Title: Everything Conceivable
Subtitle: How Assisted Reproduction is Changing Men, Women and the World
Penguin Books, 2007. 343 pages, with 57 pages of footnotes and references.
By: Liza Mundy

This is a very interesting book about the current state of affairs in the world of assisted reproduction. It is comprehensive in its coverage of almost all the latest technologies and the author has been very thorough in researching the subject. On most topics, there are insightful observations on the societal implications of current technologies. In this regard, it is a thought-provoking book.

In the epilogue, the writer states, “It was my goal to help readers understand why certain changes in the family are taking place and what their likely consequences might be. Why there is so much demand for donor eggs, now. Why there are so many more triplet sets than there once were. What life is like for those triplet parents. How embryo research and embryo politics are influencing our thought on human life and its origins. What is the real, rather than the imagined impact of medicine and science on families and culture.”

I think this would be an excellent resource if one were a health care policy maker or if one were writing a term paper or thesis on the subject but I don’t really think it’s a book to inform the infertility patient about fertility options or what to expect with treatment. It really does not seem to be intended for fertility patients as the target audience.

However, the book does provide a lot of useful information in a somewhat scholarly fashion. Most of the facts are correct, with some of the usual journalistic license.

One of the biggest challenges we face as fertility medicine specialists is how to do more to help our least-likely-to-succeed patients. What I mean here is the 42-and-over age group, patients with high FSH levels (decreased ovarian reserve), patients with very low responses to fertility medications, or those with very poor quality eggs. Some patients have a combination of the above which leads to a really dim prospect of having a baby with their own eggs.

Some people get the impression that fertility clinics avoid these patients like they have a communicable disease. They get the impression that we try to cherry pick patients to keep success rates high and make the CDC stats look good.  My impression from talking to my colleagues across the country and certainly from our own practice is that we do not try to discourage patients with poor possibilities from making a consult appointment and discussing treatment options. We all have such patients. In fact, we have so many of them at PFC, I don’t think we would have many patients at all if we tried to pre-select our best prognosis patients for IVF. When it comes to treatment, although there are challenges and sometimes the rewards are few, we don’t just throw up our hands and give up. We try to come up with a strategy to achieve the goal, looking at the emotional reserves and financial resources we have to work with, and start by making a plan.

Sometimes that plan will be to try a couple of cycles of low-tech approach, like just intrauterine insemination or Clomid + insemination, or a mid-level approach, like injections of FSH along with  insemination. We would see how things go and play it by ear from there. Sometimes, the plan will be to blast ahead to the big guns, full steam ahead to IVF. Sometimes, it’s counseling with our marriage and family therapist to begin the discussion: are we ready to move on to donor eggs? Sometimes it’s a sequence of all of the above. There really is no one plan for any one person. It’s just too complex to say one size fits all.

A certain percentage, even of the-less-likely-to-succeed patients will get pregnant with their own eggs and go on to deliver a healthy baby. The remainder may be faced with a tough decision. Do we just stop here and live child-free?  There are certain perks to that plan (sleeping in on the weekends, eating in nicer restaurants, adult vacations to name just a couple) but most people want to have a family no matter what or how. So then there is the adoption vs. egg donation question. There is no right or wrong choice here, either: just choices.

Progress has been steady at the Center this week. From last Sunday up until this coming Saturday we will do 13 egg retrievals, 14 fresh embryo transfers, 6 frozen embryo transfers and one hysteroscopy. It looks to be a fairly typical week.

Last Saturday I attended an investigators’ meeting, along with our lab director, Dr. Joe Conaghan, for a new clinical research study that we may be undertaking with Gene Security Network (GSN). GSN is one of the pre-implantation genetic diagnosis/screening (PGD/PGS) laboratories with which we work. I really can’t discuss the details of the study at this time, as we have signed a standard non-disclosure agreement with GSN, but this will be a big study to investigate how useful PGS will be to the average IVF patient.

This leads me to the topic of today’s blog: clinical research. Although PFC is not an academic institution, we are still interested in research because this is how the field of reproductive medicine advances. In fact, since there are so many private IVF clinics, much of the research on IVF is currently being done in the private sector. We would not have the field of assisted reproduction today if it were not for clinical research and for the thousands of patients who have participated in this research to this point. I’d like our readers to know that participation in research is not taken lightly by anyone conducting the studies. As investigators, we all have to be trained in the ethical conduct of research, to make sure the risks of participation are minimized and that there is potential benefit to patients from participation. Our number one goal is still to get our patients a healthy pregnancy. We will not compromise that goal for the sake of a clinical study. The study protocols are carefully reviewed by an independent Institutional Review Board (IRB), tasked with ensuring there is no harm or undue coercion to participants. In most good studies, the design of the study includes a “control arm” and the patients who are randomized into this arm receive current standard treatment. The patients randomized to the “treatment arm” receive the treatment under investigation. It is very important that the patients in the treatment arm should be expected to be at least as successful, if not more so, than the patients in the control arm.

This year, PFC is participating in at least 4 clinical studies. Some, like our acupuncture study, are designed by PFC and are only being done at our facility. Some, like the GSN study, are being designed by the company and will be done at multiple IVF centers, then GSN will pool the data.  If you are interested, please let us know. I will be posting more details very soon to our PFC website.

UPDATE: Research web page is live

It’s looking to be another typically busy week at the Center. Although the overall patient volume at PFC in 2009 was down about 10% from 2008, 2008 was a record year, so 2009 was more typical of the volume in the last 10 years. So far in 2010, we are up over this time in 2009. Many clinics in California and around the country are seeing decreased demand for IVF services, likely due to the poor economy. I heard on the radio the other day that the number of vasectomy procedures was up sharply in 2009 as well. A sign of the tough economic times, I suppose.

In 2007, the last year for which U.S. IVF clinics have official results tabulated from mandatory reporting to the CDC, the total number of  fresh IVF cycles performed in 430 reporting clinics was 142,435 resulting in 43,412 live births and 57,569 infants*. It is estimated that in western countries, about 1% of babies born are now from assisted reproductive technologies. Overall, about 36% of embryo transfers resulted in a live birth. This number continues to climb nationwide, at the same time the number of triplets and more is dropping (now at only 1.8% of live births, which is excellent). The twin percentage is still too high at 30% but we hope to also see this number declining in the coming years as overall success rates improve and we continue to emphasize to our patients the  much better outcomes of singleton pregnancy as compared to twin pregnancy.

Delayed childbearing still continues to be the biggest issue for human reproduction and fertility in the post-industrial world. This is especially true in the San Francisco Bay Area. The median age for women doing IVF in the U.S. was less than 35 but at PFC it is age 39. This may partly to do with the fact that in California, insurance coverage for fertility treatment is not mandatory, like it is in some states like Massachusetts and Illinois. Therefore, couples wait longer before availing themselves of the most effective treatment for infertility. This is also why the proportion of women undergoing IVF nationwide diagnosed with decreased ovarian reserve (i.e. diminished egg quality, a diagnosis that tracks with female age) is 10.3% but this diagnosis represents 31% of the patients at PFC.

*2007 Assisted Reproductive Technology Success Rates National Summary and Fertility Clinic Reports U.S. Dept. of Health and Human Services Centers for Disease Control and Prevention www.cdc.gov/ART/

It’s been another busy week at Pacific Fertility Center. Since Monday, we have done 13 egg retrievals, 11 embryo transfer procedures and one hysteroscopy. One thing is certain – our lab is very hard working. I’m really proud of our embryologists. We have 8 embryologists, including 2 PhDs. They are very enthusiastic and never complain about the work load. They put in the hours and virtually never make mistakes. They really are professionals.

Many people wonder why IVF is so expensive. One reason is that, unlike other medical procedures, it’s often not covered by insurance, so patients have to pay out of pocket and that can hurt. If you were undergoing, say, a kidney transplant procedure, with the attendant technological and complicated procedures involved, no one really questions the costs, mainly because medical insurance covers so much of it. Until infertility is seen as a medical condition for which treatment should be universally covered, we are unlikely to see a change in the perception of the high expense. Although IVF does cost about $15-20K for one cycle, with all possible expenses included, the increase in costs over the last 20 years have not risen to anywhere near the extent that other medical services have risen in this time period. This is because we all try to do what we can to be as efficient as possible, mindful of what it costs patients out of their own bank accounts.

Last night, the MDs and PFC managers met for our monthly meeting (usually a 3-4 hour marathon meeting!). We have managers for the following departments: nursing, billing, IT, medical records, the Egg Donor Agency, HR, clinical research and our Laboratory Director. One of the topics under consideration is how we are going to wire the Center to accommodate a large diesel generator we just purchased. We never really use the generator, it’s only there for emergency power losses. Yet we must have a functioning generator to keep the Center running in case of minor power losses, or heaven forbid, the big quake that damages significant infrastructure. We decided last night to go with the “Cadillac” plan for re-wiring, allowing us to run the entire Center for several days off the generator and allowing for flexible allocation of the electricity to some or all areas. The difference in cost was $25K for basic wiring and $39K for the most extensive and flexible arrangement. Along with rent, salaries for 70+ employees, including some very highly educated staff, these are some of the “hidden” expenses that are essential to running a world-class IVF center.

This past summer, I had the opportunity to travel to Amsterdam, Holland for the annual meeting of the European Society for Human Reproduction and Embryology (ESHRE). Though largely attended by Europeans, this scientific meeting draws physicians, embryologists and scientists from around the world to discuss their research, attend courses and lectures, and discuss the latest topics in our field. Although I don’t think this year’s meeting was as quite as good as last year’s ESHRE in Barcelona, there were still some good learning opportunities. Here are some of the highlights of the meeting:

“From Gamete to Heartbeat: The Missing Link”

This was a post-graduate course offered in conjunction with the meeting. The course covered sperm and egg evaluation,

expression of genes in the early embryo and in the endometrium (uterine lining) and some of the latest research into basic embryo implantation mechanisms.

One of the interesting talks was on gene expression in the early embryo. We have come to believe that the differences in pregnancy rates between younger and older women is mainly due to an increase in the number of abnormal chromosomes in embryos from women as they age (such as increased risk for Down Syndrome). However, this only explains part of the differences in successful pregnancy in younger compared to older mothers. New research into expression of proteins from embryonic genes is showing that in both chromosomally normal and abnormal embryos, there are differences in the number and types of genes encoding proteins in younger and older women. This suggests that it is not just changes in the number of chromosomes but subtler differences in the way individual genes are being expressed that affect the developmental competence of their embryos. Determining which genes and proteins are involved, and what the mechanisms are for regulating the expression of these genes in early embryos, will be an area of focused research in the coming years.

“Hyaluronic Acid (HA) favors selection of spermatozoa with intact DNA and normal nucleus, resulting in improvement of embryo quality” (Bologna, Italy)

This presentation (Parmegiani, et al.) looked at the percentage of sperm showing DNA fragmentation based on several methods of sperm preparation for IVF-ICSI (in vitro fertilization with intracellular sperm injection). They compared sperm in the fresh specimen 30 minutes after ejaculation, sperm that had been processed with a standard “swim-up” technique, and sperm that were placed in PVP (polyvinyl propylene), a substance used to slow sperm down so they can be picked up from a culture dish just prior to injection into the eggs. Lastly, they looked at sperm that had been placed into dishes that contain a ring of hyaluronic acid at the bottom of the dish, a substance to which some sperm will automatically bind. They looked at the percentage of sperm showing total or partial fragmentation of the DNA with each of these steps in the sperm preparation process. In the freshly ejaculated sperm, the DNA fragmentation was 16.5% of tested sperm. In the “swim-up” sperm prep, 11% were fragmented and in the PVP-exposed sperm, it was also 11%. Sperm that had bound to hyaluronic acid showed the least amount of fragmentation, at 5.3%.

These findings suggest that using HA binding to select sperm for sperm injection may result in fewer abnormalities in embryos, and possibly higher pregnancy rates. PFC is currently investigating HA binding on our own to see if it is something we would wish to routinely incorporate into IVF. The downside (like everything else!) is that HA plates are expensive.

Stress and Fertility – an enlightening symposium

Jacky Boivin, PhD., a researcher from Cardiff University in Wales, presented some very interesting data about the stresses of infertility treatment. She discussed a new study from Alice Domar’s group in Boston that surveyed why women/couples discontinued IVF treatment before achieving pregnancy (Fertility and Sterility, in press 2009). In this study, 132 women who had insurance coverage for IVF were surveyed. The two main reasons given for dropping out of treatment were the toll that infertility took on the couples’ relationship and being too anxious or depressed to continue. Among the less common reasons for dropping out were medication-related issues (such as difficulty with injections) and feeling the need for a female doctor. Dr. Boivin also discussed results from her own study that was published in the journal Human Reproduction in 2008. In that study, she developed a copingstratagem for women awaiting results of their treatment (i.e. the time between embryo transfer and first beta hCG). It is known that this is a most anxious time for women and the stress of waiting can become overwhelming. She utilized something called the “positive reappraisal coping intervention” card, or “PRCI” card. This is a small printed card that a patient can carry around in his or her pocket and it is meant to be read 2 times per day, every day during the 9-11 days between embryo transfer and first pregnancy test. The card has several little sayings such as: “During this experience I will try …to do something that makes me feel positive” and “During this experience I feel that….I’m energized or I’m creative.” This is a way of programming thoughts towards the positive and away from the negative. She and her colleagues were able to show that patient felt less stressed and felt that the PRCI was helpful during this period.

Currently, at PFC, we have begun a task force to look into ways to better incorporate counseling and tools for stress management for our patients. Please also see this recent Patient Odyssey. Support groups are a wonderful way to diffuse stress and feel more positive.

Corifollitropin: a modification of Follistim to allow a once-a-week injection.

As most people know, the medication we most commonly use for fertility treatment, Follistim, is pure human FSH, manufactured using recombinant DNA technology. The company that makes Follistim, Schering Plough, is working towards FDA approval of a modified version of Follistim, called Corifollitropin, that will make the drug very long-acting.

For those interested in the details; Corifollitropin is the recombinant FSH molecule + 22 C-terminal peptides from betahCG. It does not bind to the LH receptor. This modification lengthens the half-life of Follistim from 22-34 hours to 60-74 hours for Corifollitropin. The recommended regimen will be one dose per week, starting at baseline, then switch to daily recombinant FSH after that. After injection, peak levels are reached in 2 days then they slowly level. It may be possible to only take one injection per week!

A symposium at ESHRE presented information from the ENGAGE trial with data from 14 European and 5 Asian IVF centers, using women with body mass indices (BMIs) between 18 and 32 (generally less than 60 kg -132 lb). The patients were randomized to receive either Corifollitropin or conventional daily recombinant FSH for oocyte recruitment. The number of days of stimulation was the same in both groups (9). The number of eggs retrieved was significantly higher in the Corifollitropin group (13.3) vs. the FSH group (10.6). The rates of ovarian hyperstimulation syndrome were the same in both groups (about 3%). The pregnancy rates were 25% in the Corifollitropin group and 34% in the FSH group, a difference that did not quite reach statistical significance.

Data were also presented on a second study of Corifollitropin from the U.S. and Europe, comparing two doses of the drug. In the study, 100 mcg/dose was given to women less than or equal to 60 kg and women greater than 60 kg were dosed at 150 mcg. Over 1500 patients were included in this large trial. In this study, the average number of eggs recovered was 13.7 for the Corifollitropin group and 12.5 for the Follistim group. The mature egg and fertilization rates were the same. The percentage of good quality embryos was the same.

The clinical pregnancy rate in the Cori group was 38.9% and was 38.1% in the Follistim group. These rates were statistically the same. We expect that Corifollitropin will likely be available in the U.S. in 2010 or 2011.

The article in January’s issue of Fertility Flash, Conception at 40 and Beyond – Does IVF Help? contained some errors in the table. The following is a reprint of the article with corrections.

We all know that fertility declines with female age but what is not certain is how much does in vitro fertilization improve one’s chances of conception if a woman/couple is having problems conceiving on their own?

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

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

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

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

World-wide, over half the babies born from assisted reproduction to women over age 40 are born from ovum donation, not from their own eggs.

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

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

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

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

Another thing to be aware of is that pregnancies after age 43 are exceedingly rare, even with IVF. We encourage most women over age 43 to strongly consider ovum donation.
World-wide, over half the babies born from assisted reproduction to women over age 40 are born from ovum donation, not from their own eggs.

This past summer, Dr. Herbert and I had the opportunity to travel to Barcelona, Spain for the annual meeting of the European Society for Human Reproduction and Embryology (ESHRE). Though largely attended by Europeans, this scientific meeting draws physicians, embryologists and scientists from around the world to discuss their research, attend courses and lectures, and discuss the latest topics in our field.

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

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

Control group: Fresh IVF pregnancies

Only 14% were twins

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

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

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

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

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

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

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

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

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

Results: Avg. # embryos transferred = 2.3

Clinical pregnancy rate = 27.8%

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

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

They experienced no congenital malformations at birth.

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

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

His arguments to support this opinion:

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

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

Corifollitropin: a modification of Follistim to make it a once-a-week injection.

As most people know, the medication we most commonly use for fertility treatment, Follistim, is pure human FSH, manufactured using recombinant DNA technology. The company that makes Follistim, Schering Plough, is working towards FDA approval of a modified version of Follistim, called Corifollitropin, that will make the drug very long-acting. It may be possible to only take one injection per week!

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

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

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

	Carolyn Givens, M.D. was the first in San Francisco to successfully initiate a pregnancy using intracytoplasmic sperm injection (ICSI). She currently co-directs the Bay Area Pre-Implantation Genetic Diagnosis Program (PGD) and is director of PFC’s PGD program.
	Carl Herbert, M.D. was instrumental in the development of one of the first assisted reproductive technology programs in the United States and has been performing IVF longer than any physician in the Bay Area.

Question: A friend of mine recently conceived a couple of months after two failed IVF cycles. Did she really need IVF in the first place or did the IVF change things to make it more likely she would get pregnant on her own later?

Answer: For some couples, IVF is necessary because the woman’s tubes are blocked or because the sperm count is drastically low. For these patients, IVF is probably the only way they are going to conceive. For the rest of our patients, those with endometriosis, mild male factor, decreased ovarian reserve, age-related, or unexplained infertility, there is some chance of conception, however low it is. For these patients, IVF is a way to boost (often dramatically) the chances of conceiving sooner than later.

For example, for a couple that has unexplained infertility of one to two years’ duration, the statistical chances that they are going to conceive on their own are probably in the range of 3% per month. Depending on the woman’s age, IVF could increase that to 20-50% per month of treatment. But even if she doesn’t happen to get pregnant with IVF, and the couple continues to try on their own, their chance of conception returns to that 3% per month, so they may conceive, even after a failed IVF attempt. There is no reason that the IVF itself should make that couple more likely to conceive later.