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Ly K.D.,Cleveland Clinic | Agarwal A.,Cleveland Clinic | Nagy Z.P.,Reproductive Biology Associates
Journal of Assisted Reproduction and Genetics | Year: 2011

Despite an ongoing debate over its efficacy, preimplantation genetic screening (PGS) is increasingly being used to detect numerical chromosomal abnormalities in embryos to improve implantation rates after IVF. The main indications for the use of PGS in IVF treatments include advanced maternal age, repeated implantation failure, and recurrent pregnancy loss. The success of PGS is highly dependent on technical competence, embryo culture quality, and the presence of mosaicism in preimplantation embryos. Today, cleavage stage biopsy is the most commonly used method for screening preimplantation embryos for aneuploidy. However, blastocyst biopsy is rapidly becoming the more preferred method due to a decreased likelihood of mosaicism and an increase in the amount of DNA available for testing. Instead of using 9 to 12 chromosome FISH, a 24 chromosome detection by aCGH or SNP microarray will be used. Thus, it is advised that before attempting to perform PGS and expecting any benefit, extended embryo culture towards day 5/6 should be established and proven and the clinical staff should demonstrate competence with routine competency assessments. A properly designed randomized control trial is needed to test the potential benefits of these new developments. © 2011 Springer Science+Business Media, LLC.

Noyes N.,New York University | Boldt J.,Community Health Network Inc. | Nagy Z.P.,Reproductive Biology Associates
Journal of Assisted Reproduction and Genetics | Year: 2010

As more reproductive-age women survive cancer at the expense of gonadotoxic therapy, the need for viable fertility preservation options has become paramount. Embryo cryopreservation, often using donor sperm, has been the standard offered these women over the past 20 years. Preservation of unfertilized oocytes now represents an acceptable and often equally viable alternative, particularly for single women, due to technologic advances made in the past decade. Given such, oocyte cryopreservation's experimental designation and need for IRB approval should thus be revisited. © 2010 Springer Science+Business Media, LLC.

Shapiro D.B.,Reproductive Biology Associates | Pappadakis J.A.,Actavis Inc. | Ellsworth N.M.,Reproductive Biology Associates | Hait H.I.,Edenridge Associates LLC | Nagy Z.P.,Reproductive Biology Associates
Human Reproduction | Year: 2014

Study question: Does the type of luteal support affect pregnancy outcomes in recipients of vitrified blastocysts? Summary answer: Luteal support with vaginal progesterone gel or i.m. progesterone (IMP) results in comparable implantation and pregnancy rates in IVF patients receiving vitrified blastocysts. What is known already: In fresh IVF cycles, both IMP and vaginal progesterone have become the standard of care for luteal phase support. Due to conflicting data in replacement cycles, IMP is often considered to be the standard of care. Study design, size, duration: Retrospective analysis of 920 frozen embryo transfer (FET) cycles between 1 January 2010 and 1 September 2012. Participants/materials, setting, methods: Patients from a large, private practice undergoing autologous and donor FET using IMP or vaginal progesterone gel for luteal support were included in the analysis. IMP was used for luteal support in 682 FET cycles and vaginal progesterone gel was used in 238 FET cycles. Standard clinical outcomes of positive serum hCG levels, implantation, clinical pregnancy, spontaneous abortion and live birth were reported. Main results and the role of chance: The IMP and vaginal progesterone gel groups had similar patient demographics for all characteristics assessed. Implantation rates (46.4 versus 45.6%, P = 0.81), clinical pregnancy rates (61.7 versus 60.5%, P = 0.80) and live birth rates (49.1 versus 48.9%, P > 0.99) were not significantly different between IMP and vaginal progesterone gel, respectively. Limitations, reasons for caution: This study is limited by its retrospective design and by its lack of randomization to the type of luteal support. In addition, because noa priori expected rates of success could be provided for this retrospective investigation, it wasnot possible to estimate statistical power associated with the various outcomes presented. Wider implications of the findings: With the recent trends toward single embryo transfer (SET) and use of vitrified blastocysts in FET cycles, our data with ∼40% of cycles being SET and use of exclusively vitrified blastocysts are more relevant to current practices than previous studies. © The Author 2014.

Cobo A.,IVI Valencia | Remohi J.,IVI Valencia | Chang C.-C.,Reproductive Biology Associates | Nagy Z.P.,Reproductive Biology Associates
Reproductive BioMedicine Online | Year: 2011

Oocyte donation is an efficient alternative to using own oocytes in IVF treatment for different indications. Unfortunately, 'traditional' (fresh) egg donations are challenged with inefficiency, difficulties of synchronization, very long waiting periods and lack of quarantine measures. Given the recent improvements in the efficiency of oocyte cryopreservation, it is reasonable to examine if egg donation through oocyte cryopreservation has merits. The objective of the current manuscript is to review existing literature on this topic and to report on the most recent outcomes from two established donor cryobank centres. Reports on egg donation using slow freezing are scarce and though results are encouraging, outcomes are not yet comparable to a fresh egg donation treatment. Vitrification on the other hand appears to provide high survival rates (90%) of donor oocytes and comparable fertilization, embryo development, implantation and pregnancy rates to traditional (fresh) egg donation. Besides the excellent outcomes, the ease of use for both donors and recipients, higher efficiency, lower cost and avoiding the problem of synchronization are all features associated with the benefit of a donor egg cryobank and makes it likely that this approach becomes the future standard of care. Oocyte donation is one of the last resorts in IVF treatment for couples challenged with infertility problems. However, traditional (fresh) egg donation, as it is performed today, is not very efficient, as typically all eggs from one donor are given to only one recipient, it is arduous as it requires an excellent synchronization between the donor and recipient and there are months or years of waiting time. Because of the development of an efficient oocyte cryopreservation technique, it is now possible to cryo-store donor (as well as non-donor) eggs, maintaining their viability and allowing their use whenever there is demand. Therefore, creating a donor oocyte cryobank would carry many advantages. In the present manuscript, the current experience with oocyte donation using cryopreservation technology is reviewed. The outcomes of two recently established donor egg cryobanks at Instituto Valenciano de Infertilidad in Spain and Reproductive Biology Associates in the USA (involving a large number of cases) demonstrate that egg cryo-survival is high and that fertilization, embryo development, implantation and pregnancy rates are similar to those reported after fresh egg donation. It also provides additional advantages of being more efficient, more economical, easier for both donors and recipients and potentially also safer, because eggs can now be quarantined for 6 months (or longer) to retest for infectious diseases in the donors. It is the opinion of the authors, based on several advantages associated with the use of donor egg cryobanking, that in the future there will be fewer traditional egg donations and increasingly more cryo-egg donations. © 2011, Reproductive Healthcare Ltd. Published by Elsevier Ltd. All rights reserved.

Chang C.-C.,Reproductive Biology Associates | Nel-Themaat L.,Reproductive Biology Associates | Nagy Z.P.,Reproductive Biology Associates
Reproductive BioMedicine Online | Year: 2011

Until recently, success in oocyte cryopreservation has been very limited mainly due to poor understanding of the complex physiological processes that lead to cell damage during cryopreservation. In the past three decades, however, a wealth of information has been collected using various different animal models, which has led to development of new technologies and optimization of existing ones. The use of these models has provided the opportunity for research that may not have been possible with human material. Today, results of these studies still continue to form the basis of oocyte cryobiology. This review discusses these studies, especially the physiological impacts of cryopreservation on oocyte biology. It will also focus on the role that animal models have played in improvement strategies, validation before translating new techniques into the human model and the advances made in the human in IVF because of these animal models. Finally, existing investigations and their potential impact in other areas of research will be discussed. Until recently, success in oocyte cryopreservation has been very limited mainly due to poor understanding of the complex physiological processes that lead to cell damage during cryopreservation. In the past three decades, however, a wealth of information has been collected using various different animal models, which has led to development of new technologies and optimization of existing ones. The use of these models provided the opportunity for research that may not have been possible with human material. Today, animal models still continuously provide imperative data that facilitate further advancements in oocyte cryobiology. This review will focus on the physiological impacts, current improvement strategies and future applications of oocyte cryopreservation using animal models as they benefit not only human oocyte cryopreservation procedures, but also the human species through their usefulness in agriculture, medicine and conservation. © 2011, Reproductive Healthcare Ltd. Published by Elsevier Ltd. All rights reserved.

Nel-Themaat L.,Reproductive Biology Associates | Nagy Z.P.,Reproductive Biology Associates
Placenta | Year: 2011

Embryo viability assessment is one of the most important and challenging tasks in IVF. Evaluation of embryo quality is critical when selecting the best embryo(s) to transfer or cryopreserve. Until recently, the only instrument used for embryo evaluation was the inverted light microscope, which provided information based on morphological characteristics. Developmental and morphological information gained from microscopic assessment have been positively associated with IVF outcomes, including pregnancy and implantation rates. However, based on general statistics, it is clear that IVF currently still results in relatively low pregnancy rates, while simultaneously being associated with relatively high multiple implantation rates. Only with novel embryo assessment and selection procedures would it be possible to improve these outcomes. Accordingly, it has been proposed that it is possible to test the culture environment of a developing embryo to gain valuable information regarding its viability. Different approaches have been used. These include the measurement of oxygen consumption by the embryo and testing of the soluble HLA-G in the environment, as it was proposed that secretion of HLA-G is associated with higher implantation rates. Amino acid turnover, which appears to be correlated to blastocyst development, can be measured as an indication of embryo viability. Other approaches, such as time-lapse video observation or cumulus cell gene expression analysis, may be used in the future to gain a broader understanding of embryo viability. Proteomics and metabolomics are also useful tools for assessment of embryo developmental potential. Results from recent studies on predicting embryo viability by analyzing the metabolome of different stage embryos are promising, as increases in pregnancy and implantation rates were obtained using the metabolomic profile for embryo selection. Several novel approaches are currently being developed to aid in viability assessment. These need to be evaluated in prospective clinical trials, while considering their practicality in the clinical laboratory. © 2011 Elsevier Ltd. All rights reserved.

Capalbo A.,Center for Reproductive Medicine | Wright G.,Reproductive Biology Associates | Elliott T.,Reproductive Biology Associates | Ubaldi F.M.,Center for Reproductive Medicine | And 2 more authors.
Human Reproduction | Year: 2013

STUDY QUESTIONDoes comprehensive chromosome screening (CCS) of cells sampled from the blastocyst trophectoderm (TE) accurately predict the chromosome complement of the inner cell mass (ICM)?SUMMARY ANSWERComprehensive chromosome screening of a TE sample is unlikely to be confounded by mosaicism and has the potential for high diagnostic accuracy.WHAT IS KNOWN ALREADYThe effectiveness of chromosome aneuploidy screening is limited by the technologies available and chromosome mosaicism in the embryo. Combined with improving methods for cryopreservation and blastocyst culture, TE biopsy and CCS is considered to be a promising approach to select diploid embryos for transfer.STUDY DESIGN, SIZE, DURATIONThe study was performed between January 2011 and August 2011. In the first part, a new ICM isolation method was developed and tested on 20 good morphology blastocysts. In the main phase of the study, fluorescence in situ hybridization (FISH) was used to reanalyse the ICMs and TEs separated from 70 embryos obtained from 26 patients undergoing blastocyst stage array comparative genome hybridization (aCGH) PGS cycles.MATERIALS, SETTING, METHODSThe isolated ICM and TE fractions were characterized by immunostaining for KRT18. Then, non-transferrable cryopreserved embryos were selected for the FISH reanalysis based on previous genetic diagnosis obtained by TE aCGH analysis. Blastocysts either diploid for chromosome copy number (20) or diagnosed as single- (40) or double aneuploid (10) were included after preparing the embryo into one ICM and three equal-sized TE sections. Accuracy of the aCGH was measured based on FISH reanalysis. Chromosomal segregations resulting in diploid/aneuploid mosaicism were classified as 'low-', 'medium-' and 'high-' grade and categorized with respect to their distribution (1TE, 2TE, 3TE, ICM or ALL embryo). Linear regression model was used to test the relationship between the distributions and the proportion of aneuploid cells across the four embryo sections. Fisher's exact test was used to test for random allocation of aneuploid cells between TE and ICM.MAIN RESULTS AND THE ROLE OF CHANCEAll ICM biopsy procedures displayed ICM cells in the recovered fraction with a mean number of ICM cells of 26.2 and a mean TE cell contamination rate of 2%. By FISH reanalysis of previously aCGH-screened blastocysts, a total of 66 aneuploidies were scored, 52 (78.8%) observed in all cells and 14 (21.2%) mosaic. Overall, mosaic chromosomal errors were observed only in 11 out of 70 blastocysts (15.7%) but only 2 cases were classified as mosaic diploid/aneuploid (2.9%). Sensitivity and specificity of aCGH on TE clinical biopsies were 98.0 and 100% per embryo and 95.2 and 99.8% per chromosome, respectively. Linear regression analysis performed on the 11 mosaic diploid/aneuploid chromosomal segregations showed a significant positive correlation between the distribution and the proportion of aneuploid cells across the four-blastocyst sections (P < 0.01). In addition, regression analysis revealed that both the grade and the distribution of mosaic abnormal cells were significantly correlated with the likelihood of being diagnosed by aCGH performed on clinical TE biopsies (P = 0.019 and P < 0.01, respectively). Fisher's exact test for the 66 aneuploidies recorded showed no preferential allocation of abnormal cells between ICM and TE (P = 0.33).LIMITATIONS, REASONS FOR CAUTIONThe study is limited to non-transferable embryos, reanalyzed for only nine chromosomes and excludes segmental imbalance and uniparental disomy. The prevalence of aneuploidy in the study group is likely to be higher than in the general population of clinical PGD embryos.WIDER IMPLICATIONS OF THE FINDINGSThis study showed high accuracy of diagnosis achievable during blastocyst stage PGS cycles coupled with 24-chromosomes molecular karyotyping analysis. The new ICM isolation strategy developed may open new possibilities for basic research in embryology and for clinical grade derivation of human embryonic stem cells.STUDY FUNDING/COMPETING INTEREST(S)No specific funding was sought or obtained for this study. © The Author 2013.

Popal W.,Reproductive Biology Associates | Nagy Z.P.,Reproductive Biology Associates
Clinics | Year: 2013

There are two main reasons why sperm may be absent from semen. Obstructive azoospermia is the result of a blockage in the male reproductive tract; in this case, sperm are produced in the testicle but are trapped in the epididymis. Non-obstructive azoospermia is the result of severely impaired or non-existent sperm production. There are three different sperm-harvesting procedures that obstructive azoospermic males can undergo, namely MESA (microsurgical epididymal sperm aspiration), PESA (percutaneous epididymal sperm aspiration), and TESA (testicular sperm aspiration). These three procedures are performed by fine-gauge needle aspiration of epididymal fluid that is examined by an embryologist. Additionally, one technique, called TESE (testicular sperm extraction), is offered for males with non-obstructive azoospermia. In this procedure, a urologist extracts a piece of tissue from the testis. Then, an embryologist minces the tissue and uses a microscope to locate sperm. Finding sperm in the testicular tissue can be a laborious 2- to 3-hour process depending on the degree of sperm production and the etiology of testicular failure. Sperm are freed from within the seminiferous tubules and then dissected from the surrounding testicular tissue. It is specifically these situations that require advanced reproductive techniques, such as ICSI, to establish a pregnancy. This review describes eight different lab processing techniques that an embryologist can use to harvest sperm. Additionally, sperm cryopreservation, which allows patients to undergo multiple ICSI cycles without the need for additional surgeries, will also be discussed. © 2013 CLINICS.

Chang C.-C.,Reproductive Biology Associates | Elliott T.A.,Reproductive Biology Associates | Wright G.,Reproductive Biology Associates | Shapiro D.B.,Reproductive Biology Associates | And 2 more authors.
Fertility and Sterility | Year: 2013

Objective: To determine whether the process of oocyte vitrification affects oocyte viability in in vitro fertilization (IVF) patients between 30 and 39 years of age. Design: Prospective controlled study. Setting: Private IVF practice. Patient(s): A total of 30 women assigned and 22 qualified. Intervention(s): Denudation of oocytes, cryopreservation of oocytes using vitrification method in a medium with 15% ethylene glycol (EG), 15% dimethylsulfoxide (DMSO), and 0.5 M sucrose. Main Outcome Measure(s): Oocyte survival, fertilization, day-3 embryo quality, blastocyst formation, clinical pregnancy, implantation, and live-birth rates. Result(s): After denudation of oocytes, mature sibling oocytes were randomly allocated to the fresh and vitrified groups. The survival rate was 79.6% after vitrification/warming. Overall, no statistically significant differences were found in fertilization, day-3 embryo quality, or blastocyst formation rates between the fresh and vitrified groups. The positive β-human chorionic gonadotropin, clinical pregnancy rate, and implantation rate were 13 (59.0%) of 22, 10 (45.4%) of 22, and 16 (30.1%) of 53 for the vitrified group. The overall efficiency in achieving a live birth was 11 (5.9%) of 186 per vitrified oocyte. Conclusion(s): The impact of vitrification can be reduced to a minimal level, making it possible to achieve high pregnancy and implantation rates in this age group of IVF patients. © 2013 American Society for Reproductive Medicine, Published by Elsevier Inc.

News Article | December 19, 2016

News that a woman has given birth via an ovary frozen when she was nine years old is just one example of how technology is altering the limits of fertility. It’s well known that more and more women are delaying childbirth until their 30s and 40s to complete their education, pursue careers, or find the right partner. But since a woman’s fertility begins to decline by her late 20s, and even more dramatically after age 35, the result has been an increase in involuntary childlessness. The options for dealing with this have been limited. Some 61,000 babies were born with the use of in vitro fertilization in 2012 (accounting for 1.5 percent of all babies born in the United States), but IVF success rates also decrease with age—it works about half the time for women under 35, and less than 10 percent of the time for women older than 40. In the past, a woman unable to get pregnant through IVF had two options: egg or embryo donation, or adoption. Lately another option has gained some ground: oocyte cryopreservation. Egg freezing is nothing new (the first successful pregnancy with frozen eggs was reported in 1986), but its efficiency has been extremely low—in its first two decades of use, the method would require an average of 100 frozen eggs to result in one baby. But in recent years we’ve seen the breakthrough of flash freezing technology, also known as vitrification. With this technique, the efficiency of egg cryopreservation has improved dramatically—we now need only four to 12 eggs to have a baby. Women can now cryopreserve their eggs during their peak reproductive period (ideally under age 30) and store those eggs until they are ready to have children. A frozen egg maintains its viability at the chronological age when it was obtained—in other words, it stops aging—and the womb itself has no age-related decline in its ability to sustain implantation and carry pregnancy. It is estimated that several tens of thousands babies were born from frozen eggs in the last few years. Some people call oocyte preservation the “second sexual revolution.” A recently emerged alternative to egg freezing is ovarian tissue cryopreservation. Just last week it was reported that a 24-year-old woman in London had given birth via an ovary that had been removed and frozen when she was nine years old. The woman had been diagnosed with a blood disorder as a girl, and the ovary had been removed and frozen to save it from the damage of chemotherapy. There’s also promising research aimed at “rejuvenating” aged oocytes. One approach is to replace the cytoplasm (or one of its critical components, the mitochondria) of the “old” egg with cytoplasm or mitochondria extracted either from a young donor egg or from the patient’s own somatic cells (see “Rejuvenating the Chance of Motherhood?”). Yet another line of research takes advantage of induced pluripotent stem cells. In this process an already mature, or “differentiated,” somatic cell from the body can be treated to make it “de-differentiate” (return to its embryonic state). This process is followed by another treatment regimen to stimulate that cell to develop into a functional oocyte. This raises the possibility that we could make human eggs in the lab out of cells taken from a woman’s own skin. Rejuvenating eggs or making new ones in the lab are both exciting ideas. What’s also true is that the use of these techniques to treat human infertility is likely a very long way off. We’re making progress, but the best current advice for any woman thinking about delaying pregnancy is to freeze your eggs now, while you’re reproductively young, and use them later when you’re ready. Zsolt Peter Nagy is the scientific and laboratory director of Reproductive Biology Associates and an adjunct assistant professor at Eastern Virginia Medical School.

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