A 42 year old woman has given birth to a healthy baby boy by using embryos which had been cryopreserved (frozen and stored) for nearly 20 years.  Dr. Sergio Oehninger, Director of the Jones Institute for Reproductive Medicine at the Eastern Virginia Medical School, treated the woman who had been unable to conceive due to problems with egg production.  She had undergone almost ten years of fertility treatments without success when she was given five frozen embryos anonymously donated by another couple.  The donating couple had delivered a child in 1990 using an IVF treatment and had stored these additional embryos for over 19 years.  Of the five embryos, two survived after thawing and were grown in the laboratory for two additional days. Both embryos were transferred into the woman’s uterus but ultimately only one attached and grew.  In May 2010 a healthy baby boy weighing 6lb 15ozs was born.   

It is exciting to hear of cases like this one as it provides hope for other couples who might be able to use donated frozen embryos. The success of freezing and thawing embryos continues to improve with such new techniques as vitrification, embryo collapse before freezing or embryo assisted-hatching after thawing. Fortunately, there is also significant research data confirming the health of babies born after embryo cryopreservation. However, the majority of the cases used in the research to date have been frozen for less than five years. Therefore, we will need to gather more information on cases such as this one where the embryo storage has been for an extended time period. Happily, at least so far, there does not seem to be any “freezer burn” for embryos stored in liquid nitrogen.

-Carl M. Herbert, M.D.

I was born in 1948 in North Carolina to a red headed father who, sure that I would have similar coloring, nick-named me “Rusty”.  My father was an Ob/Gyn who eventually established his practice in Gainesville, Florida where I grew up in what was then a small southern town. Although the 1950s and 60s were interesting times in the deep south, we were quite fortunate to live in a “university” town with the University of Florida providing an important intellectual and social influence, which wasn’t present in other areas surrounding us. My father was from Manasquan, New Jersey and my mother from Brooklyn, New York, so my siblings (a family of five children) and I were mostly educated in the northeast after primary schooling in Florida. I graduated from high school, The Peddie School, and college, Rutgers University, in the garden state of New Jersey. During one summer of my college years, the summer of 1968, yes, the summer after “the summer of love”, I lived and worked in San Francisco, which is probably a major reason I now reside here. After college graduation, I returned home to attend the University of Florida where I earned an MS degree in Environmental Engineering Sciences and subsequently an MD degree, making me a fourth-generation physician.

I spent one year in St. Louis at Washington University as an intern in Ob/Gyn where I met fellow residents and long time friends Drs. Elliot and Denise Main, as well as my future wife, Katharine. At years end I moved to Nashville, Tennessee and completed both a residency in Obstetrics and Gynecology and a fellowship in Reproductive Endocrinology at Vanderbilt University Medical Center. While at Vanderbilt, Katharine and I enjoyed working together.  She as a nurse-midwife and I was a resident.  After the birth of our first child, Katharine became involved with county health care programs and I began my fellowship. I joined the Vanderbilt teaching faculty upon completion of my fellowship and served as the Director of the Reproductive Endocrinology / Infertility Division from 1989-90.

Early in my medical career, I had the good fortune to participate in some “firsts” in the field of reproductive endocrinology and infertility. While at Vanderbilt University, I did pioneering work with the first laser laparoscope and was involved with one of the first assisted reproductive technology programs in the United States. I authored several early articles on endoscopic surgery, including one of the very first articles published on the treatment of tubal disease via laser laparoscopy. I was also fortunate to be a part of those early difficult and formative years in the area of IVF and contributed to numerous articles as we tried to create additional and better ways for success.  

In 1990 I was recruited by the original Pacific Fertility Centers to join their San Francisco clinic, where I was appointed Medical Director. However, desiring to create my own concepts for care, I left PFC to become a partner and Medical Director with the San Francisco Center for Reproductive Medicine. Dr. Chenette joined me very soon thereafter. With much hard work and help from many of our current staff, SFCRM became a leading center for infertility care and assisted reproductive technology services in Northern California. In November of 1999, Dr Chenette and I joined forces with Drs. Givens, Ryan, and Schriock and took over the management of the current Pacific Fertility Center. Our vision was to create a center of excellence that was large enough to do good clinical research and answer some of the important clinical questions in our field. We all came from academic backgrounds and knew the benefits of collegial interaction, but felt there was a better way to offer patient-centered services. PFC is the culmination of our collective dreams and ambitions to create such an optimal center. We are indeed proud of the result.

After years of clinical practice in our field, I find I am most drawn to the numerous and complex ethical issues which are products of our ever changing technologies. This interest has led me to diverse activities as a 22 year membership in the Society for Humanism in Medicine, including the 2003 presidency, and a planned speaking engagement this year at the annual meeting of the American Academy of Child and Adolescent Psychiatry, regarding the ethical issues involving children conceived through reproductive technology.

When there is the “extra” time away from medicine, I enjoy the excitement of international travel, the pleasure of a good bottle of Burgundian wine, the stretch of great contemporary jazz music, and the stimulation of a unique piece of art. I have taken on the “egg” image as a passion for collecting and now own a wonderful group of vintage and modern photographs as well as “eggs” in other media, some of which you will see in our office. I have two wonderful daughters, Sarah and Rachel, and I feel so very fortunate to count myself as one of those who arise each morning looking for this day to be better than the last. 

” When you don’t know something can’t be done, it makes it possible to do.”  -Brother Thomas Bezanson  

Dr. Rusty Herbert, M.D.

My husband and I have a long history together. We met in high school, and after 10 years of marriage, we were ready to have a family. My sister had experienced trouble getting pregnant, so as a result I worried that I might have the same problem.

My worries were partially confirmed when my husband and I unsuccessfully tried to conceive. In our case, we discovered we had the unlucky combination of both male and female factor infertility. At that point we were under the care of our gynecologist. On our doctors’ recommendation, we went through IUI near the end of 2003. It was a nightmare for a lot of reasons. I reacted poorly to Clomid and did not conceive.

While I was still trying to conceive, my sister was happily on her way to having a family. She had gone to the next level of care: an expert reproductive endocrinologist at Pacific Fertility Center. We were of course delighted to hear the news of her pregnancy, but at the same time frustrated because we were still not pregnant. We had always thought that once we were ready to have a family, we would be able to get pregnant easily and naturally.

After our disastrous IUI cycle, we tried again naturally, but to no avail. Frustrated and tired, we took a break. After a while, I spoke with my sister Alison, who referred us to Dr. Herbert at Pacific Fertility Center. He was wonderful and had great bedside manner. He was positive and upbeat despite our combined infertility diagnosis. We went straight to IVF with Gonal F and Repronex. Unfortunately, my body didn’t respond well.

I really appreciated Dr. Herbert during this discouraging time. He was frank with us and indicated that my follicles were not looking good. Without good follicles, the ability to retrieve a reasonable number of quality eggs was in question, so we did not continue our IVF cycle. Dr. Herbert was very flexible; he listened, explained our options and didn’t dictate what we should do. He suggested IUI as a way to salvage the IVF cycle and much to our surprise, we became pregnant! When I got the good news that my husband and I were going to be parents for the first time, I was “over-the-top” happy calling everybody I knew. In addition, on our first ultrasound, we saw two beating hearts. We not only were pregnant, but also were pregnant with twins!

The irony is that after my sister Alison had twins, I too envisioned having twins. During our initial OB ultrasound, Dr. Herbert indicated that he saw two heartbeats. We had a scare at one point as we thought I had experienced a miscarriage. However, I had just had some bleeding and passed a blood clot. I appreciated Dr. Herbert during this time, as he remained calm at all times. Much to our delight, I gave birth to a healthy, beautiful set of twins (Justin and Eva) who are now over a year old.

I thoroughly enjoyed my experience at PFC. They were great from a logistical standpoint, and were great about getting all of the paperwork out of the way quickly. I appreciate the nurses—Anne was awesome and whenever we called she was very kind and understanding. I loved going to appointments as it was such as positive experience. Additionally, I appreciate PFC for their professionalism. Dr. Herbert was so experienced and knew what he was doing the whole time; I trusted him a lot. I truly love our children. It is wonderful for my sister and me to be able share experiences as we learn about the joys of parenthood firsthand. It is sweet irony indeed.

Leslie

Leslie’s journey to a successful pregnancy was a bit unconventional but contains several important messages for you, our patients. The stimulation of her ovaries during her first IVF attempt did not progress as we had hoped. There were fewer follicles and some were large and others small (follicle disparity). Had this been her final attempt on very high doses of medication, we might have proceeded on to egg retrieval. However, we felt the stimulation was suboptimal and we expected to improve this process in another cycle by changing the medication regimen. As Leslie and her husband were diagnosed with unexplained infertility, we also felt she might conceive by ovulating the few larger follicles which were present and using intrauterine insemination. Fortunately we were correct, and Leslie now has two wonderful children. These conversions from a planned IVF cycle to IUI cycle can produce pregnancies as often as 10% of the time as long as there are no other fertility factors like tubal damage or severe sperm problems and the age of the woman is not advanced (less than 38 years). Leslie’s story is a good example of persistence in spite of initial disappointment, of using all the options available in the most effective manner, and of “keeping the faith”. We hope Leslie’s story can be an inspiration to others who may face similar disappointments on their journey to parenthood.

Carl Herbert, MD

For some women, infertility is caused or exacerbated by having a uterus with congenital abnormalities that cause it to be misshapened. These uterine anomalies can lead to greater difficulty with embryo implantation and/or cause higher rates of miscarriage.

Until recently, a physician’s capacity to properly diagnose this problem has been limited to a hysterosalpingogram (x-ray with dye); a MRI (magnetic resonance image); a laparoscopy (surgery which limits the evaluation to the outer contour of the uterus); or a standard 2D ultrasound. The emerging technology of 3D ultrasound is starting to provide a highly improved, noninvasive, more cost effective option. Fortunately in the Bay Area, women can obtain a 3D ultrasound at the CPMC OB/GYN Ultrasound Suite which is directed by Dr. Lourdes Scheerer and two other physicians, Drs. Claire Serrato and Shelly Zaglin.

An ultrasound uses high-frequency sound waves (between 3.5 to 7.0 megahertz) sent through the body via a transducer or a scanner that is placed either on the lower abdomen or inside the vagina. The ultrasound beams scan specific areas of interest within the abdominal cavity and are reflected back onto the transducer to produce an “echo” image of the internal organs. This process had been shown to be both safe and effective.

There are several reasons why a physician would want a 3D image of the uterus, explains Dr. Scheerer. By using a 2D ultrasound one can assess the shape of the uterine cavity, but cannot assess as clearly the positioning relative to other pelvic organs (ovaries) nor the contour of the uterus itself. This information is important in assessing a possible abnormality of the uterus, and on deciding appropriate intervention.

There are some congenital anomalies of the uterus that can impact an embryo’s ability to implant and develop within the cavity. If a woman has an abnormally formed uterus, this can cause a higher incidence of miscarriage or be an obstacle to carrying a pregnancy to full term. In women experiencing unexplained repetitive miscarriages, it is important to rule out the possibility of uterine anomaly as the cause. Women with uterine anomalies can also experience higher rates of preterm labor, bleeding during pregnancy, diminished fetal growth, and fetal malpresentations (such as breech), which lead to a higher rate of Cesarean delivery.

A typical uterus is shaped like a small pear and the cavity within has a hollow triangular form. The uterus develops inside a female fetus by the fusion of two separate halves (Mullerian ducts) into a single organ. The uterus subsequently becomes hollow, creating a normal cavity. Abnormalities in the shape of the uterine body and/or the uterine cavity are called “fusion” defects because they arise from failure in the aforementioned unification and hollowing process. If there is failure of the uterine body to fuse completely, the uterine shape will be abnormal. Because the ovaries are derived from different fetal tissues, the development of the ovaries is not affected by Mullerian defects.

Failure of fusion and hollowing can present as a spectrum of abnormalities from a simple dimpling of the top of the uterus as seen in this arcuate shaped uterus

Arcuate Shaped Uterus One of the most common abnormalities is a bicornuate uterus.

Bicornuate Uterus As shown here, a bicornuate uterus has two uterine horns. Pregnancy within a bicornuate uterus typically occurs within one of the horns and pregnancy outcome is usually as normal as for a fully developed uterus. Surgery is not required for this kind of an abnormality. The uterine abnormality most commonly associated with miscarriages is a uterine septum

Septated Uterus This is an abnormality of the hollowing process where a residual midline septum is present. Normal uterine lining does not grow over a septum, so if the embryo implants in the septum, it will not have an adequate blood supply for growth. The traditional way to correct a septum was performing an abdominal surgery called a “metroplasty”, where the septum was removed, and the uterine walls sewn together. This surgery was not very successful, and nowadays we can remove a septum by hysteroscopy, which provides a much more successful outcome. For a uterine septum, surgery is the correction. Understanding the type of uterine defect one has is critical, because this will determine if surgical intervention is needed to optimize one’s chances of a successful pregnancy. A 2D ultrasound can suggest that an abnormality is present, but does not necessarily differentiate among subtle abnormalities. The advantage of 3D ultrasound is that it will better define the specific defect present. Based on this improved image, the best recommendation can be made. 3D ultrasound provides a cost-effective imaging modality, which gives good resolution when differentiating Mullerian anomalies. Dr. Scheerer reports that 3D ultrasound can also be helpful in differentiating the location of abnormal pregnancies. For example, the improved imaging can be helpful in distinguishing a tubal ectopic pregnancy, versus a corneal pregnancy. The technology that makes 3D ultrasound so reliable is evolving rapidly, partly due to the sudden popularity among pregnant women who want the better-defined early fetal images for their baby books. While this is currently “in vogue”, it is important to understand that there are no long-term studies looking at the effects of 3D ultrasounds in pregnancies. While we don’t endorse the use of 3D ultrasound strictly for photo opportunities, we think it is a very valuable tool for finding and evaluating certain uterine abnormalities. This information gives us the opportunity to optimally treat each individual person and maximize the chance for a successful pregnancy.

– Carl Herbert, MD

Q.
My friend was tested with a high FSH of 10 and she still got pregnant, naturally! Now I’m confused – I have a low FSH of 7 and have not been able to conceive, even with IVF.

A.
It is true that the follicle stimulating hormone (FSH) test can be a useful indicator of a woman’s ovarian reserve (egg quality/quantity) but it is by no means a perfect screening for egg quality and/or quantity.

FSH, a hormone produced by the pituitary gland in the brain, is released into the bloodstream and travels to the ovary where it stimulates immature follicles containing microscopic oocytes to eventually develop a mature oocyte (egg). Early in the menstrual cycle, if the blood level of FSH is high, it indicates that the pituitary is working hard to stimulate the ovaries, therefore, the number and perhaps quality of the remaining eggs is decreased.

FSH is tested on day 2 or 3 of your cycle to provide a baseline measurement. An elevated FSH level above 8 might suggest that a woman is starting to experience the loss of her ovarian reserve. Menopausal women show FSH levels that are above 40. However, there are several variables, and as with many issues surrounding infertility, it has much to do with age.

Proper interpretation of FSH levels requires a simultaneous measurement of blood estrogen (estradiol) levels. Estradiol is made by the ovary, enters the blood stream and travels back to the brain (pituitary) to help regulate FSH release. Early in the cycle, day 2 or 3, it should be less than 60. A high level of estradiol, above 80, indicates that estradiol is suppressing the pituitary and providing an inaccurate FSH reading.

Several studies have set out to determine whether women with elevated basal FSH levels should be excluded from fertility treatment. A comprehensive study in the United Kingdom analyzed over 2000 patients for four years undergoing IVF treatment. Although it found no significant correlation between FSH levels and fertilization rates or miscarriage rates, the pregnancy rates and live birth rates were lower among women with higher FSH levels. Elevated FSH levels were also associated with more frequent cycle cancellation, need for larger amounts of stimulation medication, and lower numbers of eggs and embryos with fewer embryos transferred. However younger women, even with high FSH levels, had significantly greater live birth rates compared to older women with normal FSH levels. Again, age matters, despite a normal FSH value.

A normal FSH reading, although reassuring, may be indicative of egg quantity but not necessarily quality. The follicles may be producing mature eggs, however, the quality of those eggs may not be adequate. This is especially true for women over 40 years old.

Another caveat is that most women have variable FSH readings from one cycle to another. The best indicator of treatment response, however, is typically the highest FSH reading. There is no benefit, therefore, in repeated testing of FSH over several cycles and choosing to undergo an IVF cycle when the FSH is normal.

Q.
I’m confused. I heard that metformin is an alternative to clomid for women who have trouble ovulating, but isn’t metformin a drug to treat diabetes?

A.
Metformin (brand name: Glucophage) is indeed an FDA-approved drug for type 2 diabetes. It is also a promising new treatment in the portfolio of ovulation induction medications for women with polycystic ovary syndrome (PCOS).

Many women with PCOS suffer from insulin resistance (high blood insulin levels), a problem that is thought to possibly impede ovulation and elevate male hormone levels.

By way of background, PCOS is experienced by as many as 10 percent of women of reproductive age. An inability to ovulate normally and problems associated with an overproduction of male type hormone are typical findings in women diagnosed with PCOS. The “polycystic” aspect can be seen in the ovaries via ultrasound, which reveals a large multitude of tiny follicular cysts instead of a smaller group of well-defined emerging follicles preparing for ovulation.

Many women with PCOS respond well to clomiphene citrate (brand name: Clomid), which stimulates increased blood levels of FSH (follicle stimulating hormone) and LH (luteinizing hormone) to induce the growth of a follicle and eventual ovulation. Approximately 70% of patients treated with clomiphene citrate will ovulate and 40% will conceive, the majority within three to six ovulatory cycles.

A small fraction of patients who see no improvement from clomiphene treatment alone are good candidates for metformin, or a combination of clomiphene and metformin. Offering metformin provides such women with an alternative oral medication before being directed to the injectable stimulation medications. As an insulin-sensitizing medication, metformin decreases insulin levels, which is thought to help restore the normal ovarian hormone profile (reduces male hormone), thus allowing for spontaneous growth of a follicle and ovulation to occur. Alternatively, metformin enables the patient to become more sensitive to clomiphene. It is important to note that of those patients who do not ovulate on clomiphene alone, most benefit by the combination of metformin with clomiphene.

Metformin and other insulin-sensitizing medications may offer other benefits for women with PCOS, who are reported to be three times more prone to early pregnancy loss compared to ovulatory women. In several reports involving as yet small populations of PCOS patients, the use of these drugs appears to significantly reduce the rate of early miscarriage. One must approach this news with caution, however, until prospective controlled trials on this topic are conducted.

Many physicians working in the field of Assisted Reproductive Technologies (ART) braced for the release of the latest and fifth report by the President’s Council on Bioethics, which takes an in-depth look at the practices and results of ART in the US. Now that the document has been finalized, we are instead pleasantly surprised.

A bevy of questions, recommendations and opinions emerge out of Reproduction and Responsibility: The Regulation of New Biotechnologies, leaving readers potentially baffled about what steps might be taken from its analysis. (See www.bioethics.gov) Yet the report stops short of recommending drastic or unreasonable changes, and instead calls for limitations to about a half-dozen of the most questionable practices (see below). In a reasoned and logical fashion, the report turns out to be a compendium of suggestions for federal monitoring, tracking and long-term research into the health implications of IVF babies and mothers.

The legislative limitations focus on those areas of research that are potentially driven by the promise of embryonic stem cell therapy, and/or cloning. Even in this politically charged area, the Council’s recommendations mainly address the kind of obscure research that tinkers with, or attempts to defy the basic building blocks of procreation involving egg and sperm, such as:

- No transfer of human embryos into animals
- No hybrid human-animal embryos
- No human embryos into women without live-born child intent
- No conception other than by means of uniting egg and sperm
- No conception from gametes obtained from fetus or stem cells
- No conception by fusing the blastomeres from 2 or more embryos
- No human embryos for research beyond 10-14 day stage

Given that these suggested prohibitions in the draft report evoked little outcry, the scientific and medical community appear to be palliated by this report. The last item in particular suggests a maximum 10-14 day development stage for leftover embryos donated to research. By making sure that the embryos are donated for research early in their development, this notion gently disarms the politically prevailing view that no new embryos should be used by federal-funded research to develop new lines of embryonic stem cells.

It is well known that bioethics investigations around the world are driven out of concern that human cloning research is galloping ahead, outpacing the public’s capacity to understand, let alone react to this brave new world. Media headlines announcing rat and cat cloning, and the creation of embryos from materials other than eggs and sperm seem to appear regularly in the news.

At the same time, public support for therapeutic research involving stem cells is spreading like wild-fire, prompting a majority of senators, as well as more than 200 members of Congress, including some with anti abortion views, to petition President Bush to lift the ban on new embryonic stem cell lines for federally-funded research. This should come as no surprise; 100 million Americans have various diseases that could eventually be cured by the regenerative capacities of stem cells (i.e. therapeutic cloning), even though sound science to this effect remains elusive.

The Council’s report also devotes considerable space describing the need for monitoring, testing and oversight. But again, it stops short of recommending strict new operational standards for ART practitioners, admitting that the current regulations work, notwithstanding the need for a little improvement.

Indeed, infertility practitioners are proud of the high standards they’ve established through peer-participating professional associations including the Association of Reproductive Medicine (ASRM) and the Society of Reproductive Technologies (SORT).

At the same time, the report’s recommendation for a massive and ambitious long-term monitoring project of IVF patients’ health is well founded. A 20-40 year federally funded study, following both mothers and their ART assisted children into later years, could reveal new insights into all infertility procedures and outcomes, especially if the research compliments what is already considered science.

The only caveat is additional costs of government monitoring, research and/or regulations have historically fallen back onto the consumer.

To conclude, the majority of ART physicians are in support of reining in the few rogue infertility researchers who have crossed an ethical line attempting to recreate and manipulate some of the core ingredients of procreation (i.e. reproductive cloning) with dangerous and unproven techniques. Reproduction and Responsibility is not expected to cause enormous ripples of change in the ART community. It does an excellent job of presenting the wide breadth of views on the topic, not squelching contrary opinions, but rather maintaining a healthy dialogue. We do not expect to see significant governmental controls emerge for the vast majority of couples who simply want our help in making a baby.