Miscarriage, which is the loss of a pregnancy before 20 weeks of gestation, is a common outcome of human pregnancy. Spontaneous pregnancy loss (a “pre-clinical” miscarriage) can happen very early, sometimes before a woman even knows she is pregnant or can occur later, with heavy bleeding or cramping or loss of recognizable fetal tissues. Sometimes a lost pregnancy is discovered by ultrasound exam when there is no viable fetus. When including early pre-clinical and clinical pregnancy losses, approximately 31% of all pregnancies are lost prior to birth1. The vast majority of pregnancy losses are sporadic, unpredictable and can occur for a variety of reasons. About 1% of couples experience recurrent pregnancy loss, which is the loss of 3 or more consecutive pregnancies. Recurrent pregnancy loss can be due to more than one problem, but it is less likely

So what is the reason behind the high percentage of human pregnancy loss? On an evolutionary, teleological level, human pregnancy loss rates, which are high compared to other species on the planet, may be due to the fact that raising a human infant/child to the level of independence is a very labor-intensive job for human parents. Perhaps miscarriage is one of the means, albeit a sad one, of not having too many successful pregnancies in a row and for a mother to recover fully from one pregnancy before having the next. This theory is, of course, speculative on my part and I will never be able to prove it. However, it seems to me there must be some reason why humans are built to abort almost 1 out of every 3 conceptions.

Speculative reasons aside, what is the underlying mechanism for miscarriages? There are two major areas involved: fetal reasons and maternal reasons. The evidence suggests that, in the overwhelming majority of cases, there is something wrong with the fetus.

Embryo and fetal abnormalities can include abnormalities in chromosome number – i.e. having an extra or a missing chromosome, also known as aneuploidy – or can be a sporadic, non-chromosomal abnormality that makes further development incompatible with life, for example, a major heart defect. Aneuploidy (having an incorrect number of chromosomes) is exceedingly common in human pregnancies, especially as a woman ages. Aneuploidy accounts for over half of all sporadic, spontaneous pregnancy losses2. It is also a common cause of failure of early embryos to implant in the uterus. The maternal age-related incidence of aneuploidy of human embryos can be seen in this table of data from Gene Security Network, a laboratory that performs genetic analysis on human embryos using DNA micro-array technology:

This data shows that even in women less than 30 years of age, almost 60% of embryos at 5 days of life are abnormal. However, aneuploidy does not explain the entire picture with regards to implantation success or miscarriage. One recent study found that that using newer DNA analysis techniques, some aborted fetuses showed gene abnormalities that would not be identified using the common genetic methods currently used to evaluate fetal DNA3. These studies suggest that there are sub-chromosomal level abnormalities that also contribute to human fetal wastage. One interesting area of research has involved performance of embryoscopy, (using a lighted scope to visualize an intact fetus) prior to performing a dilation and evacuation procedure (D&C, D&E), a procedure which may render the tissues unrecognizable. These video images have shown us that a substantial number of non-viable human fetuses have recognizable abnormalities, even recognizable in the first trimester, and that not all of these anatomic anomalies are associated with chromosome abnormalities 4-5,

Implantation and the successful early-stage development of an embryo is an exceedingly complex process. On the maternal side, there are a large number of growth factors and other molecules that must be expressed on cells as well as complex anatomic and physiologic processes that must occur for the process to result in a successful live birth6. There is little doubt that some uterine abnormalities can cause a normal embryo to fail to survive. These include congenital abnormalities such as a uterine septum (abnormal shape of the uterine cavity) or acquired abnormalities such as uterine fibroids that distort the endometrial cavity. The majority of these abnormalities can be surgically repaired with good results. Other identified maternal causes of fetal loss are rare but include an auto-immune abnormality, anti-phospholipid antibody syndrome, which is mainly associated with second-trimester fetal loss and poor obstetric outcomes. Endocrine abnormalities such as sub-clinical or clinical hypothyroidism (low thyroid hormone levels with or without symptoms) can cause an increase in fetal loss. There is some limited data suggesting women with thrombophilias (tendency for increased blood clotting) may have a higher risk of miscarriage. More difficult to study and substantiate are possible associations between abnormalities in progesterone levels, infection, alcohol and caffeine use.

On the paternal side, there is a growing body of evidence that increasing paternal age may lead to increasing pregnancy losses in their partners7. This effect has been noted in men older than 50 years of age.

In approximately 40% of all pregnancy losses, there is no identifiable cause. This lack of causation may lead to frustration, especially if a couple experiences two or more miscarriages. It is important to realize that miscarriages are common, even in couples with no fertility problems. Miscarriage appears to be a natural phenomenon built into our evolution and in most cases, an occurrence we are not likely to change the odds of happening, unless couples consciously try to have children at a younger age. It is also important to realize that the risks of experiencing a miscarriage do not increase until three or more miscarriages occur. That means, in a woman with one or two miscarriages, her odds of having a second or third miscarriage are the same as for a woman her age that have never had a miscarriage. Only after the third consecutive miscarriage do the odds of having another increase over the age-related background rates.

References:
1.  Incidence of Early Loss of Pregnancy, Wilcox, AJ, et al. NEJM Jul 28, 1988, (319) 189-194.
2.  Cytogenetic analyses of culture failures by comparative genomic hybridization (CGH) – re-evaluation of chromosome aberration rates in early spontaneous abortions. Fritz B et al, Eur J Hum Genet 2001, 9; 539.
3.  Identification of Copy Number Variants in Miscarriages from Couples with Idiopathic Recurrent Pregnancy Loss. Rajcan-Separovic E, et al. Hum Reprod. 2010 Nov;25(11):2913-22. Epub 2010 Sep 16.
4.  Transcervical embryoscopy: images of first trimester missed abortion. Abdala LT et al, J Minim Invasive Gynecol Jan-Feb 2010 17(1):12-13.
5.  Abnormal embryonic development diagnosed embryoscopically in early intrauterine deaths after in vitro fertilization: a preliminary report of 23 cases. Fertil Steril Nov 2004 82(5): 1337-42.
6.  Implantation and the Survival of Early Pregnancy, Norwitz ER et al. NEJM Nov 8, 2001, 345 (19) 1400-8.
7.  The effect of paternal age on assisted reproductive outcome. Dain, L, et al. Fertil Steril Jan 2011, 95(1) 1-8.

Among the most common questions we get as fertility physicians from patients trying to conceive a pregnancy are: how much alcohol is safe to consume and when? Should I stop having any caffeine altogether? How much exercise is safe while trying to get pregnant?

Because comprehensive, high quality studies to address these questions really don’t exist, we try to come up with reasonable advice based on the best data we have as well as data from studies on already pregnant patients, plus just medical common sense. That said, even amongst the six PFC physicians, we vary, albeit only slightly, in the individual advice we give our patients. In this article, I have tried to come up with a consensus opinion based on a poll of the advice all of us give to our own patients.

With regards to alcohol, we are fairly liberal in allowing small amounts of alcohol consumption while trying to conceive. According to Dr. Schriock, “My advice is, if they are trying to get pregnant, to cut back on the alcohol consumption, but if you have a party and you want to have a couple glasses of wine, that’s fine. Less is probably better, but once we do the (embryo) transfer, they shouldn’t drink at all.” Dr. Herbert’s advice is: “Then with alcohol, after embryo transfer or once you are pregnant, there is always a concern with fetal alcohol syndrome. But a glass of wine or cup of caffeine with a full stomach is not a problem.” There was just a recent article suggesting that women who drink more than two or three drinks per week have lower pregnancy rates. Generally I tell people that when they get their period, they can have a glass of wine or beer. But once they have ovulated and are in the luteal phase and they could be pregnant, try and avoid any alcohol at all. Certainly avoid any binge drinking which is very detrimental. Alcohol is also very dehydrating, which is not conducive to conception.

So what about caffeine? Again, the data in regards to caffeine consumption and fertility is very limited. Studies in women who are pregnant have suggested that heavy caffeine consumers (equivalent to 5-6 coffee servings per day) have been found to have higher rates of miscarriage. Dr. Ryan’s advice is “…one to two cups per day, max, even after (embryo) transfer.” Dr. Herbert says: “More than 4-6 cups of coffee a day has a higher risk of miscarriages associated with it, although its direct effect with fertility is unknown. They can drink decaf coffee, which is better, but if they are going to drink caffeinated coffee in the morning, they should have food in their stomach.” My advice is that caffeine is a drug that causes vasoconstriction (narrowing of blood vessels). It’s not a drug you want to expose your baby to when pregnant. Since it is sometimes difficult to stop drinking coffee cold turkey, why not try to wean oneself off of it while trying to conceive? Decaf is fine.

And exercise? How much is too much? What about moderate exercise? Dr. Schriock says “For exercise, there are two studies that I quote. The first specifically looked at IVF patients, and they divided exercise into two categories: high aerobic, example in this group is running and intense cycling, and low aerobic, the example in the low group is walking and yoga. Then they asked patients how long they had been doing that activity. They drew a line at ten years. If you started running five years ago, then it seemed to lower your chances of getting pregnant. However, if you had been running for ten years of more, then it didn’t seem to make any difference. The interpretation of that is that it takes ten years for your body to get used to an activity. But the low intensity group, it didn’t seem to make any difference if you had done the exercises once, twice, five years, or ten years. Low exercise, it doesn’t matter, but high intensity exercise, should be doing it for ten or more years.

The second study I quote is not for how long they have been doing it, but how much they were doing. If they have more than four hours of aerobic activity per week, it seemed to lower pregnancy rates. Then I discuss what would you like to do? And I finally say that this is probably a balance between exercise and stress. Because if you are using exercise as a stress reducer and you take it away, all of the sudden your body gets stressed out. Then I leave the door open to be individualized.”

Dr. Chenette’s advice is that “as far as exercise, I tell them not to do any lifting over 40 pounds. On the day of transfer, they can not do any exercising, but then after that, they can resume their normal exercise regime. However, I tell them to refrain from any exercise that involves jumping. I recommend swimming and Pilates as a source of exercise. I also do not suggest any exercise that will result in weight loss because that means that they are not getting enough calories.”

Dr Ryan’s advice? “For exercise, I say in moderation. No more than four times a week for a max of one hour to 1 ½ hours. Then, in treatment, it needs to be low impact and no hot exercises like Bikram yoga after embryo transfer.” And Dr. Herbert says, “In regards to exercise, I suggest that they do not do any training for an excessive event, like a marathon. Exercise should be reasonable. It depends on their weight and the amount of time that they exercise. It is good to continue to exercise, but in moderation.”

I think the bottom line on exercise is moderation, generally no more than 4 hours of aerobic exercise per week and no exercise with weight loss as a goal. Yoga, Pilates and non-aerobic strengthening exercise is fine but again, more moderation immediately after an embryo transfer.

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.