The Paradigm of Clinical IVF is Shifting: The Time to Incorporate Validated Technologies and an Enhanced Understanding of Physiology is Now
Seemingly each month the IVF literature provides dramatic new publications detailing advances in our understanding of the physiology of the IVF system and describing powerful new genomic and culture related tools which may be employed to improve clinical outcomes. As such, the long standing paradigm of controlled ovarian hyperstimulation, oocyte retrieval, in vitro culture, and embryo transfer within a single cycle may soon be obsolete.
Embryologists and clinicians have known for decades that the substantial majority of embryos are not reproductively competent and that the endocrine milieu which accompanies controlled ovarian hyperstimulation compromises endometrial receptivity. These barriers to some extent have been overcome through careful clinical management and progressively optimized culture conditions, but IVF remains an inefficient process. A recent national review found that less than 19% of the embryos deemed of sufficient quality to be transferred ultimately implanted and progressed to delivery.
A number of new insights and technologies now provide the opportunity to bypass some of these barriers and to minimize the impact of others. The logic of embryonic aneuploidy screening is undeniable, but early efforts with FISH failed. The technology was imprecise and the results unreliable. Additionally, biopsies were typically done on day 3 at the cleavage stage which we now know is detrimental and reduce the reductive potential of those embryos by almost 40%.2 In contrast, trophectoderm biopsy at the blastocyst stage is safe and may be employed without harming embryos.
Validated assays which provide copy number analysis of all 24 chromosomes are now available. Both SNP-arrays and qPCR have class one data demonstrating the positive and negative predictive values of the test and a randomized clinical trial demonstrates higher implantation and delivery rates. Array CGH holds promise and some clinics have encouraging results. Unfortunately, the predictive value of an abnormal result has not been assessed. The proportion of embryos labeled as aneuploid which in fact possess significant reproductive potential and could have resulted in delivery of a normal infant remains unevaluated and thus unknown. Still, validated assays are available and more data is accruing at a rapid rate for all of these platforms. Embryonic aneuploidy screening has come of age.
Enhanced embryo selection through trophectoderm biopsy and aneuploidy screening has resulted in dramatic increases in implantation rates. Of course, this would in no way attenuate the adverse impact of impaired endometrial receptivity. Recent studies have improved our understanding about the onset of secretory transformation and the role which the early and enhanced progesterone rise might have on the window of implantation. The range of time in which embryos fully blastulate varies significantly and the fact that progesterone levels rise as much as a day earlier in stimulated cycles compared to natural cycles means that some embryos with excellent reproductive potential will not be ready to implant until after the optimal window of receptivity has passed. Given the dramatic improvements in cryopreservation, vitrification of these embryos with synchronous transfer the following cycle is indicated. While the liberal use of vitrification seems radical, it is not. Survivals are typically greater than 95% and implantation rates are excellent. Even embryos which have previously been biopsied tolerate vitrification very well.
Vitrification may soon find a routine role in optimal practice. There are now RCT’s demonstrating that obstetrical outcomes are better in cycles which follow the transfer of cryopreserved embryos than those which are transferred in fresh cycles. The adverse impact of the hyperstimulated milieu may extend far beyond initial implantation.
Given that the endpoint of treatment is a healthy newborn delivered at term, programs may soon be culturing all embryos to the blastocyst stage, performing trophectoderm biopsy, and then vitrifying them for transfer in a subsequent cycle if they are determined to be euploid. This paradigm does not represent “Star Wars” or a glimpse into the distant future. There are high quality class I data which indicate that each of these technologies or approaches to clinical management are already validated. The future is now.
Is the clinical paradigm of clinical IVF shifting? The foundation of good clinical practice – based on careful and methodical study of these issues – has already moved. Application of the new paradigm provides enhanced delivery rates. Synchronous transfer of a single euploid embryo provides delivery rates of 55 to 65% through maternal ages of 42. This exceeds current national delivery rates for all age groups even though those transfer involve much larger numbers of embryos and result in high rates of multiple gestations. Given that the majority of the long term complications of IVF relate to multiple gestation, it is now possible to offer enhanced delivery rates in fewer treatment cycles with near elimination of that risk and its accompanying serious iatrogenic complications.
Some programs will lead the way. Others will be hesitant to embrace this new paradigm and implement them more slowly. Still others will turn a “blind eye” to the scientific literature and continue the traditional paradigm producing inferior outcomes and greater patient risk, but they do so at their own peril.
Kathleen H. Hong, MD1
Richard T. Scott, Jr, MD, HCLD1,2
1 Division of Reproductive Endocrinology, Department of Obstetrics and Gynecology, Robert Wood Johnson Medical School- UMDNJ
2 Reproductive Medicine Associates of New Jersey
Dr. Richard T. Scott, Jr. IVI-RMA CEO, a founding partner of Reproductive Medicine Associates of New Jersey (RMANJ), a world renowned leader in reproductive medicine and cutting edge technology. Dr. Scott was also one of the pioneers of IVF and comprehensive chromosome screening.
More authored articles by Dr. Richard T. Scott.