughtful and relevant.

While not the sole focus of the lectures, a definite theme running through the meeting addressed the current interest in the fundamental health of sperm and eggs. There were several talks covering the data (or lack thereof) of stress and our modern chemical-laden environment on reproduction. There was some discussion of the role anti-oxidants and other nutritional supplements play in reproduction. Dr. David Meldrum from Southern California and Dr. Peter Schlegel from Cornell Medical Center touched on whether or not anti-oxidants may be useful in improving eggs and sperm, respectively. The preliminary data is intriguing, but much further study will likely be needed. However, because anti-oxidant nutritional substance show so many benefits in other aspects of human bodily function, there is hope they will also be shown to be beneficial for reproduction.

Dr. Sarah Berga, Professor and Chairman of the Obstetrics and Gynecology Department at Emory University Medical Center in Atlanta, gave several excellent talks. Dr. Berga’s area of research interest is in the effect of stress and diet on reproduction. She is a thinker and applies scientific evidence to the theories of hormones and stress. She is an excellent speaker and has always been an open, accessible and friendly colleague of mine.

One of Dr. Berga’s talks focused on the topic of “What is Stress?” She defined two aspects of stress: metabolic stress and psychogenic stress. These two different aspects of stress result in the same pathologic process potentially leading to impaired reproduction. She discussed psychological stress that emanates from a sense of the “lack of control” that many of us, but especially individuals suffering from infertility, feel when faced with this challenge. In some individuals, there may be overly high personal expectation of oneself and of others, which contributes to a sense of failure. With regards to physiologic or metabolic stress, a harmful result of stress may be hypothyroidism. That is, decreased levels of thyroxine (thyroid hormone) may be a result of psychological stress, leading to metabolic stress, and in severe cases can contribute further to infertility and increased risks of miscarriage. In turn, it becomes the quintessential vicious cycle. With regards to diet, normal and healthy caloric intake can lower cortisol levels, which is good. Cortisol, an important adrenal hormone produced in response to stress, also shortens telomeres – the pieces of DNA on the ends of chromosomes that protect our chromosomes from damage and slows the aging process. Dietary caloric restriction and an over-energized metabolism can result in a person becoming significantly underweight.   Potentially, this could further raise cortisol levels and, in women, may contribute to lack of ovulation and infertility. Thyroid hormone levels drop, trying to slow down metabolism and hang on to calories. Furthermore, for the pregnant woman, the only source of thyroid hormone for the baby comes from the mother, and hypothyroidism in pregnancy is a serious challenge for the developing fetus. Thus far, other than thyroid hormone replacement (a band-aid for the problem), a potential solution is to attempt to break this cycle. Cognitive Behavioral Therapy (CBT) and techniques such as conscious relaxation (Mind-Body training) have shown promise in reversing these trends.

Another interesting speaker at the conference was Dr. Douglas Carrell, PhD, Associate Professor of Surgery (Urology), Obstetrics and Gynecology, and Physiology, University of Utah School of Medicine. One of his talks concerned how to locate the best sperm to inseminate eggs at the time of IVF, especially in men with male factor infertility, but potentially for all men. He spoke about various tests that some scientists currently advocate for determining whether a man’s sperm is capable of producing healthy embryos and healthy babies, such as DNA fragmentation assays. His bottom line take on this is that no one test on one sperm sample is likely to predict that all sperm are bad all the time. He also addressed an area that has interested us at Pacific Fertility Center: Hyaluronic Acid (HA) binding test and the Annexin separation sperm quality test. The HA binding test uses the phenomenon of good sperm binding to hyaluron prior to selecting that sperm for egg injection (ICSI). The Annexin separation test uses a similar substance to select out sperm that are apoptotic (DNA heavily damaged). While intriguing, neither test has yet been put to a definitive randomized controlled-trial, which would be needed to show improvement in pregnancy rates.

These are just a few of the many topics covered at this very interesting and thought-provoking meeting. I am fortunate to be a part of a fertility center that believes in the value of attending and participating in meetings that allow us to share ideas and concepts.  This sharing of ideas will no doubt lead to the further understanding and treatment of problems in human reproduction.

-Carolyn Givens, M.D.

Every year thousands of families are created with the assistance of in-vitro fertilization. Many of those newborns are twins. While some may see this as a double blessing, it is important to understand that there are many potential risks associated with multiple gestation. Statistics show that a higher percentage of twins are born prematurely compared to singleton pregnancies. Premature birth can cause complications resulting in physical impairment, learning disabilities, and even death. In addition to the increased risk to the children born from a multiple pregnancy, there is also an increased risk for the pregnant woman of complications associated with carrying multiples.

Pacific Fertility Center (PFC) has been taking steps to minimize the risk of multiple gestation for several years. “We have worked actively to increase pregnancy rates and decrease the number of multiples,” comments Carolyn Givens, M.D. “Balancing high pregnancy rates with low pregnancy risk improves pregnancy outcomes. Our goal is to achieve this balance and reduce the risk of multiple gestation.”

PFC recently completed the analysis of our Elective Single Embryo Transfer (eSET) program for 2009. The twin rate was significantly lower, and, triplets were eliminated entirely. 79 patients underwent an embryo transfer procedure where they elected to transfer only one embryo created from their own eggs; these 79 transfers resulted in 38 pregnancies, two of which were identical twin pregnancies (the embryo split from one into two) and NO triplets. Compare this statistic to patients choosing to transfer two embryos: 159 patients, with embryos derived from their own eggs, transferred two embryos resulting in 80 pregnancies, of which 31% were non-identical twins and two triplet pregnancies (again from one of the embryos splitting).

Patients that choose eSET have excellent pregnancy rates with a single embryo. eSET embryos are grown for 5 days in the lab to the blastocyst stage, which allows for selection of the healthiest embryos for transfer. The transfer of fewer embryos provides for the healthiest outcomes; eSET produces high pregnancy rates while minimizing the risk of multiple pregnancy. “For many patients, there is no advantage to transferring more than one embryo. It is all about educating our patients. Given this information, these numbers and the potential risks of twin pregnancies, many will choose to transfer only one embryo,” says Carolyn Givens, M.D.

At PFC, careful consideration is given to the number of embryos transferred to each patient. Our goal is to create healthy singleton pregnancies. Utilizing advanced embryo culture techniques, the highest quality embryos can be selected for transfer. Special environmental conditions, advanced culture media, and the delicate handling of gametes and embryos is required; these efforts result in better embryos, with higher implantation and pregnancy rates.

In addition, PFC has developed an outstanding and robust program for freezing embryos not transferred in the fresh cycle. Using a technology called vitrification, we have been able to achieve pregnancy rates with frozen embryos that are very similar to those using fresh embryos. “The outstanding success of our freezing program has allowed us to be confident in transferring just one embryo at a time, which all but eliminates the risk of triplets or higher pregnancy,” says Dr. Joe Conaghan, PFC Lab Director. He adds, “We have been so successful with embryo freezing over the last 3 years that our embryologists are in high demand to provide training across the country and around the world. Our goal is to help our patients overcome infertility and build their family; one healthy baby at a time.”

Endometriosis was a puzzling disease when first described by pathologist Rokitansky in 1860. Though we now have a clearer understanding of some aspects of the biology of this disease, it still remains largely a mystery 150 years later.

Endometriosis affects about 5 million women in the U.S. Of women with infertility, approximately 25% are diagnosed with endometriosis. The symptoms fall into two categories: 1) pelvic pain, most significantly with menses, and 2) infertility. The definitive method to diagnose this disease is surgery. A laparoscopy is performed to obtain tissue biopsies of typical peritoneal lesions (peritoneum is the internal layer overlaying pelvic organs including the uterus, fallopian tubes and ovaries); and confirm the presence of endometrial glands in those biopsies. The American Fertility Society has created a classification scheme which grades the disease (Grade I-IV). It is important to understand that there is not necessarily a correlation between pelvic pain and the severity (or grade) of the disease. Another method for presumptively diagnosing endometriosis is with ultrasound, if the patient has endometriosis ovarian cysts (endometriomas), or with MRI if one there is endometriosis growth in the
uterine muscle layer (adenomyosis).

A diagnosis of even minimal to mild endometriosis (stage I and II) can have significant consequences on fertility success rates. A fertile 30 year old woman has about a 25% chance of pregnancy per month (fecundity rate). A patient diagnosed with minimal to mild endometriosis has about a 3% monthly fecundity rate (1, 2, 3). If surgery is performed to dissect and remove the visible endometriosis lesions, the fecundity rate improves to 6%; but this is still much lower than the 25% afforded a fertile 30 year old. If that same patient undergoes ovarian stimulation and insemination cycles, her monthly fecundity rate increases to 11% (4). If the combination of ovarian stimulation/IUI treatment is going to increase chances of pregnancy, results are usually seen within the first 3-4 treatment cycles. Undergoing additional IUI cycles is not typically beneficial, and proceeding to in-vitro fertilization (IVF) treatment would be the next step. For patients with severe endometriosis, gonadotropin/IUI therapy is of minimal assistance. Most patients with moderate to severe endometriosis (stage III and IV) will need to pursue IVF therapy (5).

IVF studies from the 80s and 90s indicate that patients with endometriosis have a slightly lower chance of achieving a pregnancy than patients with other infertility diagnoses (6). With current IVF laboratory techniques and current ovarian stimulation strategies, this difference will probably disappear—but up-to-date studies are needed as proof. When assessing if the lower pregnancy rate is because of a uterine or ovarian issue, it appears that the uterus of endometriosis patients is effective in providing a supportive environment for the embryo to attach (7). However, the oocytes (eggs) from endometriosis patients, particularly those with endometriomas, seem to have some compromised quality (8). This lower egg quality seems to lead to less healthy and effective embryos, and therefore overall lower pregnancy rates.

We clearly understand that strategies of suppressing endometriosis growth by using medications such as birth control pills, Danazol, Lupron or others, does not lead to improved pregnancy rates (9). The concept of a fertility “rebound” post-medical suppression has been proven false over-and-over again. These strategies only lose potentially precious time for the patient. Similar strategies of using medical suppression post surgical removal of endometriosis also fail to improve fecundity rates. The best approach is to move forward with an appropriate form of fertility treatment as soon as the patient desires fertility.

How to treat endometriomas has been debated, but we now have some studies to guide us. Collectively these studies indicate that patients who have undergone surgery for their endmetrioma(s) have the same IVF outcomes as those where the endometrioma(s) was left alone (10). We feel that the patient’s current clinical situation should be scrutinized carefully before recommending ovarian surgery for a patient who is seeking fertility. With surgical removal of an endometioma (ovarian cystectomy), we know that the ovary where surgery is performed will have fewer eggs and less normal ovarian tissue post surgery (11). This implies that we will have a lower chance of gathering eggs in an IVF cycle. Additionally, the patient will have a greater chance of having an elevated FSH after a cystectomy procedure, especially if she undergoes cystectomies of both ovaries (11). The risk of premature ovarian failure (POF or premature menopause) for a patient undergoing cystectomies of both ovaries for endometriomas is about 2% (12).

Historically the strategy for treating endometriosis has been to surgically remove or hormonally suppress its growth with various medications. As we better understand the biology of this disease, we can use more targeted therapies which interrupt the biochemical pathways that promote the growth of endometriosis lesions: aromatase inhibitors, estrogen and progesterone receptor blockers, angiogenesis inhibitors, etc. All of these types of medications are being studied in endometriosis patients. The future may hold some promising new medical options.

In summary, endometriosis clearly affects fecundity rates, even with minimal and mild disease. Using hormonal medications to suppress endometriosis provides no improvement in pregnancy rates, and surgical intervention provides minimal improvement. Most patients will need to pursue fertility treatment. For patients with moderate to severe disease, they most often will need to pursue IVF. For patients with endometriomas, careful consideration has to be given to all factors (age, assessment of egg quality, prior fertility treatment, etc.). The patient needs to be fully counseled prior to surgery, including risk of diminished ovarian quality (DOR) and premature menopause (POF). Patients with adenomyosis seem to have impaired implantation rates, and those with severe adenomyosis may need to consider a gestational carrier. Having a clear understanding of endometriosis as it impacts fertility, and having realistic expectations with each treatment type is most important when choosing fertility treatment options.

– Isabelle Ryan, M.D.

References

1. Jansen RP, Fertil Steril 1986; 46:141-3
2. Marcoux et al, NEJM 1997; Jul 24; 337(4):269-70
3. Parazzini, Hum Reprod 1999; 14(5):1332-4
4. Tummon et al, Fertil Streil 1997; 68(1):8-12
5. Dmowsky et al, Fertil Steril 78:750 2002
6. Barnhart et al, Fertil Steril 2002; 77:1148-1155
7. Diaz et al, Fertil Steril 2000; 74:31-34
8. Simon et al, Hum Reprod 1994; 9, 725-9
9. Hughes et al, Cochrane Database Syst Rev 2007; 3:CD000155
10. Tsoumpou et al, Fertil Steril 2009; 92, 75-87
11. Li et al, Fertil Steril 2009; 92(4):1428-35
12. Busacca et al, Obstet Gynecol 2006; (195), 4

UPDATE: This study is currently on hold while we attend to some administrative details. Please check back to this blog often, as we will keep our readers updated.  You may also call the New Patient Coordinators at 415 834-3095 for more information.

PREVIOUSLY: Pacific Fertility Center is pleased to announce that as of October 1st we are enrolling patients into a groundbreaking research study to determine the value of combining acupuncture with IVF. Traditional

Chinese medicine has been practiced in throughout Asia for thousands of years:in the last decade, the west has been following suit.

There have been sufficient peer reviewed studies to warrant a clinical trial in which there are predictable parameters of patient involvement. One of the first studies involving acupuncture and IVF was published by Paulus et al in the journal Fertility Sterility in 2002. The Paulus study reported the influence of acupuncture on the pregnancy rate in patients who undergo assisted reproductive therapy. Clinical pregnancies were documented at 42.5% of patients in the acupuncture/IVF group, whereas pregnancy rates were 26.3% in the control group, using IVF alone. In this study, the acupuncture was performed before and after embryo transfer only.

How does acupuncture affect fertility? A review article in Alternative Therapies (Anderson 2007) suggested four possible mechanisms by which acupuncture could improve the outcome of IVF: modulatingneuroendocrine factors; increasing blood flow to the uterus and ovaries; modulating cytokines; and reducing stress, anxiety, and depression.

Stillbirth, loss of a baby at delivery, is a painful challenge.  The suffering associated with the loss of a child, even before birth, can be overwhelming.  Especially acute for women that have conceived utilizing assisted reproduction, the loss of a pregnancy fought through reproductive technology can overwhelm a couple.  Stillbirth is a rare risk of pregnancy; the challenge facing us as reproductive medicine experts and obstetricians is how to reduce that risk.

The technologies of in vitro fertilization (IVF) and intracytoplasmic sperm injection (ICSI) have enabled pregnancy for thousands of families with sperm, egg, and uterine problems.  With IVF, egg quality can be optimized using fertility drugs to produce more eggs.  Blocked fallopian tubes can be bypassed.  Weak sperm can achieve pregnancy by ICSI, where, using a microscopic needle, the sperm cell can be introduced into the egg.

No-one should expect these techniques to be foolproof.  While mechanical problems can be improved, other weaknesses in the reproductive system cannot.  Small deviations in the genetic code of the sperm or egg, missing chromosomes, aging, uterine defects, etc cannot be fixed by treating the sperm cell or embryo.

Thus the problem – these pregnancies established by high technology, are at higher risk.

A recent study from Denmark looked at stillbirth in children born after IVF/ICSI  and found that the risk was higher in children born after IVF/ICSI than natural pregnancy.  Out of 16,525 births to fertile women the chance of stillbirth was 0.37%, that is, 3.7 out of 1000 births.  Out of 742 babies born to women after IVF/ICSI there were 12 stillbirths, 1.62%, that is 16.2 out of 1000 births.

But more importantly to our patients, the liveborn baby rate after a successful IVF/ICSI treatment  and pregnancy is 98.4%.  The liveborn baby rate after a successful natural conception and pregnancy is 99.6%.  Almost all of the successful pregnancies after IVF/ICSI are liveborn.

Reproductive technologies, like IVF and ICSI, are enabling pregnancy and family building where it was not possible before.  All of our patients must be informed of and recognize the risks associated with fertility treatment.  These risks should not, however, dissuade anyone from considering these therapies.  On the contrary, the overwhelming likelihood is that, once a pregnancy is established, it will progress successfully to delivery and a healthy child.

We need to recognize these risks to provide help understand and take measures to reduce the risks to all children.  We will continue to watch these studies carefully in our ongoing effort to assure our patients of excellent pregnancy rates, at low risk.

Footnote:

1. K. Wisborg, H.J. Ingerslev, and T.B. Henriksen  IVF and stillbirth: a prospective follow-up study  Hum. Reprod. Advance Access published on February 23, 2010.

By the end of the year we will have started a new and very exciting research project in our lab. We have partnered with a company called Incept Biosystems (www.inceptbio.com) to do a clinical trial of a new embryo culture system called microfluidics.

The traditional culture dish with medium droplets under oil as described by Brinster, R.L., 1963, Exp. Cell Res., Vol. 32

This involves culturing embryos in very small volumes of culture media inside a chip specifically designed for this purpose. Tiny pumps regulate the flow of culture medium in and out of the chip without causing the embryos to move around.

The traditional vessel for embryo culture is the petri dish, where small droplets of culture medium are overlain with a highly purified mineral oil. The culture medium, regulated in much the same way as pharmaceuticals, is one of the most highly tested and expensive components of the IVF laboratory operation. We typically make droplets of medium that are in the 50-200µl size range, and the oocytes or embryos are placed in the droplets for 24-48 hours at a time. This is a static culture system where nutrients are depleted by the developing embryos and waste products (e.g. ammonia from amino acid breakdown) accumulate over time. The droplets are large enough to make sure that the supply of nutrients is more than adequate and that waste is diluted to the point of not harming the embryo in any way. The embryos are changed into fresh medium at least every 48 hours.

This system for embryo culture has been in use since human IVF began in the late 1970′s and early 1980′s. It was actually developed in the early 1960′s by a pioneer of mouse embryo culture, Dr Ralph Brinster, at the University of Pennsylvania. Some early human embryologists cultured embryos in small test tubes without the mineral oil, but nowadays, despite the age of this technique, it is very unusual to find a facility that does not use the droplets under oil method. After 45 years, perhaps it is time for a change?

A microfluidic system for embryo culture has been in development for over 5 years at the University of Michigan in Ann Arbor. Professor Gary Smith combined the talents of his graduate students in physiology with those of engineering students and came up with a device that has had outstanding results with growing mouse embryos. Professor Smith is no stranger to IVF, as he was the director of the University’s IVF Laboratory for many years and he was instrumental in designing and testing the vitrification system that we now use to preserve oocytes and embryos. He solicited venture capital to start Incept Biosystems with the intent to bring microfluidics into human IVF labs. Incept Biosystems were onsite at PFC during the last week of October to train our embryologists on the use of the system. We did several trials with mouse embryos to achieve proficiency with the system and then we will actively recruit patients to enroll in a clinical trial using the system.

The clinical trials are being run at 3 centers in the US. In addition to PFC, patients will participate at the Fertility Center of San Antonio and at Southeastern Fertility Center in Charleston, South Carolina.

A schematic of a microfluidic embryo culture device with fresh medium in blue and spent medium in red. The embryo is contained at the base of the chamber, where the blue medium ends.

Patients that are asked to participate will have to consent to the study, where their embryos will be divided into 2 groups for culture in the microfluidic device and in the traditional petri dish. The culture media will be the same for all the embryos, but half will be in a replenishing media current (microfluidics) and half will be in our traditional static culture.

Microfluidics has had impressive results with mouse embryos where it significantly increased rates of development and implantation over those for embryos grown in static culture. Cell numbers for the microfluidic embryos were almost twice as high as for traditional culture (110 vs. 65), and pregnancy rates from transferred embryos were increased by 22%. Incept Biosystems have tested the new technology extensively and have been able to obtain surplus IVF embryos donated for research for human trials. There are some nice videos on their website that showcase the equipment and procedure, and detail the mouse embryo results. Professor Smith presented the results and won the prize paper at the 2008 American Society for Reproductive Medicine (ASRM) meeting (Smith et al., 2008, Fertility and Sterility, Vol 90, pages S1-S2), and these results will soon be published in a peer reviewed journal.

We will be asking for participants to join the study, beginning in November and continuing for 2-3 months. This is a short study requiring enrollment of only 20 patients, but a larger study is planned for next year subject to favorable outcomes here. If you are interested in the study and would like more information, please ask your physician at your next visit.

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