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.

An Example X-Ray of a normal HSG	An example X-Ray of an abnormal HSG

Infertility due to blocked fallopian tubes was a common cause of infertility in the 1970’s and 1980’s. Some textbooks from that era quote an incidence as high as 25% of all infertility causes. At Pacific Fertility Center in 2005, only 10% of our in vitro fertilization patients were noted to have a tubal factor contributing to their infertility. Fallopian tube damage is most commonly due to prior infection with a sexually transmitted disease such as gonorrhea or Chlamydia. Most chlamydial pelvic infections are relatively asymptomatic and may go unrecognized; therefore many patients with tubal obstruction are unaware they have a tubal problem. Better safe-sex practices and improved screening of young women are possible factors for the lower incidence of tubal disease we are seeing, at least in our Bay Area infertility population.

Even though there is less tubal factor infertility these days, if there is a tubal obstruction, the course of fertility treatment becomes quite definitive: in vitro fertilization. No other treatments, including surgery, are likely to result in a healthy intra-uterine pregnancy. Therefore, we are still advocating some type of screening test for tubal factor in the evaluation of infertile couples.

There are two common ways to determine whether there is tubal obstruction. One is surgery, where dye is passed through the cervix, uterus and tubes, and there is direct visualization of the flow of the dye out the ends of the tubes into the pelvis. The other is the HSG, or hysterosalpingogram. The HSG is an X-ray procedure that involves placing into the cervix a small flexible catheter with a balloon around the tip to hold the catheter in place and close off the cervical opening. Radiographic contrast dye is then instilled into the uterine cavity, using a syringe attached to the tube. Under X-ray visualization, the dye is tracked into the uterine cavity and into the tubes. Pictures are taken during this process to document the shape of the uterine cavity and whether or not the dye enters and flows through both tubes into the pelvis.

HSG procedures are usually performed by radiologists; however, if there is difficulty placing the catheter securely into the cervix, the radiologist may ask the patient’s gynecologist to assist. This test is valuable in determining tubal blockages, but it has some disadvantages. It is very important to get the balloon properly inflated in the cervix to keep enough pressure on the fluid (no back flow into the vagina) so it will enter the fallopian tubes. Unfortunately, this pressure on the walls of the uterus can cause the uterus to contract, causing the patient to experience significant cramping. For this reason, it is recommended the patient take 2 or 3 ibuprofen prior to the procedure.

In some cases, the pressure is enough to cause the smooth muscle walls of the fallopian tubes themselves to spasm, blocking any dye from entering the tube. Sometimes the dye flows so easily through one tube that there is not enough pressure generated to get the dye to fill the other tube. These are some of the drawbacks of the procedure. This is why, even when we get a report of one-sided tubal obstruction, we are often skeptical that this is really due to some abnormality of the tube.

Although there are some false positives associated with this test, if the dye fills both tubes and does not flow out the ends of the tubes, this is highly suggestive of true tubal obstruction. In this instance, IVF is indicated.

1. A healthy woman in her late 30’s or even in her 40’s, will have the fertility of a younger woman.
   Although it is always better to be healthy, especially when it comes to carrying a pregnancy, the likelihood of conception is tied to the age of a woman’s eggs and is not closely related to her general health.
2. You should have sex every other day during the fertile window.
   For most men, sperm recovery is very rapid. Sometimes when an IVF cycle is done and there are many eggs to fertilize, we ask for a second semen sample. We are often amazed when the second sample, collected just 2 hours after the first sample, has even better numbers. So, rather than attempting to “save up good sperm” by having less frequent intercourse during the most fertile time period, we recommend more frequent intercourse. A home ovulation predictor kit is useful to time sex to ovulation. When using the ovulation predictor kit, we recommend sex on the first day of the LH surge and the next day too.
3. Fertility medications are associated with a higher risk of cancer.
   In the early 1990’s, some concerns were raised that taking fertility medications might be associated with a higher lifetime risk of ovarian cancer. Since then, several studies have been published that did not find this to be true. Because of this thorough and extensive research we feel comfortable using these medications not only on patients, but our egg donors as well.
4. Fertility medications (especially injectable fertility medications) cause women to be emotional wrecks.
   Although Clomid (clomiphene citrate) has well-known side effects related to its anti-estrogen effects, the injectable fertility medications do not tend to cause the same negative mood alterations. These drugs increase estrogen levels, a hormone which tends to have positive affects on mood.
5. Using fertility drugs and getting multiple eggs might use up my future eggs and cause me to go into menopause earlier than expected.
   Humans usually only ovulate one mature egg each month. This egg is contained in the dominant follicle and grows in one ovary or the other. For each dominant follicle that develops in any particular cycle, there are several other follicles/potential eggs available that are also trying to become that dominant follicle. The number of these other “antral” follicles varies from woman to woman and to lesser degree, from cycle to cycle. In general, the number of antral follicles declines with female age. Once the dominant follicle has been selected and the egg ovulated, the menstrual period or a pregnancy begin, and the other antral follicles, undergo programmed cell death, called atresia. The use of fertility medications rescues this group of antral follicles from atresia. For this reason creating multiple mature follicles and obtaining multiple eggs in any one cycle does not use up future eggs. We are simply rescuing eggs that would have otherwise died that month.
6. Having a miscarriage is a good sign that a woman is fertile.
   Approximately 70% of miscarriages are due to abnormal chromosomes (DNA) in the embryo. As a woman ages, more and more of her eggs become abnormal In fact, at age 40, only 1 in 10 eggs on average has normal chromosomes; so a woman at that age may only ovulate one normal egg per year. While a miscarriage may indicate that fertilization and implantation can occur, it doesn’t necessarily mean that overall egg quality is good. Egg quality is the best indicator of the ability to produce a viable pregnancy.
7. Stress is a major cause of infertility.
   There is enough circumstantial evidence to indict stress as a collaborator when it comes to fertility; however, there is very little evidence to convict stress as a major perpetrator. Usually there is some other underlying cause to the problem, even if it is just age-related sub-fertility (decline in fertility due to female age and therefore higher numbers of abnormal eggs). Stress, however, can compound the problem and possibly negatively impact egg quality and uterine lining quality. Look for a new addition to our website, the Domar Fertility Stress Questionnaire, to assess your stress levels.
8. In Vitro Fertilization can help women in their late 40’s and even 50’s to conceive with their own eggs.
   Despite the number of celebrities having babies in their mid-forties and beyond, these babies may not necessarily have been the result of an in vitro fertilization process using their own eggs. While we respect a woman’s right to privacy and their decision not to divulge this little detail, the perception left with the public is that fertility treatments can extend one’s reproductive life. Unfortunately, this simply is not true. There is a very, very low probability of improving one’s success of conceiving after age 43 by using assisted reproduction, unless the woman considers using donor eggs.
9. In Vitro Fertilization success rates are low.
   Across the United States, including patients of all ages, the delivered success rates for in vitro fertilization have risen from about 20% in the mid-1990s to about 35% in the mid-2000s. During this same period, fewer embryos were being transferred to the uterus per cycle and the triplet and higher-multiple pregnancy rates dropped dramatically. Though it may take more than one attempt to conceive, the majority of patients are successful.
10. Very few people ever experience infertility.
    Many fertility patients feel they are the only ones in their circle of friends and acquaintances suffering from infertility. At times, it seems as though everyone else is having a baby. Actually, one in six couples is having trouble with conception, they just may not talk about it. Since they are not pushing a stroller, there is no outward visible sign of their fertility status. When couples decide to share the story of their fertility quest, they often find there are many of their peers experiencing similar difficulties. They discover friends who can not only relate but also provide valuable support.

For many people, the dream of having a family also includes the dream of having children of both sex. Since most families today are much smaller than in generations past, the odds of having two or three or even four children of the same sex is fairly high.

Throughout human history, there always has been interest in methods to sway the chances of conceiving a child of a particular sex. Today, in the 21 st century, it is quite clear that many of these sometimes bizarre and sometimes simple home remedies have no basis in fact.

There are ways to significantly shift the odds of having a child of one sex or another. Sex is conferred on an embryo by whether an X-bearing sperm (for a girl) or a Y-bearing sperm (for a boy) enters the egg. Unfortunately, despite highly publicized claims, there are no proven effective “at home” methods of sperm separation. Nor does timing of intercourse relative to ovulation affect the 50:50 sex ratio. By natural methods, the ratio remains a flip of the coin.

The only commercially available method for sperm separation that appears to be effective is the sperm sorting process available through Microsort.net. This method involves using a fluorescent DNA dye that attaches to either X or Y chromosomes. The sperm then passes through a cell sorter that separates the sperm based on the fluorescence. This method is still under FDA investigation for safety and efficacy but does appear to do a reasonable job in separating sperm, especially if the desired sex is female.

Mirosort reports a 90% success rate with separating X-bearing sperm and a 73% success rate in separating Y-bearing sperm. There have been only a few hundred babies born thus far, but there does not appear to be any increase in birth defects. Because this process is still considered “experimental,” couples wishing to participate, will have to travel to either Fairfax, Virginia (Microsort headquarters) or an affiliated clinic in Southern California for fresh sperm insemination.

Unfortunately, after Microsort processing, the number of sperm available for insemination is severely decreased. Freezing and thawing of sperm, which would allow the sample to be shipped to another location, reduces these numbers even further. Because sperm counts are so low after sorting, it is usually necessary to do in vitro fertilization with sperm injection (IVF-ICSI) to significantly improve the fertilization in the IVF laboratory. PFC is a participating site in the FDA investigation for Microsort. We have used sperm specimens that had been previously Micro-sorted for IVF-ICSI.

Researchers at UC Irvine recently published a study describing the use of lasers to “trap” the heavier and slower moving X-bearing sperm to separate it from the lighter Y-bearing sperm. In the future, this process may provide an alternative to Microsort. However, it is not yet commercially available.

Beyond the Microsort technique, the only way to improve the odds of selecting one sex over another at close to 100% accuracy is to undergo Pre-Implantation Genetic Screening (PGS). PGS uses a DNA-binding technique to determine if there are a correct number of chromosomes in the embryo at the time of IVF. To complete this screening, embryos on Day 3 of culture (5-10 cells) undergo a biopsy to remove a single cell. The rest of the embryo remains in culture in the IVF laboratory. The removed cells are analyzed for the correct number of chromosomes. Currently, PFC with its cytogenetic partner, Genetics and IVF Institue screen embryos for 3-12 chromosomes. This screening is called “aneuploidy screening.” We allow our patients to know and select the sex of their normal embryos for transfer if they so wish.

Although IVF with PGS is the most effective method for sex selection, it is certainly the most expensive and there is no absolute guarantee that the transfer of the screened embryos will result in pregnancy. A PFC physician can best discuss the odds of success, based on the woman’s age and the couple’s history of childbirth.

Many couples undergoing PGS are doing so to screen for specific genetic defects or are specifically undergoing sex selection because of their risks of having a genetic disease that only affects males (X-linked diseases).

On the other hand, PGS for elective sex selection, either for “family balancing” or even for having a first child of a particular sex poses difficult ethical issues. Just because we have the ability to choose the sex of a child, should we? What will the couple do with normal embryos of the undesired sex? At PFC, we do not encourage PGS for elective sex selection. However, if a couple is undergoing IVF and wishes to undergo aneuploidy screening, we do allow them to select to transfer embryos by sex. We encourage all patients to consider donating excess embryos of the undesired sex for adoption by other couples.

Women or couples interested in this procedure should discuss it with their Reproductive Endocrinologist. At PFC, we also refer our PGS patients for a special genetic counseling session at California Pacific Medical Center in preparation for this process.

Title: The Joy of Pregnancy
Subtitle: The Complete, Candid, and Reassuring Companion for Parents-to-Be
Author: Tori Kropp, R.N.

For many of our patients, who successfully conceive at PFC, a major shift in thinking follows the moment they realize that their pregnancy is viable. Shelving all the fertility literature, now it’s time to get educated about pregnancy. Hundreds of books on the subject of pregnancy can be found, but which one to read?

Finally we have a thoroughly enjoyable, informative and readable book by Tori Kropp, a labor and delivery nurse for many years at our own California Pacific Medical Center. “The Joy of Pregnancy” celebrates the miracle of pregnancy, labor, birth and brand-new parenthood. It embraces these experiences for what they should be: a time of joy and excitement, not of fear and guilt.

Tori has not only worked in Labor and Delivery at California Pacific Medical Center in San Francisco for many years, but she has also taught childbirth classes for thousands of expectant parents. As a mother herself, she has experienced pregnancy and birth first hand. She really has seen it all. Her calm, reassuring manner, helped many parents-to-be welcome the birth experience with knowledgeable assurance.

This book is written in an honest and open style. The medical terminology is minimized and practicality is emphasized. The many “Tori’s Tips” in the book are gems resulting from her knowledge and experience. They serve as little pearls of pregnancy wisdom. A glossary of medical terms at the end of the book is very useful. The questions and answers sprinkled through the book are entertaining, yet filled with practical and informed answers. Special sections for fathers are also included.

The last section of the book is one that is often missing in books about pregnancy: it is all about the first few weeks of parenthood. Breast-feeding and caring for your new baby are covered, again with an eye to being relaxed and enjoying the experiences.

We highly recommend this new book as you journey from infertility to family.

Question: I am 35 years old and single, but am still hoping to find my life partner. I am getting a little concerned as my gynecologist has asked me about my plans for having children. She mentioned that I might want to consider freezing my eggs for future pregnancies. Is this something I should do?

Answer: Vitrification is a very new process for preserving unfertilized eggs. As noted in this month’s lead article, PFC has successfully been vitrifying oocytes from proven egg donors. Our first birth from this process occurred in October. Three additional pregnancies from this trial are ongoing. PFC undertook this vitrification trial in order to develop expertise with the technology of oocyte vitrification. For this reason, our study population was confined to donor eggs from healthy donors in their mid-twenties who had successfully completed conventional egg donation.

Why do we want to freeze eggs? For the many single young women diagnosed with cancer and facing fertility-threatening chemotherapy, egg vitrification will provide a fertility preservation option. This group of women has a compelling reason to consider undertaking the procedures and costs involved with in vitro fertilization. The potential threat to their ability to have their own biological children in the future may justify the unknowns that are involved with preserving their eggs in this manner. These unknowns include whether their eggs will survive the vitrification process and whether egg vitrification will ultimately prove to be as safe as conventional in vitro fertilization and embryo cryopreservation. The answers to these questions may not be answered until the patient’s eggs are warmed, fertilized and implanted, which may be years later.

We recognize that a much broader spectrum of the population will look upon oocyte vitrification as a way for women to preserve their fertility. Single women, such as you, who have not yet met their life partner, may be particularly interested in this option. In addition, it may also become an option for women in their 30’s who wish or need to delay their childbearing.

Many questions remain unanswered. Will eggs from women in their 30’s do as well as eggs from proven egg donors in their 20’s? Logic suggests older eggs will not do as well, but will the differences be significant? How many eggs would a woman need to preserve in order to have a reasonable chance for one or two children in the future? How many IVF cycles will that take? Is it safe to rely on these preserved eggs? Would having preserved eggs change a woman’s approach to reproductive planning in her life?

These are not trivial issues. They are important, life-changing concerns. For these reasons, we are not encouraging single women to prematurely jump on the egg vitrification bandwagon. Stay tuned. This area is changing rapidly.

Dr. Carolyn Givens

Question: I am 38 years old with age-related infertility (at least that is what my doctor, a Reproductive Endocrinology and Infertility Specialist (REI), thinks). It has been suggested that I undergo super-ovulation with injectable Follicle Stimulating Hormone (FSH) along with intrauterine insemination. I really don’t want to have twins, if possible, and certainly not triplets or more! But ideally, I would like to have more than one child. Even if I am successful in having one baby now, I am worried about trying to have a second child when I am 40 or more. What do you suggest?

Answer: We agree that having one baby at a time is the safest thing for you and your family. However, undergoing FSH super-ovulation is intended to create more eggs in one cycle in order to increase the odds that one or two will fertilize and implant. This helps to overcome the relative inefficiency of conception for women in their late 30’s. The risks are as you stated, twins or more. Luckily, the risks that a woman undergoing this treatment will get triplets or more is really fairly low – on the order of less than 10% of all pregnancies, with careful monitoring. The risk of twins is higher – on the order of 20% of such pregnancies.

If a woman at 38 years old has no identifiable cause for infertility, the goal is usually to get 3-6 follicles. Most of the time, if the treatment is successful, the pregnancy will be a singleton pregnancy (one baby). Your issue of wanting to have a second child and concern for difficulties beyond age 40 is a real one. You may want to discuss with your REI the option of in vitro fertilization. If your doctor thinks you may be a good responder to fertility medications, you could have extra embryos to freeze, which provides some back-up and allows you to preserve some embryos from 38 year old eggs for down the road.

Patients contemplating conception must consider lifespan expectations as part of their decision on whether to conceive. Such considerations are not, however, a reason to withhold treatment, and are ultimately the individual and family should decide.

– Dr. Carolyn Givens

In April of this year, Dr. Carolyn Givens attended the annual meeting of the Pacific Coast Reproductive Society in Palm Springs, California. This is a meeting attended by approximately 200 infertility specialists, embryologists, nurses and other fertility professionals.

At the meeting, Pacific Fertility Center’s study entitled “Outcomes of Natural Cycles vs. Programmed Cycles for 1390 Frozen Embryo Transfers” was presented by Dr. Givens in an oral presentation in the scientific portion of the meeting program.

Following the presentation, Dr. Givens was awarded the Society’s Practicing Physician Award for the best scientific presentation by a physician in full time private practice. Congratulations to Dr. Givens!

Many IVF programs routinely schedule frozen embryo transfers (FET) to occur on specific days by putting their patients on estrogen and progesterone to prepare the uterine lining for implantation. This allows for a flexible schedule for the clinic and the patient, i.e. it allows the clinics to group FETs together and avoid weekend transfer procedures. However, the patient must remain on both estrogen and progesterone to support the pregnancy for up to 12 weeks.

More and more, clinics are starting to schedule FETs in natural cycles, timed to natural ovulation with minimal medications. This does mean that a transfer can occur any day of the week. Due to tradition and convenience, some clinics remain hesitant to switch to natural cycle FETs. Part of the problem is that there have been very few studies showing what the success rates were in natural vs. programmed FET cycles. The few studies that have been published have reported on a fairly limited number of cycles.

Pacific Fertility Center has always been a proponent of natural cycle FETs. Because we do about 400 FETs each year, we have been able to gather a large number of cycles to evaluate. Most of our patients we evaluated for this study were in natural cycles but some patients had to do programmed cycles because they did not ovulate regularly or because they had to travel some distance to come to PFC for their FET and needed to have the more precise scheduling that a programmed cycle affords.

In our study, we looked at 1,378 frozen embryo transfers done between 2000-2005. Of these, 934 were done in patients using embryos from their own eggs and 444 were done in patients using embryos from donor eggs. The bottom line is that there were no differences in delivered pregnancy rates within both groups of patients (own eggs and donor eggs) between those patients having a transfer timed to natural ovulation or those patients with estrogen-progesterone uterine preparation.

Because we feel that a natural cycle is less costly, requires no blood tests and (usually) fewer ultrasounds and injections, patients find this a desirable alternative to the more common, programmed FET. In addition to these patient-friendly reasons for choosing natural cycle FETs, we now feel PFC has solid data to justify this approach.

Preliminary results of this study were presented at an oral presentation at the Pacific Coast Reproductive Society meeting in Palm Springs this past April (see sidebar).

This study has just been submitted to Fertility and Sterility, the major reproductive endocrinology journal of the American Society for Reproductive Medicine. We expect full publication after the peer review process is completed.

Carolyn Givens, MD

“Outcomes of Natural Cycles vs. Programmed Cycles for 1378 Frozen Embryo Transfers” Carolyn R. Givens, M.D.a, Leslie C. Markun,b Isabelle P. Ryan, M.D.,a Philip E. Chenette, M.D.,a Carl M. Herbert, M.D.,a and Eldon D. Schriock, M.D.a Submitted July 2007 to Fertility and Sterility.