Highlights of the 16th Annual In Vitro Fertilization and Embryo Transfer-A Comprehensive Update-2003 Meeting, Santa Barbara, California (Part II) By David R. Meldrum, M. D. 

The 16th Annual In Vitro Fertilization and Embryo Transfer Comprehensive Update, July 2003, directed by Dr. Meldrum in conjunction with the Office of Continuing Medical Education, UCLA School of Medicine each year since 1987, attracted over 200 participants from the U.S. and around the world most of whom have been actively involved in IVF. Over the years Dr. Meldrum has gathered a renowned group of faculty who are excellent speakers, each of whom assume the responsibility for being right up to date on their assigned topics. Most U.S. IVF programs make a point of having one of their team attend at least every couple of years.

MALE FACTOR

Dr. Peter N. Schlegel (Cornell University Medical Center, New York, New York) spoke on evaluation of severe male factors. In azoospermic males, testicular biopsy is not usually necessary prior to sperm retrieval, but testing for Y chromosome deletions can be helpful since sperm have not been retrieved with complete deletion of the AZF-b or AZF-a portion of the Y chromosome. Men with sperm counts less than 5-10 million per ml should have a karyotype. The female partner of men with bilateral congenital absence of the vas deferens should be tested for cystic fibrosis mutations, since one can assume that the male is a carrier and available panels may not include all CF mutations that might be present in these men.

Dr. Agarwal (Cleveland Clinic) spoke on analysis of sperm chromatin and its relationship to male fertility and IVF outcome. Newer tests such as the sperm chromatin structure assay (SCSA) have shown that a high level of fragmentation of sperm DNA correlates with lower fertility and IVF success. The SCSA does not correlate with sperm morphology. Other studies have shown correlations of DNA fragmentation with increased oxidation products. It is therefore likely that antioxidants such as are available in nutritional supplements for men (e. g. FertilityBlend for Men) may have benefits in improved sperm DNA integrity. Sperm preparation methods may also be important. For example, Puresperm increases DNA integrity 450%.

Dr. Gianpiero Palermo (Cornell Medical College, New York, New York) spoke on ICSI, particularly with respect to whether it increases abnormalities. There have been reports of increased chromosomal abnormalities in ICSI offspring, most of which may be due to abnormalities in men with very abnormal sperm. Otherwise, the rates of congenital abnormalities and development have been the same as non-ICSI patients.

Dr. Schlegel spoke on sperm retrieval techniques. Their percentages of sperm retrieval in non-obstructive azoospermia have been 70% for XXY, 81% in hypospermatogenesis, 47% with maturation arrest, 25-30% with Sertoli-cell only, and 50% with prior chemotherapy. Only 33% have viable sperm after thaw. In men with sperm in the ejaculate found only with high speed centrifugation have lower pregnancy rates. Testicular retrieval of sperm may yield an improved outcome for these men.

IMPROVING IVF SUCCESS

Dr. Palermo spoke on their research in mice on nuclear transfer. They have been able to transfer immature nuclei from oocytes with induced cytoplasmic defects into donor oocytes whose nuclei have been removed, resulting in reconstituted oocytes, which are able to mature, to fertilize with ICSI, and to have normal embryo development. Limited studies were done in humans, although embryo development was sub optimal. Studies have also been done using somatic nuclei. This research is still quite preliminary. Progress will require demonstrating normal fetal development in animal models and improved culture techniques for maturation of immature oocytes in humans, but it remains a possibility in the future that such techniques could be a means to providing young cytoplasm for improved development of nuclei from older women.

Dr. William Schoolcraft (Colorado Center for Reproductive Medicine, Englewood, Colorado) spoke on the use of assisted hatching (AH). Although the literature has been mixed, the overall bulk of evidence shows improved outcomes with AH. It is highly technique dependent, which probably explains why not all IVF programs have seen improved success with AH. This was shown in one study reporting no benefit in which there were multiple clear deficiencies in technique.

Dr. Richard Scott (Reproductive Medicine Associates of New Jersey, West Orange, New Jersey) spoke on immunologic testing before IVF. His extensive review clearly showed that there is no benefit of testing for antibodies to phospholipids or thyroid or testing for natural killer cells or immunophenotype in women before IVF, including those with failure to become pregnant in prior IVF cycles.

Dr. Dominique de Ziegler (Hopital de Nyon, Nyon, Switzerland) spoke on uterine morphology, blood flow and contractions, which all influence implantation. His elegant presentation illustrated that the uterine factor remains an area with the most potential for improvement of IVF results.

Dr. Bill Yee (Reproductive Partners Medical Group, Southern California) spoke on treatment of the hydrosalpinx before IVF. Both salpingectomy and tubal interruption have resulted in normal IVF success. Rarely the enlarged tubes after tubal interruption can cause pelvic pain. There is a clear consensus that an ultrasound-demonstrable hydrosalpinx should be removed before IVF. A hydrosalpinx which is not visible on multiple transvaginal ultrasound scans may not interfere with IVF outcome, particularly if an endometrial biopsy shows normal integrin.

Dr. Gabriel Garzo (Reproductive Partners Medical Group, La Jolla, California) spoke on the luteal phase and transfer technique. Supplementation with both progesterone and estradiol enhances IVF success. Oral progesterone is not effective. Embryo transfer success is maximized by doing a trial or mock transfer, dilating the cervix if necessary, thorough cleaning of the cervix prior to transfer and by using ultrasound guidance.

Dr. Joseph Gambone (UCLA School of Medicine, Los Angeles, California) spoke on pregnancy outcomes following IVF. Although many studies have shown no differences between IVF and normal pregnancies in abnormalities, recent publications have suggested as much as a two-fold difference. This could represent publication bias or a statistical outlier. With so many studies showing no difference, it is likely that any increase is very small. There have been reports of increased prematurity or small for dates. A very recent report of these same associations with ovarian stimulation for intrauterine insemination suggests that these differences may be due to ovarian stimulation or infertility rather than to IVF. A small increase of placenta previa has been reported. This may be due to the variable placement of embryos with embryo transfer and could be reduced by ultrasound guidance. There have been reports of rare imprinting disorders being associated with IVF. Investigations are ongoing to determine whether these disorders are associated with any particular culture conditions or manipulations. It is important to keep perspective. Relative to the 2-3% chance of a major abnormality with any pregnancy, any possible increase related to IVF is probably a fraction of a % and may be related to infertility rather than the procedure. This issue continues to be subject to extensive scrutiny by our profession.

RPMG-TWENTY YEARS AND 4,000 IVF AND GIFT BABIES LATER, FERTILITY DOCTORS STILL GET KICK OUT OF BRINGING JOY TO INFERTILE COUPLES

It has been 20 years now since Dr. David Meldrum and Dr. Bill Yee of Reproductive Partners Medical Group (RPMG) led this country’s pioneering efforts into the exciting and uncharted world of in vitro fertilization.

Dr. Meldrum was a faculty member at UCLA and Dr. Yee at USC in the 1980s before deciding later to join forces in ultimately forming RPMG, one of the country’s leading fertility centers. Dr. Yee opened one of the first private practice infertility programs in the country, and also performed the country’s first frozen embryo transfer, resulting in a successful pregnancy and delivery. Dr. Meldrum performed the first ultrasound-guided egg retrieval resulting in a successful pregnancy and introduced IVF to a group of visiting Chinese physicians interested in duplicating the program in their country. He helped launch China’s first IVF program.

Over the course of their distinguished careers, the two fertility specialists have been involved in the conception and birth of more than 4,000 babies from assisted reproductive technology (ART), not to mention countless others in which they performed conventional fertility treatments and surgery that resulted in pregnancies and births.

Describing their work over the past 20 years as “challenging” and “fulfilling,” both doctors entered the field for different reasons. Dr. Meldrum was working in general infertility and surgery at UCLA when he became convinced that IVF was a far better approach than surgery. He and his wife were experiencing fertility issues of their own at the time, and despite the fact that he was on the ground floor of breakthrough IVF research; his wife became pregnant as a result of ovarian stimulation through the use of Perganol. She later delivered quadruplets, who are now 28.

Dr. Yee discovered his life’s work purely by luck, he says. As a senior OB/GYN resident in 1982, he was unaware that USC even had an IVF program. Dr. Yee was merely investigating the delay of a surgery when he was asked if he would assist with an egg retrieval procedure, which then was performed surgically using a method called laparoscopy. When the eggs were removed and he later examined them under a microscope, he immediately became excited by what he saw. “I fell in love with the human egg,” Yee said. “It was an incredible sight to behold.”

Over the years, both doctors have witnessed significant changes in the techniques that have been instrumental in the rapid growth, popularity and success of IVF in just two decades. Once the exclusive domain of university medical schools up until the 1980s, IVF programs later moved into the private practice realm, which opened up and exposed the new procedure to many more doctors and patients. Technological advancements in egg retrieval, embryo freezing, ICSI, and egg donation, plus continuing societal pressures on women to conceive by a certain age, have kept IVF at the forefront of infertility solutions and have contributed greatly to its increased acceptance and success worldwide.

Even after 20 years, Drs. Meldrum and Yee still find themselves enthusiastic over the evolution of IVF and the tremendous strides it has made, and continues to make. “Just when you think everything about IVF has been discovered, you hear about some new procedure or technique or technology that gets you excited and you want to learn about,” Dr. Meldrum said. He cites an example of a recent study indicating that biopsies performed on the lining of the uterus in the cycle before IVF takes place actually produced improved pregnancy success rates. The study suggested the body’s healing reaction to the biopsy allowed embryos to attach more effectively to the uterine lining and flourish, resulting in more pregnancies in the study group. “A fortuitous observation,” Dr. Meldrum said.

Besides the new procedures and technological advancements that keep them on the cutting edge of fertility and excited about their work, the doctors agree that the real rewards come in the form of patient gratification. When couples return to RPMG’s annual Parent’s Day celebrations with their children or the doctors are invited to attend birthday parties for IVF children because they are considered part of the family, their pride swells. “I just received a graduation picture from my first successful IVF case, a young woman who is now 19 and living in Colorado,” Dr. Meldrum said. “That’s when all this really hits home and is extremely rewarding.”

Dr. Yee truly enjoys the thread of humor contained in remarks he often hears from joking fathers who introduce him to others as “the guy who got my wife pregnant.” “We all laugh about it, but it’s very nice that they consider you such an important part of their families,” Dr. Yee said.

The doctors are also in agreement about the reasons behind the tremendous success rate of RPMG. The group’s success is the result of the combined knowledge, experience, commitment and dedication of the staff, and its team approach to each case. It’s also the result of proven leadership and outstanding administrative and technical support. But in the end, success is ultimately in the hands of the couple, and fate.

“We do our jobs by bringing sperm and egg together,” Dr. Yee said. “After that, it’s up to Mother Nature to do her part.”