Preimplantation Genetic Testing Where are we going? Genomics Clinical Medicine Symposium Sept 29,2012 Jason Flanagan, MS,CGC

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1 Preimplantation Genetic Testing Where are we going? Genomics Clinical Medicine Symposium Sept 29,2012 Jason Flanagan, MS,CGC

2 Overview Discuss what PGD and PGS are Pt examples What we have learned Where is the field going Implications for your practice

3 History About 160 IVF cycles per year High IVF Rates Decided PGD because sending pt out

4 Why do we do PGD?

5 Background Info In Vitro Fertilization

6 Embryo Development Egg Retrieval Embryo Transfer Day

7 What is the Goal of IVF? To get eggs To get embryos To have viable embryos to transfer To have a positive pregnancy test To achieve a heart beat To carry a baby to term To bring home a healthy baby

8 What is PGD Genetic Testing We have to do IVF first One or two cells from an 8 cell embryo is examined. Not a guarantee, but significantly can reduce risk

10 What PGD is capable of? Testing embryos we have One shot/one cell Only can test for known mutations Not a screen of the genome Can not modify genes Takes a long time to set up Example Cystic Fibrosis F508 normal F508 normal

13 Treacher Collins

14 X-linked Hydrocephalus ndex.htm

15 PGS v PGD PGS PGD Screen CGH Test has to be tailored Chromosomes to patient Reasons Cost is more Primary-Prevent MR Set up is longer Secondary Age RPL Failed IVF cycles Chromosome rearrangement Known risk

16 Genetic 101 PGS PGD

17 Our Policy for Offering PGS Over age 35 Three or more miscarriages More than one failed IVF cycle Familial translocation Undergoing PGD for single gene issues

18 Why do we do PGS Decrease the likelihood of having a baby with a chromosome issue

19 But what if Could PGS also increase pregnancy rates Could decrease miscarriages Could be a cost benefit Could take the place of prenatal diagnosis

20 PGS with FISH Little benefit/maybe even harmful Missed many/wrongly diagnosed many

21 How successful is PGS with FISH?

ASRM 2008 and Proposed 2012 There is good evidence to recommend against the use of PGS as currently performed to improve live birth rates in patients with advanced maternal age.

22 ASRM 2008 and Proposed 2012 There is good evidence to recommend against the use of PGS as currently performed to improve live birth rates in patients with advanced maternal age. There is insufficient evidence to support the use of PGS as currently performed to improve live birth rates in patients with recurrent pregnancy loss. There is good evidence to recommend against the use of PGS as currently performed to select the best embryo to transfer in good prognosis patients. *No study prior to 2011 *All based upon FISH data

23 PGS

24 Our Laboratory 3000 genomic regions 6000 independent measurements 250 measurements on every chromosome Can be completed in as little as three hours

25 13;14 Translocation

26 Recessive Condition and Age

27 What is going on? Chromosome issues 60-90% of the embryos Expected was 20-50% Some had no normal embryos

28 IVF Success Rates In US

29 Dogma

Adapted from Reprogenetics Data 80 70 60 50 40 30 20 10 Implantation Rate after PGS

30 Adapted from Reprogenetics Data Implantation Rate after PGS Aneuploidy Rate Cycles with no viable embryos Expected Implantation Rate

31 Can PGS also decrease miscarriage?

32 RPL Hormonal PCOS, Diabetes, Imbalances Structure Immune/Autoimmune Blood Clotting?????? Chromosome rearrangements Single gene mutations

33 Dogma 20% of pregnancies end in loss Fetal aneuploidy accounts for c. 20% losses (Hassold & Hunt, 2001). Inherited Thromobophila poses a significant/modest increase risk for miscarriage and should be treated with prophylactic therapy.

34 RPL

35 Unexplained/Failed IVF

36 New thoughts 80% of conceptions result in loss Of those ~80% are due to chromosome problems This is not seen in other species and is mostly a human phenomenon (mice-1-4%, cows ~4%,pig ~4%) A prospective study of 102 IVF couples 90% of FVL carriers first embryo transfer was successful (defined as successful implantation of the embryo) compared with 49% in F5 negative (Gopel et al,2001 ). van Dunne et al, 2005 thrombophilic factors are protective in the first trimester 1 in 3 or greater has an inherited thrombophilia Frequency of Aneuploidy Related to Age in Porcine Oocytes Miroslav Hornak

37 Should everyone be offered? If Doing IVF-should everyone be offered If more than one miscarriage or 2 or 3 All couples with infertility? Just talk about it with everyone, women over 35?

38 New Clinical Trial Patients undergoing IVF 51.8% success without IVF 76.1% success if adding PGS Of those who got Pregnant 87.2% had a delivery if doing PGS 68.3% had a delivery if not doing PGS 35% chance each cycle to take home a baby with IVF 66% chance each cycle to take home a baby if doing PGS Dr. Richard T. Scott Jr. et al

39 Implications of Data May be no need to screen prenatally Only need to transfer one Reduce the number of multiples one screened embryo is better than two unscreened Decrease Postnatal complications Cost effective Transfer one would save estimated $18K per IVF patient

40 What else have cases taught us

41 Donor to sister

42 Sister did IVF with PGS

com/ 8p23 deletion http://www.rarechromo.

43 Deletion Syndromes are described 2q35 deletion syndrome 8p23 deletion NP.pdf

44 42 years old

Things to consider http://www.google.com/imgres?q=consider+comic&um=1&hl=en&safe=off&rlz=1c1wzpd_en US407&tbm=isch&tbnid=EAcI7aAThaM8WM:&imgrefurl=http://comicpanda.

45 Things to consider US407&tbm=isch&tbnid=EAcI7aAThaM8WM:&imgrefurl= 16&imgurl= d0fb7abed94.jpg&w=780&h=474&ei=kis_umn8kyxiqgguxocoba&zoom=1&iact=hc&vpx=63 7&vpy=588&dur=13778&hovh=175&hovw=288&tx=168&ty=91&sig= &page=2&tbnh=122&tbnw=201&start=47&ndsp=54&ved=1t:429,r:2,s:47,i:230&biw=1680&bih =965

46 Drawbacks Cost 1. Biopsy -$ Genetics-» $2000 for PGS» $3850 for PGD IVF-13K Damage to embryo/reduce viability No DNA intact/can t detect everything Mosaicism All the embryos are abnormal

Day 5 or Day 3 Day 5 Day 3 Reprogenetics Data presented at NSGC 2011 Implantation Rate Aneuploidy Rate 30-34 85.7% 40.4% 35-39 63.8% 49.2% 40-42 77.7% 61.

47 Day 5 or Day 3 Day 5 Day 3 Reprogenetics Data presented at NSGC 2011 Implantation Rate Aneuploidy Rate % 40.4% % 49.2% % 61.1% Implantation Rate Aneuploidy Rate % 50.5% % 65.1% % 77.7% Clinical pregnancy is around 30 percent higher when all embryos are frozen European Society of Human Reproduction and Embryology

48 Study of Day 5 or Day 3 Less Biopsies-aneuploid embryos less likely to make it to day 5 Implantation rate was not significantly different across ages when chromosomes were controlled for Day 3 implantation rate is not due to a screen issue. The most significant issue is uterine receptive issue. (may be function of age) Miscarriage rate were significantly reduced Decrease risk for multiples because of routine single transfer

49 Conclusions PGD is a well known and accepted process of inherited conditions Should be standard of care/covered benefit All patients should be offered genetic screening today because of the option of doing PGD diseases Cost is reasonable

50 Conclusion PGS has remaining questions, but Moving toward transfer of one May be moving toward day 5 biopsy and frozen transfers Cost effective to do PGS for all IVF pts May increases pregnancy rates, but more importantly the take home rate Need more studies with CGH, studies after 2012

51 Practical Implications: RPL Greatest risk is Chromosomal Not inherited/but spontaneous Second greatest risk is hormonal Early in pregnancy, thrombophilia factors may be beneficial Couples with RPL should have POC testing should be CGH Couples with RPL should discuss PGS

52 Sensitivity for RPL Even if chromosome abnormalities make up the majority Still important to do a workup If nothing obvious, most couples will have success if they keep trying IVF w/pgs is expensive and not an option for all Therefore, much sensitivity is required

53 Ethical Concerns When and who presents PGS Will insurance cover it? Is it only for elite, modern eugenics? Does it stop with chromosomes whole genome Should it be offered if no genetic counseling has been done?

54 End with a case DO is 33 Seen by us originally for 3 miscarriages and now is having difficulty getting pregnant Did full workup-mthfr Het Was on Lovenox Did IVF-failed cycle Did Frozen-Miscarriage-POC (trisomy 8) Why didn t we offer her PGS?

55 Questions

PGS Embryo Screening

PGS Embryo Screening Contents What are chromosomes? 3 Why should I consider chromosome testing of my embryos? 3 Embryo testing using preimplantation genetic screening (PGS) 4 How does PGS and the chromosome