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)

I had a case recently which demonstrated to me the utility of Gene Security Network’s (GSN) Microarray Chromosome Analysis with Parental Support.  A 40 year old patient had previously had a miscarriage and underwent a D&C procedure, complicated by her hemorrhage and appropriate vigorous curettage.  Following that procedure, her endometrial cavity appeared compromised with both filmy and dense adhesions found at a subsequent hysteroscopy.  Some of the adhesions were lysed but the question of the competency of her uterus remained.

She conceived again with fertility treatment but had a fetus that underwent demise between the 6 and the 7 week ultrasounds.  I really wanted to know if the pregnancy loss was due to her uterine compromise or due to fetal aneuploidy. 

We performed a suction D&C and the chorionic villi as well as a sample of maternal blood was sent to GSN for Microarray Chromosome Analysis evaluation.  The results of this testing indicated a fetal karyotype of 47,XX,+10 (Trisomy 10).  Unique to this testing, GSN was able to determine that the abnormality was of maternal origin.  Also, if the result had been 46,XX,GSN would have been able to definitively rule out maternal cell contamination (MCC). GSN provided me with a report in less than a week.

With this information, we knew we could proceed on without further treatment to her uterus.  We considered egg donation because it was likely this loss was due to the egg and subsequent embryo’s chromosomal non-disjunction and it was less likely to be a uterine issue.  GSN’s POC testing helped me guide this patient’s future treatment decisions.

-Carolyn Givens, M.D.

In November I had the opportunity to travel to Shanghai, China to attend a conference on emerging molecular technologies (Molecular Medicine 2010). As an invited speaker, I presented a talk concerning the use of micro-array DNA analysis to evaluate single human embryonic cells for both genetic disease and chromosome copy number (see lead article in this issue). As part of my talk, I presented the case of one of the patients featured in this issue’s Patient Odyssey. She was our first patient to have her embryos screened for both myotonic dystrophy and for chromosome copy number.  As a result of this successful testing, she is due to deliver her healthy daughter soon.

The trip to Shanghai itself was quite interesting. My husband accompanied me and we were there for one week. The population of Shanghai is about 20 million! The number of high-rise buildings and skyscrapers continued for dozens of miles before even entering the city center. The subway system there is excellent and street traffic was not too bad. The traffic was constant, though, with beeping horns heard 24 hours a day. The weather in November was fairly pleasant but the skies were always hazy, with a combination of marine layer and pollution. The city was full of incredible shopping destinations with rows of designer shops with every name brand designer you can think of. The local shops’ goods, however, were very low-end and left a lot to be desired.  In the usual tourist areas, street people were constantly trying to get us to follow them to view their “knock-off” counterfeit goods. We visited several parks and temples and tried to take in as much local culture as possible. The traditional Chinese architecture and culture is disappearing quickly in this fast-paced economy.

We had the opportunity to visit an IVF center in Shanghai, affiliated with one of the local hospitals. This center performs over 2,000 IVF cycles per year (compared to 800 a year at PFC). The center was not as clean as I would have hoped and there was a very crowded waiting room of patients waiting for ultrasound scans, blood tests and procedures. I did not get the sense that providing accommodating customer service was high on their list of priorities. Speaking to one of the laboratory staff there, it does seem as though they do most of the same type of IVF work we do at PFC, with the exception of ovum donation, surrogacy and sex selection, all of which are not allowed in the IVF centers in China.

Overall, it was a fascinating trip and I enjoyed the chance to tell others about the exciting new genetic technology affecting fertility patients.

-Carolyn Givens, 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.

Finally, I would like to share my philosophy about my role as a fertility physician and the set of beliefs that guides me in my relationships with my patients.

1. Be honest. My number one role as a physician is to care for my patients. This sounds so obvious, but I, as I suspect is true of most doctors, went into medicine because I wanted a career where I could provide for the medical and the emotional needs of those I CARE for. My job is to provide the best information to my patients, based on sound medical evidence (i.e. research studies) so that they can make informed decisions about their own care. Sometimes, the information I provide is good news: your chances are good, we can help you. Sometimes, the news is not so good: your chances of conceiving are statistically very low and you may need to consider alternatives. Whatever the situation, my job is to provide this honest assessment in a compassionate manner and help my patients come to the right decision.
2.  Commit to the treatment. Once the patient and I have made a decision on the course of treatment based on the best information, I commit myself to this completely. We may modify the plan as we gain more information in the process, but I am fully committed when it comes to implementing the treatment plan.
3. Keep striving to be the best. This means attending meetings, reading journals, staying current with research studies and applying sound data to keep the treatments we prescribe grounded in the best medical information. If I don’t know the answer to a problem, I do my best to find it.
4. Use information wisely. I do not jump into the latest fad in fertility treatment. After 20 years in this field, I have seen a lot of hot ideas come and mostly go. What sounds so good on the surface often, under the careful scrutiny of well done studies, does not end up being the magic bullet everyone had hoped.  However, other promising ideas (e.g. ICSI, egg and embryo vitrification, microarray PGD) do turn out to be sound. The beauty of PFC is that as soon as we can verify a treatment to be sound, we can incorporate it into our practice.
5. Strive for the overall health of our patients and their family. My responsibility is to ensure that my patients’ treatment is safe as well as effective. This means not only the safety of the patient during treatment, but also the fetus and baby.  We are working very hard to minimize multiple gestations, even twins, because this is the one thing we can do that will directly impact the health of our patients’ children.
6. Live compassion. If a physician does not take the time to get to know his or her patients and their individual needs, how can there be treatment of the complete person?  In my scrapbook I have saved the thank you cards, baby announcements and yearly holiday greetings from my patients of the last 15 years, so one day I can look back with pleasure on my life’s work. But the greatest compliment comes from the patient who tried very hard to conceive and could not, despite their and my best efforts, and says to me “thank you for giving me all you could. I know you tried your best and I was well cared-for.” That means the world to me.

 -Carolyn Givens, M.D.

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

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

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

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

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

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

-Carolyn Givens, M.D.

After 10 years of publishing newsletters, many with personal stories from our own employees, we have decided that it is time to do personal stories on our own physicians. So this is the first of our five physicians’ own stories we will be sharing with our readers over the next several issues. We hope you enjoy these stories and get to know our PFC doctors a little better.

I was born in Wahiawa, Hawaii in 1957, two years before Hawaii became a state. My mother was a Nisei Japanese woman, born and raised on the Big Island of Hawaii, where I hope, if I live long enough, to retire someday. My father was a Texan, raised on a dry land cotton farm in the Panhandle of Texas. He was adopted so I don’t know his genetic and ethnic background, but we suspect perhaps Welsh-Scottish. My parents met in Hawaii during WWII. I grew up the youngest of four children. I have two older sisters, with whom I am very close, and I had an older brother I loved very much but lost to kidney cancer two years ago. My mother never got to graduate from high school as she had to help her father in his general store, but she was a remarkably intelligent woman with a life-long thirst for knowledge. She received her G.E.D. at age 42; in another time, she could have been a very accomplished career woman. I was very lucky to have her for a stay-at-home mom. My father finished high school and joined the Navy just before WWII. He never went to college, but worked for the US government all his life in civil service for the Army. He rose to quite a high rank by the time he retired, due to his diligence and competence. We lived in Hawaii until I was 8 years old, then we lived in Okinawa, Japan during the Vietnam War (1965-1973). After that, my father was stationed at Ft. Hood, Texas. It was good for him to return to his home state after 35 years on islands, but hard on my mother and me, who had always lived on tropical islands with Asian culture. I graduated from high school in Central Texas and, not knowing what I wanted to do, enrolled at the University of Texas at Austin, because it was inexpensive and close to home. This was a stroke of luck because I received a wonderful education there for very little money, and it paved the way to medical school. I worked all kinds of low paying jobs to help pay my way through college, as my parents didn’t really have much money. I entered the university as an English major, as I loved literature, but quickly realized there would be no work in that field. I took a biology course my freshman year and absolutely fell in love with it. I considered being a biologist, a veterinarian (I love animals!) and eventually realized I wanted to work with people, not animals and not at a research bench. I went to medical school in Dallas, at the University of Texas Southwestern Medical School. This school has an incredible reputation for excellent research (they are always in the top 2-3 medical schools in the nation to receive NIH grant money), a well-developed program of philanthropy that supports their mission, and most of all, the best teachers one could have. I feel truly blessed to have been able to attend that wonderful medical school. During medical school, I had a job (always working!) in a research lab that was doing research on how the genes that make FSH work. That experience exposed me to reproductive endocrinology early in my career. I was even able to publish a few papers during medical school. Small stuff, but it felt great at the time.

During medical school, I discovered I liked many different specialties, but really liked caring for women. It was natural for me to go into obstetrics and gynecology. I stayed at Southwestern because their teaching hospital is Parkland Memorial Hospital, an incredible training ground for residents. During my four years there, I delivered thousands of babies, performed or assisted about 600 Cesarean sections and did all kinds of gynecologic surgery. It was very hard work, but gave me a sound foundation and a lot of confidence that I could do most anything. I remained interested in Reproductive Endocrinology, although at the time, in vitro fertilization was just beginning to develop around the country and wasn’t the major emphasis in the field. Back then, the specialty was more about taking care of menopausal women, doing surgery for infertility (especially endometriosis, because at the time, we thought surgery helped fertility for these patients, something we now know isn’t really true) and doing microsurgery to put the tubes back together for women who had previously had their tubes tied and now wanted to be pregnant again (we now treat this with IVF). I decided that rather than going into practice in general ob/gyn, I would continue two more years of training to become a Reproductive Endocrinologist.

After 17 years in Texas and 8 years at Southwestern, I knew I wanted to go somewhere else and gain new experiences and exposure to different teachers. I only applied to a few fellowship programs and was fortunate to be accepted to my first choice: the University of California San Francisco. During my fellowship there, I met and was taught by the best mentor one could have, who is now my close friend and partner, Dr. Eldon Schriock. At the end of my fellowship, I was incredibly fortunate to be recruited by him and the department to stay on as a faculty member. While there, we instituted many new techniques into the infertility program such as ICSI and PGD. We doubled the size of the IVF program. We also taught many of the Reproductive Endocrinologists that now practice in the Bay Area, including our own Dr. Isabelle Ryan. While at UCSF, we almost merged with Drs. Carl Herbert and Philip Chenette, who were in private practice in San Francisco, but due to a variety of reasons, we were unable to realize the merger with them within the UCSF system. We got to know them very well, though, and we knew we could work together.

Dr. Givens was born in Hawaii in 1957, 2 years before Hawaii became a state.

Since I finished my fellowship, I knew I wanted to be part of a world-class fertility center that could provide the best care for our patients. For many reasons, during the late 1990s, this was becoming more difficult to do within the University. In 1999, when the previously existing Pacific Fertility Center came up for sale, Dr. Schriock and I got together with Drs. Herbert and Chenette and took the opportunity to realize our dream. We were able to recruit Dr. Ryan to join us. It has been a challenging but very exciting 10 years at PFC but now we are all able to say that the dream has become a reality. I am getting to do what I love to do every day.

On a personal level, I met my husband Michael when I was at UCSF. We were so sure about each other that we married 7 months after we met! I was a little older by then and at first we struggled with the idea of whether we would try to have a family. Since neither of us had any family living close by and my professional career (as well as his business) was very time consuming, we realized we would be stressed-out parents living the day-care life. We finally decided to live child-free. I only regret not having adult children to be proud of and having grandchildren to spoil. We now live in Marin and our children are our two dogs that I adore and spoil way too much. I love gardening, boating, cooking, reading and travelling. I don’t really have a passion for any particular hobby, just a passion for my work. But someday, as I said, I hope when I retire to return to Hawaii. Even though we left there when I was young, it is a big part of my family’s history and culture. I feel most at home with the aloha I feel when I am there. I would love to volunteer at an animal shelter after retiring. I still sometimes wish I had gone into veterinary medicine, but I think I will enjoy it more as a volunteer and since I have the best job in the world, that will have to wait for another lifetime.

— Carolyn Givens, M.D.

Since Pacific Fertility Center came into existence in November of 1999, we have been offering genetic pre-screening of IVF embryos for couples with recurrent miscar- riage, repeated IVF implantation failure and sex selection for family balancing. For most of the last decade, a technology known as Fluorescent In-Situ Hybridization, or FISH has been used to screen embryos. FISH is employed to probe a cell removed from a Day 3 embryo to determine the chromosomal makeup for anywhere from three to twelve of the cell’s 23 pairs of chromosomes. With time, we, as well as everyone else in the reproductive genetic world, came to realize the serious limitations of this technology.

In the last 2-3 years, as the Human Genome Project has been completed and as more DNA-related biotechnologies have emerged to evaluate human genes, these methods are being utilized to analyze human embryos. The technology now available—the ability to analyze large numbers of genetic locations on each human chromosome, and quantify that genetic material, with the previously well-established techniques to amplify a single cell’s genetic material up to hundreds of thousands of copies—has allowed PGS to take a quantum leap forward. It is now possible to more accurately analyze all 23 chromosome pairs from a single embryo; not only to determine if the correct number of copies of each chromosome is present, but also to look at single gene mutations.

At the end of 2009, Pacific Fertility Center began working with a new biotech company called Gene Security Network, located in Redwood City (genesecurity.net). This company uses gene microarray technology to analyze amplified DNA from a single cell.

It then uses microchips to analyze 30,000 genetic loci in a quantitative manner. In addition, their unique technology allows us to compare the analysis of the embryos’ cells to the parent’s chromosomes to ensure that all the genes are being properly analyzed. It does appear that the error problems that plagued FISH technology have been overcome with this new, more sophisticated, method.

In October of 2009, Dr. Conaghan and I were invited to tour the GSN laboratory and see the technology in action. We met with David Johnson, the lead scientist at GSN, who explained the cell process; from the amplification of the DNA, to arranging the chromosomes on chips, to DNA analysis, to synthesizing the data generated with the parental genetic data to come up with a full analysis of that cell’s genome. In order to process the cells between the day of embryo biopsy (Day 3) and receive the results on the day of embryo transfer (Day 5), their technicians work around the clock in shifts. GSN has a very cold, clean room to replicate the single cells into multiple copies. They cannot allow any outside contamination, not even from a single cell. They videotape the cell duplicating process so if any errors subsequently arise, they have a video record of what the laboratory technician did. We found this to be very impressive. We also saw how the chips were coated with DNA and analyzed. We were shown the sophisticated software that generates the final report detailing the genetic makeup of each embryo from the cells in which they originated. All in all, the tour gave us great confidence in the quality control and scientific integrity at GSN.

Even with this 21st century technology, we continue to biopsy Day 3 embryos because it provides us with a 48 hours window to send the cells to the lab and complete the analysis in time for transfer. However, we have not yet found a way around the problem of mosa- icism. GSN and microarray technology appears to have largely solved the resolution error problem but it can only tell us what is in the chromosomal make-up of the single cell. It cannot tell us whether or not that cell represents what is truly going on with the rest of the embryo. We are currently looking at the possibility of biopsying Day 5 embryos. The set back would result in having to freeze these embryos due to the time constraint in analyzing the genetic material in time for fresh transfer. With all of the innovation occurring daily in the genetics field, we hope that this puzzle will be resolved.

— Carolyn Givens, M.D.

Previous Fertility Flash articles about PGS:
2 Methods of Gaining Info Prior to Implantation
PGD & PGS: Why Genetic Counseling is a Prerequisite
The Benefits and Pitfalls of PGS