Our fertility doctors and staff members are passionate about providing the very best for our patients. We have a unique relationship with the Department of Reproductive Medicine, University of California, San Diego as all of our doctors have full time or clinical faculty appointments. This relationship enables us to have access to cutting-edge research on fertility treatments. Learn more about the ongoing research performed by each of our fertility doctors.
Optimal Uterine Anatomy and Physiology Necessary for Normal Implantation and Placentation – Dr. David Meldrum
In our first review, Dominique deZiegler emphasizes the many changes that occur in the endometrium in women with endometriosis. Many changes also occur due to the higher hormone levels inherent in the ovarian stimulation for egg retrieval. For some women with endometriosis, those cumulative changes can prevent implantation. By transferring the embryo in a deferred cycle with hormone levels mimicking a normal menstrual cycle, implantation can be restored. Placental development is also improved, which reduces pregnancy complications. With the current evaluation for infertility not routinely including laparoscopy, endometriosis often remains undiagnosed, which is one of many reasons we generally recommend deferred transfer. Daniela Galliano from Spain describes the many structural abnormalities that can prevent implantation such as fluid-filled tubes where the fluid enters the endometrial cavity and alters endometrial function. Polyps must also be removed to maximize implantation. We routinely recommend either a saline sonohysterogram or an office hysteroscopy to thoroughly evaluate the endometrial cavity. Other important abnormalities to look for are uterine fibroids, adenomyosis, and endometritis, a difficult to diagnose chronic infection of the endometrium. Ettore Cicinelli, from Italy, has done the most work on endometritis. Although it is very uncommon in women prior to a first IVF attempt, endometritis becomes progressively more important with failed cycles.
de Ziegler D, Pirtea P, Galliano D, Cicinelli E, Meldrum D. Optimal uterine anatomy and physiology necessary for normal implantation and placentation. Fertil Steril 2016;105:844-54. PMID: 26926252. Read more.
Importance of Embryo Transfer Technique in Maximizing Assisted Reproductive Outcomes
Bill Schoolcraft, who has been one of my most successful trainees and is now a full professor at UCSD working with us on clinical IVF and teaching, covers embryo transfer technique in complete detail in our second review. There is no more important part of IVF. Bill began using ultrasound-guided embryo transfer over a decade before it became routine for most programs. If the embryo doesn’t end up in an optimal part of the endometrial cavity without disturbing the endometrium and/or inducing uterine contractions, the entire cycle can be lost. Undoubtedly embryo transfer is even more important when transferring a single embryo. One of the reasons that deferred transfer has better results is that the uterus is more relaxed, which prevents the transfer fluid from being forced out of the uterine cavity. Tubal pregnancy is less common for this reason.
Schoolcraft WB. Importance of embryo transfer technique in maximizing assisted reproductive outcomes. Fertil Steril 2016;105:855-6. PMID: 26940790. Read more.
Both Slowly Developing Embryos and a Variable Pace of Luteal Endometrial Progression May Conspire to Prevent Normal Birth in Spite of a Capable Embryo
In the third review, we cover the important issue of synchronization of the developmental stage of the embryo to that of the endometrium. Asynchrony can occur either due to a slowly developing embryo or to a variable pace of endometrial progression. Richard Scott’s group and others have found that slower embryos can fail to implant in a stimulated cycle, when the endometrium is generally accelerated, whereas they can develop normally when replaced in a deferred cycle. Carlos Simon has found that in about one-fourth of women with failed implantation the endometrium can be delayed in a natural or hormone replacement cycle. This can be evaluated by doing an endometrial biopsy during the normal window of implantation measuring an array of gene products associated with a receptive endometrium. An ongoing multicenter trial is being carried out to assess whether implantation can be restored by altering the timing of embryo replacement in those cases where the implantation window is displaced.
Franasiak JM, Ruiz-Alonso M, Scott RT, Simón C. Both slowly developing embryos and a variable pace of luteal endometrial progression may conspire to prevent normal birth in spite of a capable embryo. Fertil Steril 2016;105:861-6. PMID: 26940791. Read more.
Optimal Endometrial Preparation for Frozen Embryo Transfer Cycles: Window of Implantation and Progesterone Support
In the fourth review, Bob Casper and Elena Yanushpolsky review the information on how best to provide hormone replacement for deferred cycles to maximize implantation. This is an area that is sure to further evolve and improve overall IVF success.
Casper RF, Yanushpolsky, EH. Optimal endometrial preparation for frozen embryo transfer cycles: window of implantation and progesterone support. Fertil Steril. 2016;105:867-72. PMID: 26820769. Read more.
Local and Systemic Factors and Implantation: What Is the Evidence?
In the fifth review, the evidence regarding local and systemic factors is assessed. Embryo implantation involves an incredibly complex interaction between the embryo and the endometrium. Research is providing explanations for the altered receptivity found in many pelvic conditions and gradually clinical tools are being honed that may identify specific defects in individual women. Large numbers of transfers of chromosomally normal embryos have yielded new information on systemic factors, at times disproving the importance of factors initially thought to be important based on small studies.
Fox C, Morin S, Jeong JW, Scott RT Jr, Lessey BA. Local and systemic factors and implantation: what is the evidence? Fertil Steril 2016; 105:873-84. PMID: 26945096. Read more.
Examining the Many Potential Reasons Why Euploid Blastocycts Do Not Always Result in Viable Pregnancies – Dr. David Meldrum
Dr. Meldrum, as an Editorial Editor for Fertility and Sterility, has devoted two back-to-back “Views and Reviews”:
In my introduction, I emphasize that a better embryo (part 1) will maintain a better conversation with the endometrium (signals from the embryo improve the endometrium and vice-versa), but even the best embryo will fail if the uterine environment is not adequate to sustain normal implantation and placentation. Our efforts to maximize the birth rate with transfer of a single embryo make this an even more important field of research.
Meldrum DR. Introduction: Examining the many potential reasons why euploid blastocysts do not always result in viable pregnancies (and deliveries): part 2. Fertil Steril 2016;105:841-3. PMID: 26930618. Read more.
Meldrum, DR. Introduction: Examining the many potential reasons why euploid blastocysts do not always result in viable pregnancies: part 1. PMID: 26730497. Read more.
Effects of Aging and the Environment on Egg Quality
In our review of effects of aging and the environment on egg quality, we discuss adverse effects of decreased cellular energy supplies in the aging egg and the recent finding that those effects can be largely reversed in the aging mouse by co-enzyme Q-10. Although experience in the human is preliminary, a trend toward improved chromosome distribution was noted. We also reviewed the adverse effects of decreased male hormone levels as women age and the adverse effects of obesity, smoking, alcohol, and psychological stress. We emphasized that the oocytes destined to ovulate are developing over a 3 to 6 month period. Therefore patients should be encouraged to wait to have the maximal impact of interventions such as exercise in the obese woman, cessation of smoking, completion of psychological interventions such as a mind/body program, dietary improvements, exercise, and supplements such as antioxidants or omega-3’s. We understand that couples hate to wait but even for the older female, the benefit of those interventions may improve their success more than any small reduction due to postponing their IVF cycle. Although 3 to 6 months may be ideal, 4 months may be a reasonable compromise and at least a maximal effect will be realized before any subsequent egg harvest. See www.lifechoicesandfertility for details.
Meldrum DR, Casper RF, Diez-Juan A, Simon C, Domar AD, Frydman R. Aging and the environment affect gamete and embryo potential: can we intervene? PMID: 26812244
Effects of Ovarian Stimulation
In our review of the effects of ovarian stimulation, we discussed gathering evidence that the stimulation itself has adverse effects on egg quality. That is the reason we have generally used lower gonadotropin doses, particularly as the ovarian stimulation proceeds. In some women with reduced embryo quality we suggest using a mild stimulation. As women age, inclusion of luteinizing hormone (LH) in the stimulation appears to have more importance. That is also likely ideal for all women whose own LH is suppressed by medications such as estrogen or oral contraceptives to synchronize the resting eggs so they mature together. Women who are unsuccessful with IVF or respond poorly to stimulation have lower growth hormone (GH) levels surrounding their eggs, and growth hormone levels decrease with age and increase when male hormone levels are restored. Therefore use of GH in women having IVF is replacement of normal hormone levels analogous to use of thyroid hormone to correct a deficiency. In very low prognosis women the delivery rate can be increased 3 to 4-fold. Even with the high cost of GH, a 50% increase in success would be worthwhile, which is why we recommend it in many older women even for the first cycle. We discuss the importance of FSH in the final maturation of the eggs and the modifications of the final trigger to assure that adequate FSH levels are achieved. Male hormone levels are also important for ovarian response and egg quality and that is discussed in the first review above.
Bosch E, Labarta E, Kolibianakis E, Rosen M, Meldrum D. Regimen of ovarian stimulation affects oocyte and therefore embryo quality. PMID: 26826273
The Importance of the Laboratory Environment for Maintaining Egg and Embryo Quality
In the third review of this series, we discuss the importance of the laboratory environment for maintaining egg and embryo quality. Of greatest importance is the use of 5% oxygen rather than to expose these sensitive cells to room air concentrations (about 20%). That is something we have been using for about 15 years since the earliest reports and because 5% is the normal level exposed to the eggs and embryos in pelvic tissues, but some programs are just now making that change. We have also been careful over the years to keep the culture conditions constant, such as with our use of pediatric isolettes to maintain conditions during the brief periods required for procedures. For many years, we have used cells from around the eggs to culture embryos for women who have had prior cycles with poor embryo quality. Although well supported in published studies that technique is not available in most programs. Many such factors aim to restore normal physiology (in the body, the cells remain around the egg longer than with standard IVF).
Swain JE, Carrell D, Cobo A, Meseguer M, Rubio C, Smith GD. Optimizing the culture environment and embryo manipulation to maintain viability. PMID: 26851765