SCIENCE PULSE    3D Ultrasound Enhances Diagnosis

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

               
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ASK THE EXPERTS    Frequency of Intercourse

Question: I’m confused about how often to have intercourse around the time of ovulation. Some things I have read say it should be not more than every other day while my doctor tells me it should be daily. What is the right answer?

Answer: There may be no exact right answer for everyone. Indeed, there might be a slight decrease in sperm concentration on the second or third straight day of ejaculation. However, for most men, there are still millions of active sperm present on the second or third day. As such, it may be better to have more sperm available in the reproductive tract during the window of fertilization for the egg.

My bias is to have intercourse as frequently as possible when you know you are soon to be, or in the process of, ovulating. The best method to detect when this is occurring is to use an ovulation predictor kit such as Ovu-Quick or Clear Blue Easy. When the kit detects the surge, have intercourse on that day and the next day. Beyond that, it is probably too late. If you don’t want to get that technical, subtract 16 days from your usual cycle length and start having intercourse daily from that day of the cycle for the next 3-4 days. For example, if your usual cycle length is 30 days, begin having intercourse on about day 14 and continue to day 16 or 17.

CRITICAL REVIEW    What’s the Fuss About DHEA?

The public’s appetite for promising pills that purportedly slow down the aging process is stronger than ever. Sensationalized claims revolving around Dehydroepiandrosterone (DHEA), a natural steroid hormone produced from cholesterol by the adrenal glands, has followed this trend.

DHEA is a hormone secreted by the adrenal gland whose level in the body peak at early adulthood and then decline with age. As the most abundant steroid in the body, DHEA is chemically similar to testosterone and estrogen.

Because low DHEA levels brought on by aging also correlate with age-related diseases, DHEA supplements are openly marketed to prevent the effects of aging. Because a woman’s fertility declines with her age, it is no surprise that DHEA has been associated as a “promising” drug to offset age-related infertility. Yet there have been no scientific studies or evidence revealing that adjusting DHEA levels changes the development of age-related diseases. Nor has there been evidence that DHEA slows down the decline in fertility. Simply stated, there is no evidence that increasing DHEA slows down, stops, or reverses the aging process.

Some past rodent studies indicated DHEA was effective in controlling obesity, and prevented cancer, arteriosclerosis and diabetes. As a result, DHEA was quickly promoted as a miracle weight-loss drug. Yet no human studies have duplicated these results.

Nevertheless, DHEA has received considerable acclaim, with some authors touting it as a “superhormone” or “the youth and health hormone.” Articles on DHEA abound. In fact, DHEA received over 850 citations in a Medline search and 52 publications come up on an Amazon.com search.

A search of serious scientific research examining DHEA’s impact on fertility is scanty. There are less than a handful of scientific presentations or papers on the topic. Just last year a study (Fertil Steril. 2005; 84(3):756) conducted at the Albert Einstein College of Medicine announced: Increased oocyte production after treatment with dehydroepiandrosterone. This paper focused only on one 42 year old woman, whose number of oocytes retrieved increased after undergoing eight IVF cycles over the course of a year with DHEA supplementation. Not only did she take a DHEA dietary supplement, she also underwent acupuncture. Since she froze her embryos, it is not reported whether any of her eggs led to a successful pregnancy.

To date, no sound or controlled scientific studies have been designed to examine whether DHEA is able to reverse the results of aging on ovarian reserves.

A research paper was presented at the 2005 ASRM conference (O-101 by D. H. Barad and N. Gleicher). This retrospective cohort study examined 45 women previously diagnosed with decreased ovarian reserve who were treated with 25 mg DHEA for 4-48 weeks before undergoing ovulation induction for IVF. The study concludes that DHEA increased oocyte production and quality. Yet no pregnancy or live birth outcomes were reported. Both Drs. Barad and Gleicher are already offering “DHEA Therapy” in their practice.

Very little of the encouragement to self-administer DHEA is coming from the physician community, especially those who are initiating viable scientific research. Elizabeth Barrett-Connor, MD, professor and chair, department of family and preventive medicine at University of California, San Diego calls DHEA “a modern day snake oil”. Her initial research revealed that higher natural levels of DHEA in older men may help protect them against heart disease yet she recognizes the need for more studies.

Self-medicating by using DHEA supplements is a form of testosterone therapy. It is not likely to affect each individual in the same way due to variable existing androgen levels in the body and a lack of consensus on what are normal or benchmark levels. Increasing DHEA (and thus testosterone) may well lead to additional facial hair and possibly acne for women. Until more is known, taking DHEA is a risky gamble based on insubstantial evidence.

The hype about DHEA as a way to improve fertility will only continue as the public seeks information that they want to hear. An entire chapter is devoted to DHEA in an online book called “Mothers over 40”. If there were such an easy panacea to reverse the impacts of aging on infertility, the benefits would have been known much sooner.

PATIENT ODYSSEY    Overcoming the Odds

So often I hear or read about what a mistake it is to postpone having children. As if for all of us this is a conscious choice. I wasn't waiting until the perfect career moment, or until I achieved some lofty goal. I was waiting for a committed mate with whom to start a family. So at 39, my husband and I began what would become, in total, a six-year infertility odyssey.

I was not naďve going into this. I was, in fact, planning for a difficult time. I expected to chart my cycles, which would of course be unsuccessful, for six months, and, armed with all this useful data, insist on a referral to a fertility specialist. Imagine our surprise when I became pregnant on our first try. The pregnancy ended at around 10 weeks, when we went for our first ultrasound and was told there was no heartbeat. In a testament to denial and hope, and despite my initial pessimism and the dismal statistics for my age group, I never truly believed I would miscarry.

My emotional recovery from my first loss was complicated by a difficult physical recovery. Nonetheless, a few months later I was pregnant again, only to miscarry at six weeks. I was distressed and angry, resentful of every pregnant belly I'd pass on the street, feeling sabotaged by my own body. The wait just to get an appointment with the fertility specialist within my health plan was six months, so we anxiously turned to PFC, knowing that every cycle was a precious commodity.

We launched in with Dr. Ryan, taking every reasonable test, only to find that things looked pretty good and this was simply going to be luck of the draw. After several trying months of unexpected delays and barriers, we upped our odds with injectables and conceived our amazing daughter, Hannah. I remember that my first thought, after the nine days of shots, the trips to the City for ultrasounds, the anxious OPK readings, and the agonizing two-week wait, was that it had been ridiculously easy. That was five years ago. We have a son on the way now. I can feel him squirming around in there, poking at my bladder as I write this. We suffered many losses and deep disappointments to get to this point, and I have three sharps containers full of needles to prove it.

I can't imagine what it must be like for women who breeze through conception and pregnancy, but I know I have benefited from the difficulty of my experience. I have gained a profound sense of wonderment about the entire miracle of pregnancy. I have an appreciation for the life I've brought into this world, and the one on its way, that I could never have found with any other path. I have developed a depth of sensitivity for those struggling to do what comes so easily to others that has enabled me to support them in a way I could never otherwise have done.

Maybe this isn't the course I would have chosen, given the option, and there are some wounds that never heal, but after six long years, we are finally at a point where we can breathe. We can put the exhausting cycle of hope and grief behind us. Like us, anyone who has come out the other side of infertility gains a sense of their strength, endurance and resolve. And anyone who has found their way through infertility, whatever their path, knows the almost overwhelming sense of relief we feel down to our bones, every single day.

FROM US TO YOU    Blastocyst Transfer and Freezing

It is not common to freeze embryos on day 1 after retrieval since at this time we have very limited information on their development, but this is the stage at which embryos best tolerate freezing and thawing. In 2005, 92% of embryos thawed at this stage survived, compared to 64% of embryos surviving after freezing on day 3. However, the lack of embryo development information on day 1 means that we are probably freezing many embryos that have little or no chance of establishing a pregnancy. We therefore prefer to let the embryos grow for at least another 2 days to make sure that we only end up with good quality embryos in our freezer.

In the last 2 years we have been doing more and more transfers on day 5-post retrieval (blastocyst transfer). Delaying the transfer an additional 2 days allows us to get a much better picture of which embryos in a cohort are really strong and healthy. By day 5, the embryo should have reached the blastocyst stage, which is characterized by the presence of a fluid filled cavity or cyst in the embryo. Embryos that reach the blastocyst stage by day 5 have a higher chance of implanting after transfer when compared to embryos transferred on day 3. However, not all embryos that look healthy and strong on day 3 will make a blastocyst. We estimate that it takes 3-4 nice day 3 embryos to achieve a nice blastocyst on day 5. Therefore, blastocyst transfers are usually undertaken only by patients with many nice embryos on day 3. Also, patients at high risk for a multiple pregnancy and/or those wishing to transfer only one embryo often decide to do their transfer on day 5.

After a day 5 transfer, surplus blastocysts can be frozen for later use. They can be frozen on day 5, or if they are developing a little more slowly, on day 6. Blastocysts have many more cells (up to 200 cells) than day 3 embryos (up to 12 cells) and we employ a different method for freezing them. All freezing techniques involve dehydrating the embryo, so the fluid filled cavity in a blastocyst will collapse during freezing. When thawed and placed inside the incubator in the laboratory, the cavity will begin to re-expand and the blastocyst should be fully inflated about 4 hours later. Blastocysts that show little or no signs of re-expansion are unlikely to implant after transfer.

The technology that allows us to grow embryos to day 5 or 6, continues to improve, and in line with this, we are offering blastocyst transfer and freezing to more patients. In particular, our ability to culture embryos in a reduced oxygen environment reduces stress on the embryos and therefore provides healthier embryos for transfer and freezing. In 2005, slightly less than 10% of our fresh and frozen embryo transfers were performed on day 5, but this number is likely to increase dramatically in 2006. Individuals using donor oocytes comprised almost half of the day 5 transfers, since we tend to have many embryos to choose from in these cases. Blastocyst transfer will not be an option for everybody, and not everyone will have enough blastocysts to transfer and freeze. We are freezing blastocysts almost every day now and transfers with thawed blastocysts are becoming a regular part of our laboratory routine. If you think that you might be a candidate for a blastocyst transfer, please talk to your physician for more information.

ANNOUCEMENT    MIND/BODY@PFC Registration Openings

Workshops are taught by Pacific Fertility Center's experienced fertility caregivers Peggy Orlin, MFT and Allison Chamberlain, RN, trained by Alice Domar, PhD, Harvard Medical School pioneer in the development of stress reduction tools and techniques for infertility.

Saturday, May 6th from 9AM to 4PM

Call 888 834-3095 for fee and workshop information and registration forms.

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-- Best regards from all of us at Pacific Fertility Center.