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.

Successful conception does not just involve eggs and sperm and the reproductive tract. The reproductive system, just as all other areas of human physiology, works best when the entire organism is healthy and balanced. This includes not just physical health, but mental health and sexual health.

With respect to physical health, most of what we should be doing is just common sense. For women, mild to moderate regular exercise is best. Although data on the level of exercise that is optimal for conception is scarce, probably no more than 4 hours per week of aerobic exercise may be best¹. Much higher levels can lead to too low a level of body fat for women (optimal body fat for women should be about 20% of total body weight). Excessively lean women (less than 10%) have more problems with proper reproductive hormonal functioning when it comes to ovulation. And while speculative, it is likely humans evolved mechanisms to limit female reproduction in times of starvation (low body fat may mimic a starvation mode) and when we are too much on the run as well. A study published in 2002 looked for associations between exercise levels and pregnancy and birth outcomes in exercising pregnant women². The study reported that women who exercised heavily during pregnancy had smaller babies, more labor inductions and longer labor and well as more colds and flu than more sedentary pregnant women. These are surprising results! Despite these studies it is likely that some moderate amount of exercise helps to promote a sense of well-being and the mental composure to deal with the stresses of every day life and the stress of dealing with fertility issues. Cardiovascular fitness can only be a good thing for pregnancy and beyond.

For men, there really are no restrictions on physical activity. The one exception would be too much bicycling for men hoping to conceive with their partner. The current bicycle saddles do affect testicular function in men who are frequent riders. In general, maintaining good physical shape enhances sexual functioning and of course, sex is important for conception! Speaking of sex, for men to have optimal sexual health, it is important to avoid excessive alcohol. While alcohol does lower mental inhibitions, it also inhibits erectile function, so excess alcohol, contrary to popular belief, does not enhance the sexual experience. Long term excessive alcohol also causes liver damage and raises estrogen levels in men. Higher estrogen levels can lead to smaller testicular volume and lowered sperm production. There is no problem with an occasional drink – just be aware of how much. Avoid intoxication, dehydration, hangovers, and the other consequences of excessive alcohol intake.

As many of our patients are aware, the experience of trying to conceive, especially if it’s taking a long time, can take a toll on sex and intimacy in a relationship. It is so important for partners to be patient with each other and make the effort to maintain the romance and intimacy which keep the relationship healthy. Yes, plan to have sex on the most fertile days of the month, but don’t stop having it before and after the fertile times as well! There is no medical evidence that sex is harmful during the post-ovulation or early pregnancy period. Try to keep the sex-as-fun-and-special attitude alive throughout the month, including baby-making sex days. If there are stresses associated with this issue, we can provide referrals to psychologists that specialize in counseling about sexual health and are professionals in this area. Remember that our sex lives will outlive the infertility, the new baby and the growing children experiences. So it is crucial to nurture this aspect of the relationship.

There is no question that having a good sexual relationship promotes intimacy and better communication. This is so important when it comes to supporting each other. Fertility problems can be a crisis time in the lives of young adults. Sometimes the crisis situation can bring a couple closer together and sometimes it can cause them to feel isolated, even from each other. Communication is essential. For most women, communication is usually inherently verbal; she wants to talk about it and about her feelings. For most men, dealing with painful feelings, such as that recent negative pregnancy test or that recent miscarriage can be difficult for him to verbalize. Add to this frustration, the obvious sorrow of his female partner and men can feel helpless. It doesn’t necessarily help to try to force people to talk about these feelings, at least until they are ready. Letting him go the gym or shoot some hoops with some friends might be a better way for him to initially deal with bad news. But when the time comes, talking and acknowledging each other’s feelings and understanding how each person deals with difficult situations can make a relationship much stronger.

References:

1. Effects of Lifetime Exercise on the Outcome of In Vitro Fertilization  Morris, Stephanie N.; Missmer, Stacey A.; Cramer, Daniel W.; Powers, R Douglas; McShane, Patricia M.; Hornstein, Mark D.Obstetrics & Gynecology. 108(4):938-945, October 2006.

2  Antpartum, Intrapartum, and Neonatal Significance of Exercise on Healthy, Low-Risk Pregnant Working Women. Maqgtann, Everett F., Evans, Sharon F., Weitz, Beth, Newnham, John. Obstetrics & Gynecology. 99(3):466-472. March 2002.

We all know that people that are not particularly health-conscious can conceive, many times easily or even unintentionally. However, conception is a much more common event when the involved parties are young, and eggs and sperm are much more likely to be genetically normal. It may also be that the reproductive system has not been subjected to years of accumulated age-related, environmental damage. Successful conception does not just involve eggs and sperm and the reproductive tract. Just as in all other areas of human physiology, the reproductive system works best when the entire organism is healthy and balanced. This includes not just physical health, but mental health and sexual health. 

It makes sense that healthy people are more likely to have healthier babies, and this may be especially true in the later reproductive years. For example, a woman in her forties with mild high blood pressure is going to have a safer pregnancy when she keeps her weight down and consistently takes her medications for blood pressure. Similarly, the liver function may be negatively affected by the cumulative effects of drinking alcohol over many years and the liver is crucial to clearing toxins from the body.

The feeling of lack of control is one of the main issues for women and men facing the challenge of infertility. No one can know exactly when they are going to conceive, but for infertility patients undergoing fertility treatments, even the how of conception is being determined by medical factors that again are out of their control. One way to gain back some control is to take charge of our health and nutrition. Eating healthy and living healthy can only help one’s chances for successful conception. Furthermore, when a pregnancy is achieved, the habits set prior to conception and continued during gestation will provide for the best physical environment to nurture the developing fetus. In this issue, we present information about nutritional needs during pre-conception and early pregnancy. The goal of pre-conception nutrition is to promote the health of the gametes (eggs and sperm) and to set the nutritional habits that will carry on into pregnancy and breast feeding.

Certainly the most important component in eggs and sperm is the DNA, which carries the genetic material from the parents to the embryo. DNA molecules are long linear chains of nucleic acids, sugars and proteins. Damage to and degradation of DNA is a consequence of living.  The energy packets in all our body’s cells, including sperm and eggs, are called mitochondria. Mitochondria contain DNA and produce important enzymes for metabolism and energy production. Molecular by-products of metabolism, oxygen free radicals and nitric oxide species, are constantly forming in our bodies .These free radicals can damage both nuclear and mitochondrial DNA. All living organisms have developed many mechanisms to protect their DNA from the environmental damage of excessive nitric oxide and oxygen free radicals. Anti-oxidant nutrients and vitamins are essential to support these protective mechanisms. Truth be told, we all should be ingesting anti-oxidants throughout our lives to protect our DNA and all our tissues from assaults from the outer (and inner) world, but no time is more crucial for the next generation than at conception and fetal development. There are known substances and chemicals in the modern world that can overwhelm our highly evolved physiologic protective processes. Just one well-known example is phthalate ester, a chemical used to soften plastics such as in disposable water bottles, which leaches into the water it contains. These phthalates have been shown to have toxic effects in animal studies on the reproductive system¹ and have been found in urine and breast milk of pregnant and lactating women². Unfortunately, phthalates are only one of many, many chemicals we are exposed to on a regular basis. So, there are substances to avoid, when possible, but can we really avoid every harmful chemical? Not likely. What we can do, beyond avoiding these chemicals,  is make sure we are getting the nutrients, vitamins and minerals that help our own enzymes and proteins to protect our DNA.

There are numerous books on nutrition for pre-pregnancy and pregnancy. It is not possible to cover this topic exhaustively in this series of two articles. Suffice it to say that there is no one diet that has been conclusively shown to promote fertility. It is common sense that nutritionally empty diets, especially those that promote obesity, are clearly harmful to conception. Diets lacking in essential vitamins and minerals can have consequences beyond infertility, such as very poor pregnancy outcomes and malnourished babies. One recent article from the Netherlands² looked at the diets of women undergoing IVF. They measured blood levels and follicular fluid levels of some essential vitamins and minerals in these women. To paraphrase their findings: In women, two dietary patterns were identified. The “health conscious–low processed” dietary pattern was characterized by high intakes of fruits, vegetables, fish, and whole grains and low intakes of snacks, meats, and mayonnaise, and positively correlated with red blood cell folate (β = 0.07). The “Mediterranean” dietary pattern that is, high intakes of vegetable oils, vegetables, fish, and legumes and low intakes of snacks, was positively correlated with red blood cell folate (β = 0.13), and vitamin B6 in blood (β = 0.09) and follicular fluid (β = 0.18). High adherence to the “Mediterranean” diet increased the probability of pregnancy by 40%. Their conclusion was “A preconception “Mediterranean” diet by couples undergoing IVF/ICSI treatment contributes to the success of achieving pregnancy.”

So avoiding environmental toxins and eating a healthy (possibly “Mediterranean”) diet may be helpful for general health, fertility and pregnancy, but what are the specifics? What to avoid? What to include? For some very general guidelines, see the side bar to this article. For more comprehensive help, I recommend the book “Fertility and Conception” but Dr. Karen Trewinnard³, listed in the References. Please also look for PART 2 to this article next month for more nutrition and health advice and information.

References:

SIDEBAR: 

What to Avoid (a much-abbreviated list):

1. Drinking from plastic water bottles.
2. Microwaving food in plastic (and especially stryofoam!) containers
3. Pesticides and herbicides – whenever possible, buy organic, when not possible, wash fruits and vegetables well.
4. Heavy metals such as lead (soldering, stripping old paint from walls), mercury (in high-food chain fish) and cadmium (cigarettes, solder materials, pesticides)
5. White foods: too much white bread, refined sugar, white rice, potatoes 
6. Too much salt and butter, fried foods
7. Caffeine – it’s a blood vessel constrictor
8. Alcohol – more on this next issue.

What to Include (somewhat abbreviated):

1. Olive oil rather than butter
2. Fish that do not contain mercury (e.g. salmon, most shellfish, halibut, flounder)
3. Organically-grown fresh fruit and vegetables
4. Whole grains
5. Omega-3 Fish oils
6. Anti-oxidants such as blueberries, cranberries, tomatoes (lycopene)
7. Pre-natal vitamins containing at least 800 mcg folic acid and 2000 IU of Vitamin D3 (for a more thorough discussion of the essential vitamins and minerals, see the website www.essbeg.com)

Empowering a woman’s choice using fertility preservation

Protecting and preserving fertility is a new way of empowering reproductive choice. The fertility of youth is no longer a limited resource, constrained by age.  Women can now pursue their reproductive lives at their own pace, rather than according to the obligations of biology.  Reproductive choice means having children when you want them, rather than when you must have them.

Fertility preservation, specifically egg freezing, is changing the way we think about building families.  Through fertility preservation, eggs can be stored and saved for use a later. 

The potential of fertility preservation replaces the tick of the biological clock

The tick-tock of the biological clock influenced reproductive choice in the last decades.  The sacrifice of delaying family while assembling a career, home, and relationship worked in an economic sense.  It did not, however, fit well with the designs of biology. 

Eggs work best at a young age, when there are more of them, and they are more vital. The best pregnancy rates occur in women ages 18-30.  With declining egg numbers and egg quality, pregnancy rates are lower in older age groups, while miscarriage rates and chromosome defects become more common.

Biology wastes eggs

The limit of egg quantity and quality is a consequence of our biology. From mid-gestation through menopause, there is a continuous stream of egg follicles that grow to a certain stage and then are lost.  This pool of eggs is never replenished. Each woman is born with a set number of eggs (over a million), and by puberty perhaps 300,000 remain. Ovulation will happen only 500 times in a woman’s reproductive years. and will result in a child less than 1% of the time.  From start (gestation) to finish (menopause), 1 in a million eggs results in a child.  This constant and dynamic process of decline continues through the reproductive years, uninterrupted by birth control pills, pregnancy or ovulation.

Fertility preservation provides the potential for protection against future infertility

Fertility preservation is a relatively simple process.  The first step is for a woman to see her fertility doctor for an ultrasound and physical exam.  On ultrasound the ovaries are measured and the number of follicles determined.  A treatment calendar with a schedule of injectable fertility drugs is initiated.

Using fertility medications for approximately ten days, multiple eggs begin to mature in the ovaries.  Under sedation, the eggs are retrieved, a process that takes about 10-15 minutes.  The eggs are then cryopreserved and placed in frozen storage.

At a later time, the eggs can be thawed, inseminated with sperm (ICSI is recommended), and the embryo(s) created transferred back into the uterus to develop into a pregnancy.

Technology of Fertility Preservation is improving

We are continuing to optimize the outcomes of oocyte cryopreservation.  In a series of women under age 30 where eggs were cryopreserved, egg survival was 88%.  Over half of the eggs fertilized, and two thirds of transfers resulted in pregnancy.  As of January 2011 Pacific Fertility Center has 8 delivered babies from cryopreserved eggs.

The limits of biology continue to constrain outcomes of those eggs that survive.  Not all eggs have the capacity to produce a viable embryo.  This variable is very age dependent.  In a healthy woman under the age of 30, approximately one third of her eggs(33%) are capable of producing a viable embryo.  In women over the age 40, this ratio changes to one in twenty (5%).

Fertility Preservation:  reproductive choice

The message is this:  Fertility is optimal in your youth.  If you have not started your family, you should consider freezing your eggs for use in the future.

-Philip Chenette, M.D.

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

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.

The American Society of Reproductive Medicine Meeting (ASRM) is the major fertility meeting in the United States.  The meeting is held once a year and highlights the latest developments in fertility treatment. This year, several members of the Pacific Fertility team where able to attend the conference in Denver, Colorado.   

The major presentation at the meeting was an update on the FASTT (fast track and standard treatment) trial. This is a study of 500 couples with unexplained infertility in women 39 years of age or younger.  Couples were randomized to either standard treatment or fast track treatment. Standard treatment was 3 cycles of clomiphene/IUI (fertility pills), 3 cycles of FSH/IUI (fertility injections), then in vitro fertilization (IVF). The fast track treatment followed the same protocol, but omitted the FSH/IUI.  Couples in the fast track group achieved pregnancy sooner, with fewer treatment cycles, and at less cost. 

IVF programs, like our program at Pacific Fertility Center, are achieving excellent pregnancy rates by transferring one or two embryos in an IVF procedure.  This fast track approach also reduces the risk of multiple pregnancies by excluding FSH/IUI treatment; a protocol that poses a significant risk of multiples.  Pregnancy rates remained good through the first 3 IVF cycles; 78% of patients became pregnant in the fast track group.  When completed, this study should help couples decide between FSH/IUI treatment and IVF.

Preimplantation genetic diagnosis (PGD) continues to be an active area of research.  PGD has been very effective in helping patients at risk of having a child with a genetic disorder. However, it has been controversial as to whether PGD improves pregnancy rates in couples with infertility and no genetic disorders. Older studies indicated no benefit, but we have come to realize that the older technology was inaccurate and incomplete. The older studies used fluorescent in situ hybridization (FISH) for chromosome testing. In this process, only a portion of the 23 chromosome pairs could be analyzed and the accuracy of the test was very poor.

The latest techniques are now very accurate and complete. New techniques use DNA fingerprinting technology, where all 23 pairs of chromosomes are analyzed. One of the first randomized controlled trials of PGD was presented at this meeting. In this trial, the pregnancy rate was much higher in the treatment group.  Embryos were biopsied on day 5.  This protocol allowed the cells for biopsy to be taken from the trophectoderm, the part of the embryo that develops into the placenta. This technique may prove to be safer for the embryo and decrease the chance of a misdiagnosis due to mosaicism.  However, challenges still remain. The current technology in its most common form requires biopsy on day 5, freezing of all of the embryos, and then thawing normal embryos for transfer after the genetic diagnosis is complete. As the speed of the evaluation improves, biopsy and transfer on day 5 will become more common, and there will be no need to freeze and thaw the embryos.

PFC has been very active in helping women preserve their fertility when facing chemotherapy for breast cancer.  Letrozole is a medication used to help grow eggs and keep estrogen levels low during stimulation in IVF cycles. Women have the option to do an emergency IVF cycle, which allows them to preserve their eggs or embryos and use them after their breast cancer treatment is completed. In a recent study, which proved to be very reassuring, 129 women used this protocol to collect eggs. They were followed for up to 7 years. Relapse rates of breast cancer were compared to a similar group of women who opted not to do IVF prior to chemotherapy. The relapse rate in the IVF group was lower than the group that did not undergo IVF, 2% vs. 25%. The pregnancy rates in the IVF group were very good, resulting in 36% per frozen embryo transfer. Women with breast cancer can be safely offered this protocol when undergoing fertility preservation prior to chemotherapy.

Insulin resistance is common in women with polycystic ovarian disease (PCOD). In these women, the insulin does not work as well, resulting in higher insulin levels to maintain normal blood sugar levels; similar to Type II diabetes.  Metformin is a medication that improves insulin function and has been used to improve pregnancy rates in women with PCOD.

In a recent study, women with 2 previously failed IVF cycles and without PCOD were randomized.  One group went through one cycle of IVF with metformin, and the other group without metformin.  The metformin group had higher pregnancy rates, 33% vs. 2%. Insulin resistance is associated with aging and stress, which are common among women who repeatedly fail with IVF. As a result, metformin may help women without obvious signs of insulin resistance.

Adenomyosis was the topic of another very informative session. Adenomyosis is a benign disorder where the endometrium (the lining of the uterus) grows into the muscle of the uterus. It may be the single most common undiagnosed gynecological condition and the most common cause of gynecological pain. Adenomyosis may be a normal part of uterine aging.  Adenomyosis is commonly associated with fibroids and endometriosis, and is more common in women who have already had a pregnancy. The most common symptoms are: heavy menses, painful menses, pelvic tenderness, and infertility.  In the past, an MRI scan was needed to make the diagnosis. However, new studies show an ultrasound is just as accurate, both sensitivity and specificity, as MRI. Adenomyosis can be found in up to 25% of infertile women. The role of adenomyosis in causing infertility remains controversial. However, current studies indicate large areas of adenomyosis and adenomyosis near the endometrium can decrease fertility.  Now that an ultrasound can be  used more commonly and can accurately diagnosis adenomyosis, the impact of adenomyosis on fertility will be better defined.

Attending this annual meeting of professionals in the field of reproductive technology is always informative. We look forward to meeting with colleagues from around the country and sharing the latest research. Several of the research projects currently in progress at PFC were discussed at this meeting.

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.

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.”