“Nothing is more powerful than an idea whose time has come."
As we approach the Christmas season, I am reminded of the story of the three wise men. Illumina’s ASRM Product Theatre took place in Baltimore this year and our three speakers came not bearing gifts but each with a different story to tell about Preimplantation Genetic Screening: One of safer clinical practice, one of cost-effectiveness, and one about the incredible advances in technology which are transforming IVF clinical practice.
The first speaker, Dr. Bruce Shapiro (Fertility Center of Las Vegas) led us through the astonishing facts about the fairly dire consequences that can arise from twin versus singleton pregnancies. The ugly side of the incredible success the US has enjoyed in terms of IVF birth rates is the unacceptably high rate of twin births (accounting for 26% of all IVF birth events in 2013 and a 16-fold higher incidence compared with natural conception). The adverse medical consequences arising from some twin pregnancies appear to be a laundry list of a pediatrician’s worst nightmares including very low birth weight, preterm birth, hearing loss, digestive problems, cerebral palsy, and neonatal death. Indeed, to better emphasize the increased likelihood of fetal death in twin pregnancy, Dr. Shapiro compared and contrasted this risk with other possibly more prosaic risks. He showed that the risk of death for a fetus in a twin pregnancy was 2,000 times that of general anesthesia and 9 times higher than that of a combat soldier completing a one year tour of duty in Iraq – a sobering statistic.
The new paradigm for IVF is to aim for the best chance of a healthy singleton baby and not necessarily the highest success rate at any cost. The message is clear: the simplest way to reduce twin pregnancies is to transfer fewer embryos – ideally transferring them one at a time (i.e. elective single embryo transfer or eSET). The requisite for eSET is excellent embryo culture, vitrification (a method of freezing), and selection of the most viable embryos for transfer to the uterus.
Bruce’s clinical experience shows that, by combining the trinity of blastocyst culture, vitrification and preimplantation genetic screening (to avoid aneuploidy), clinicians now have excellent tools to deliver safe and effective IVF: the highest possible pregnancy rate with the lowest possible chance of multiple pregnancy and very few miscarriages. Most practitioners today agree that, both statistically and medically speaking, twin pregnancies are the biggest single risk to patients undergoing IVF and are largely avoidable. This is before you even begin to consider the financial costs of multiple births to patients and the wider society. Did someone say costs? Read on…
The second speaker, Dr. Kaylen Silverberg, Medical Director of the Texas Fertility Center, spoke about the cost-effectiveness of PGS drawing on his previous work in finance. Dr. Silverberg is a dynamic speaker whose enthusiasm for any IVF topic is infectious. In this case, his discussion of cost-effectiveness, which can be a rather dry subject was illuminating and compelling. Cost-effectiveness is likely one of the most significant questions left to address in the transformation of PGS from an occasional treatment for specific patient indications to a routine part of every IVF cycle.
In his presentation, Dr. Silverberg defined cost-effectiveness as “an assessment of whether the cost of a specific action (medical treatment in this case) is greater than, less than, or equal to the actual benefit resulting from that action;” but stressed that this rather dry definition can be distilled down to the simple question: “Is PGS worth the cost?”
To answer this question, Dr. Silverberg developed a model that considers all of the factors relating to an IVF cycle using PGS as well as the resulting possible clinical outcomes and provided cost estimates for each item. In this way, he was able to demonstrate that, while PGS definitely comes at an additional cost to patients when you consider biopsy, cell preparation, transport and diagnostic testing (and in many centers, intra-cytoplasmic sperm injection (ICSI) and vitrification are standard), this cost is offset or even dwarfed by the costs incurred by the adverse outcomes which can arise at much higher frequencies in the absence of PGS, notably miscarriage and multiple births. Indeed, when costs associated with multiple births and miscarriages are compared with costs incurred using PGS, the average cost savings per patient per birth using PGS was an impressive $24, 625 for patients under 35 years of age in the model. This cost savings per patient was more than doubled ($56, 852) if the patients were older than 35 years. To date, the model is conservative and does not even consider the potential savings which arise from fewer IVF or frozen cycles, lifetime costs associated with twin morbidity, fewer babies with chromosome abnormalities, decreased embryo storage costs, and the intangible ‘costs’ relating to lost time and stress associated with failure.
Although the model was generated using U.S.-specific costs and outcome data, the cost/benefit principles are both fundamental and universal and could be adapted for any country where this information is freely available.
Professor Mark Hughes, the founder and CEO of Genesis Genetics, is a true pioneer in the world of PGD. What is striking is that, after years of pursing his lips, shaking his head and avoiding its use, he delivered a lecture about the benefits of PGS. What a difference a decade and new technology makes. His refusal to embrace PGS in its infancy was almost entirely due to the limitations of fluorescence in situ hybridization (FISH) - the only technology available at that time for PGS. As with many others, Dr. Hughes understood and was convinced by the simple rationale that clinical outcomes could be improved by eliminating aneuploidy embryos from the transfer cohort. However, the simple fact that PGS version 1 (aka FISH on cleavage stage embryos) was bedeviled by high false positive rates and the biological reality of high day 3 mosaicism rates made this test a non-starter for use in his laboratory. The introduction of chromosome screening techniques which could simultaneously analyze all 24 chromosomes with high accuracy such as array CGH (aCGH) and more recently, next-generation sequencing were the game changer for him. Combining these accurate, reliable, and reproducible technological advances in aneuploidy diagnosis with embryological advances in improved blastocyst culture and biopsy as well as dramatically more efficient freezing and thawing via vitrification now meant that samples could be batched, effectively increasing access to the technology and creating the potential to lower the cost to patients. In terms of the data quality and quantity obtained, Dr. Hughes likened the availability of Veriseq PGS (Illumina’s next-generation sequencing solution for PGS) to looking at the night sky using the Hubble telescope versus the naked eye if FISH were used (with aCGH somewhere in between - but definitely using a telescope). My crude representation of the wonderfully descriptive imagery he described is depicted in figure 1. In summary, all three technologies (FISH, aCGH, and NGS) allow you to see some part of the chromosome and answer the simple question: is it there or not? As you move towards NGS, the picture becomes ever more detailed and clear (like using the newest 4D television). As we begin to understand the clinical significance of mosaicism and sub-chromosomal gains and losses in early human development the ability to see ‘through the Hubble telescope’ rather than with the naked eye becomes ever more important. As with all great scientists, Dr. Hughes understands the benefits and limitations of technology and concluded with the reminder that there is still more to learn and that, in our enthusiasm to adopt the latest diagnostic technology, we should remember that in the complex but fascinating world of IVF, there are still many other factors (apart from the genetic test) that need to be optimized to ensure the best outcomes for patients.
In summary, the combination of blastocyst culture, vitrification and preimplantation genetic screening using the latest NGS technology is already having a major impact on reducing adverse IVF outcomes and improving desirable ones. Perhaps we have entered a new era – Next Generation IVF – an idea whose time has finally come.
Figure 1: (Click to enlarge) A representation of the night sky as seen with (a) the naked eye (b) a conventional telescope (c) the Hubble telescope.