Should IVF centers offer preimplantation genetic diagnosis? Yes.

CONTROVERSIES IN OB/GYN Should IVF centers offer preimplantation genetic diagnosis? By Anver Kuliev, MD, PhD and Yury Verlinsky, PhD Yes. PGD can improve ART efficiency and practice standards. Preimplantation genetic diagnosis (PGD), a new approach to detecting and avoiding transfer of embryos with genetic abnormalities, is an alternative to embryo transfer based on morphologic criteria currently in use in IVF practice.1,2 Although PGD was originally introduced as an alternative option to prenatal diagnosis of preexisting genetic conditions, it has special value for practices using assisted reproduction technology (ART) because genetic factors contribute considerably to infertility problems. Because more than half the women who seek IVF are of advanced reproductive age, PGD provides an obvious tool for preselecting embryos and preventing transfer of those with age-related aneuploidies, which are major contributors to spontaneous abortions and implantation failure. PGD and advanced maternal age PGD for chromosomal abnormalities is performed by using fluorescent in situ hybridization (FISH) analysis with commercially available chromosome-specific probes to test either single blastomeres removed from eight-cell preimplantation embryos, or the first and second polar bodies removed from oocytes following their maturation and fertilization.3 To date, PGD for age-related aneuploidies has been used in approximately 3,000 IVF cycles on poor-prognosis patients, resulting in improved implantation and pregnancy rates in IVF patients of advanced maternal age.2-6 Although additional randomized, controlled studies may be needed to further quantify the impact of PGD on IVF efficiency, available data now leave no doubt about the clinical relevance of avoiding transfer of chromosomally abnormal embryos. The clinical value in using PGD to improve pregnancy and implantation rates in poor-prognosis IVF patients is obvious given the fact that almost half of the oocytes and embryos from such patients have chromosomal abnormalities. No fewer than three quarters of these chromosomally abnormal embryos are eliminated before implantation, as only one in 10 recognized pregnancies are chromosomally abnormal. So incidental transfer of defective embryos in the absence of chromosomal testing is a likely contributor to implantation and pregnancy failures in IVF patients of advanced maternal age. Of the chromosomally abnormal embryos that implant, most lead to spontaneous abortions and further impact the pregnancy outcome. Risks of "blind" selection In light of these data, the current IVF practice of "blind" selection of embryos for transfer is hardly an acceptable procedure to use in future IVF patients of advanced maternal age. Besides the extremely high risk of establishing an affected pregnancy from the onset, it will significantly compromise the already very low likelihood of pregnancy in these patients because the current tendency is to limit the number of transferred embryos to two. Although culturing embryos to day 5 (blastocyst) may allow preselection of more developmentally competent embryos compared to day-3 culture, at least one in five aneuploid embryos will still be capable of developing into a blastocyst.7 Therefore, these abnormal embryos will not be eliminated in the current shift to blastocyst transfer, but may implant and lead to spontaneous abortions, compromising the outcome of the pregnancies generated from the implanted normal embryos in multiple pregnancies, which in itself represents a severe IVF complication. In fact, in the future, this important complication may be avoided by preselection and transfer of the single blastocyst that has the greatest potential for developing into a healthy pregnancy. Such testing is currently possible for nuclear abnormalities and may soon become a reality for cytoplasmic disorders as well. PGD in younger patients While PGD counseling and aneuploidy testing may soon become standard practice for IVF patients of advanced age, preselection of aneuploidy-free embryos may have even greater value for younger IVF patients because of the much larger number of oocytes available for testing. Therefore, IVF patients will need to be informed about the availability of PGD so they have the option of being counseled about it. This will improve standards for ART practice because the current practice of "blind" selection of embryos for transfer based on morphologic parameters will be supplanted by preselection of chromosomally normal embryos with the highest possible potential to result in pregnancy. As a tool for reliable preselection of aneuploidy-free embryos, PGD can potentially contribute to prevention of the birth of children with chromosomal disorders and also be a useful tool for improving ART efficiency and standards of care. h REFERENCES 1. News Around the World: Report of the 10th Annual Meeting International Working Group on Preimplantation Genetics, in association with 3rd International Symposium on Preimplantation Genetics, Bologna, Italy, June 23, 2000. Tenth Anniversary of Preimplantation Genetic Diagnosis. J Assist Reprod Genet. 2001;18:64-70. 2. International Working Group. Preimplantation genetic diagnosis: experience of 3,000 clinical cycles. Reproductive BioMedicine Online. 2001;3:49-53. 3. Verlinsky Y, Kuliev A. An Atlas of Preimplantation Genetic Diagnosis. New York, NY: Parthenon Publishing Group; 2000. 4. Munne S, Magli C, Cohen J, et al. Positive outcome after preimplantation diagnosis of aneuploidy in human embryos. Hum Reprod. 1999;14:2191-2199. 5. Gianaroli L, Magli MC, Ferraretti AP, et al. Preimplantation diagnosis for aneuploidies in patients undergoing in vitro fertilization with a poor prognosis: identification of the categories for which it should be proposed. Fertil Steril. 1999;72:837-844. 6. Verlinsky Y, Cieslak J, Ivakhnenko V, et al. Prevention of age-related aneuploidies by polar body testing of oocytes. J Assist Reprod Genet. 1999;16:165-169. 7. Magli MC, Jones GM, Gras L, et al. Chromosome mosaicism in day 3 aneuploid embryos that develop to morphologically normal blastocysts in vitro. Hum Reprod. 2000;15:1781-1786. Controversies in OB/GYN focuses on controversial issues pertaining to the clinical practice of obstetrics and gynecology and reproductive medicine. The authors have been selected for their ability to articulate a particular point of view, regardless of their own personal convictions. We hope that these short essays will provoke discussion and help Contemporary OB/GYN's readers clarify and refine their own practice management. You can join in the dialogue by completing and faxing in the response form at the end of this article or sending us your opinion (pro or con) via e-mail to judy.orvos@medec.com. A summary of the correspondence we receive will be published in a future issue. David B. Seifer, MD, Department Editor Department of Obstetrics, Gynecology, and Reproductive Sciences UMDNJ-Robert Wood Johnson Medical School New Brunswick, N.J. Dr. Kuliev is Director of Research, Reproductive Genetics Institute, Chicago, Ill. Dr. Verlinsky is Director of Reproductive Genetics Institute, Chicago, Ill. Yury Verlinsky, Anver Kuliev. Should IVF centers offer preimplantation genetic diagnosis? Yes.. Contemporary Ob/Gyn 2003;3:54-60.