Preimplantation genetic screening (PGS)

Transcription

1 Preimplantation genetic screening (PGS) Dagan Wells Reprogenetics UK

2 In vitro fertilization (IVF) A highly successful medical intervention Infertility treatment revolutionized Estimated that >5 million babies born following IVF 1-5% of all births in industrialized countries But..the process is inefficient

3 In vitro fertilization (IVF) Worldwide only 30% of IVF cycles produce a pregnancy Choose most viable embryo - based (primarily) on morphology Methods are subjective and provide only rough guide 85% of embryos transferred do not implant Solution to poor embryo selection transfer more embryos! Significant risks of complications for mother and child 20-25% of IVF pregnancies are multiple gestations

4 In vitro fertilization (IVF) Improved methods needed for embryo selection (eset) Could genetic tests provide a more definitive, less subjective assessment?

5 Aneuploid embryos (%) Chromosome abnormalities (aneuploidy) Chromosome abnormality is extremely common in embryos Problem increases with advancing maternal age 46 chromosomes per cell Female age Data from >50,000 embryos analyzed by Reprogenetics

6 Aneuploid embryos (%) Chromosome abnormalities (aneuploidy) Aneuploidy is almost always lethal (failed implantation/miscarriage) While aneuploidy increases with age, implantation rate decreases implantation rate Female age Data from >50,000 embryos analyzed by Reprogenetics

7 Concept of PGS Standard embryo evaluations do not reveal embryos with the wrong number of chromosomes IVF treatment usually results in the production of several embryos Ideally, one embryo is transferred to the uterus after chromosome screening or Munne et al., 1993

8 Preimplantation genetic screening (PGS) Polar body Blastomere Trophectoderm Analysis of chromosomes Anticipated benefits for IVF patients Reduce aneuploid syndromes Reduce miscarriage Increase embryo implantation/pregnancy rate

9 Does PGS work?

10 PGS the controversy Several randomized trials conducted almost a decade ago suggested that PGS does not improve IVF success rates However All studies screened a limited set of chromosomes In RCTs only one third of the chromosomes were tested Method used was FISH accuracy questionable Mosaicism Comprehensive chromosome analysis methods superior to FISH Biopsy at the blastocyst stage is superior to cleavage stage (less risk of damage, less mosaicism)

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12 Evidence that PGS has clinical value New comprehensive methods shown to be highly accurate: ~98% Highly predictive: Aneuploid embryos transferred rarely produce a viable pregnancy (Scott et al., Fertil Steril 2012) RCTs have now been carried out using the modern PGS methods All show that PGS provides a significant advantage

13 1 st Randomized trial: acgh + single embryo transfer, <35 years old Control PGS patients age <35 <35 replacement Day 6 Day 6 replaced 48 (1) 55 (1) pregnancy rate 45.8% 70.9% P<0.05 ongoing preg rate 41.7% 69.1% P<0.05 multiples 0 0 Yang et al. (2012)

14 2 nd randomized trial: qpcr, <42 years old PGS Control age N embryos replaced implantation 79.8% 63.2% P=0.002 sustained implant 66.4% 47.9% P=0.03 delivery rate 84.7% 67.5% P=0.01 Scott et al., 2013 Fertil Steril.

15 3 rd randomized trial: Transfer of 1 euploid embryo vs. 2 untested ongoing pregnancy rate 2 untested blastocysts 1 euploid blastocyst Fresh transfer 70% 65% NS Twins/triplets 48% 0% P<0.001 Forman et al. (2013) Fertil Steril. Mean maternal age 35 (patients <43)

16 PGS eliminates the effect of maternal age on miscarriage 40% 35% 30% 25% 20% 15% 10% 5% 0% < No PGS * PGS ** *SART, ** Harton et al. (2013) Fertil Steril, and unpublished data

17 Implantation rate PGS eliminates the negative effect of maternal age on implantation 60% 50% 40% 30% 20% No PGS * PGS (acgh) ** 10% 0% < >42 Maternal age *SART, ** Harton et al. (2013) Fertil Steril, and unpublished data

18 Who should be offered PGS?

19 Should all patients be offered PGS? Traditional PGS indications are: Advanced reproductive age (female) >34? >36? >39? Recurrent miscarriage 2 or more? 3 or more? Multiple failed IVF treatments 2 or more? 3 or more? Severe male factor? Increasing evidence that good prognosis patients benefit

20 Should all patients be offered PGS? # of blastocysts egg donors % of patients with normal embryos <35 years years years years N = 3,571 cycles and 19,356 embryos, up to 8/2013. Ata, Munne et al. (2012) Reprod Biomed Online and unpublished data. >42 years Avoid Down s. Avoid miscarriage % 85% 72% 60% 58% 24% % 97% 95% 88% 69% 54% Increase pregnancy? % 99% 96% 92% 85% 65% >10 100% 100% 98% 98% 92% 83%

21 Aneuploidy assessment - conclusions What can aneuploidy screening potentially offer? Achieve very high efficiency eset Faster time to pregnancy Avoid unnecessary embryo transfers Avoid cryopreservation of non-viable embryos Reduce miscarriage rate Reduce risk of Down syndrome Should all patients be offered aneuploidy testing Probably. However, management of patient expectations is vital

22 Future of perspectives on PGS

23 % of IVF cycles that include PGS Increasing PGS adoption PGS utilization in the USA

24 Cost per case (GB ) Increasing PGS adoption Technical developments have helped to push down costs PGS cost at Reprogenetics UK 33% reduction in three years 85% reduction Average cost for PGS Minimum cost for PGS Wells et al., 2014 Journal of Medical Genetics; Kung et al., 2015 RBM Online

25 Key point There is increasing evidence that genetic screening of embryos is of value to the majority of patients undergoing IVF Has the use of genetics to select embryos reached its zenith? No! The best is still to come Methods will become cheaper (e.g. NGS Wells et al., 2014) Viable embryos will be revealed with more certainty (e.g. MitoGrade Fragouli et al., 2015 PLOS Genetics)

26 Samer Alfarawati, PhD Dagan Wells, PhD Elpida Fragouli, PhD Samer Alfarawati, PhD Roy Naja, PhD Katharina Spath, MSc Dhruti Babariya, MSc Nada Kubikova, MSc Maurizio Poli, PhD Araz Raberi, MSc Sarah Taylor, MSc Krista Miramontes, MSc Kethan Suvarna, MSc Tishy Bruce