How to evaluate success with PGS

Transcription

1 How to evaluate success with PGS Don Leigh ASPIRE April 2014

2 IVF... What can be done to improve things? ~2/3 of clinical miscarriages are caused by chromosome aneuploidy Some aneuploidies are not observed in miscarriages and believed to be implantation/development lethal IVF implantation rates decrease with increasing age IVF embryos show variable aneuploidy rates (5-70% age related) Natural pregnancies show an age related increase in incidence of trisomy 21 PGS should provide an opportunity to improve the success of an embryo transfer Transfers have emotional, time and monetary costs Implantation failures and miscarriages have high emotional cost, larger time costs, health costs and significant monetary costs It is a logical conclusion that identifying and avoiding the transfer of aneuploid embryos will change the implantation rates and also the miscarriage rates

3 Why the question about PGS efficacy? Randomised Trials Sizes: 60-~400 patients Biopsy stage: 8x blastomere (1/2 cells), 1x blastocyst Prognosis group: AMA (5), Good (3), RIF (1) Outcomes Implantation rates: Control 7%-60% Test 14%-56% Miscarriage rates: Control 4%-38% Test 20%-70% Mastenbroek et al 2011

4 What did PGS offer? Aneuploid embryos were identified and excluded but most results were poorer X X X X The simplest conclusion was that PGS is in fact detrimental to transfer outcomes...!!

5 PGS back then..... ESHRE data XI Implantation rate: 13%-35% ave. 22% Miscarriage rate: 6%-39% ave. 16% Polar Body (RGI) Implantation rate: ~32% Miscarriage rate: decreased Literature Implantation rate: 20%-35% Miscarriage rate: <10% FISH- 5c, 7c, 9c

6 The arguments back then... Poor Biopsy technique Poor biopsy technique damages the embryo 1 blastomere- development stage sometimes not appropriate 2 blastomeres- reported already as detrimental Poor analysis Poor technique High analysis failure rate indicative of poor lab practices Wrong screening set used 5-9 chromosomes tested- but these are not the most prevalent aneuploidies observed in embryos (35-60% coverage) Mosaicism Cleavage stage embryos often mosaic. Wrong identification and exclusion. Loss of good cells leaving poorer embryo. Rejection of good embryos

7 A laboratory process can have a major impact on success Polar Body Technically the most challenging (good technique essential) Debate on whether it is inclusive enough to identify sufficient aneuploidies Day 3 Day 5 Mosaicism may be relevant (but realistically how relevant?) Some technical challenges (good technique important) Need extended culture (not difficult in a good lab) Technically straight forward Time needed for analysis- freezing?

8 A breakthrough...? Wells et al 2008 Implantation failure patients Day 5 trophectoderm biopsy Vitrified embryos CGH 24 chromosome screen Finally.. Total chromosome screen Implantation rates approached 70%

9 PGS now.... Now all gross chromosome abnormalities were identifiable- including those aneuploidies leading to implantation failure and miscarriage typically 40% to 70% of embryos are aneuploid and should not be used Now more and more studies report similar positive implantation rate changes after PGS But Wells group also did D5 biopsy Frozen cycles Were these the important differences?

10 Stage of biopsy % Screening must improve outcomes >60% just to overcome impact of biopsy 50% 40% 30% control biopsy 20% 10% 0% Treff et al 2011 day 3 biopsy day 5 biopsy

11 To measure Success- the interested parties... Patient Clinician Laboratory Clinic (Finance, marketing,... )

12 Success- for the patient Patients come to the clinic for many reasons Subfertility Implantation failure, miscarriage Advanced maternal age Monogene disorder/translocation Recurrent miscarriage patients just want a pregnancy A continuing pregnancy This will not be achieved for some patients Actually, the patient actually wants a baby A healthy baby Possibly babies- healthy babies- this will not be achieved for a significant number of patients

13 Success- for the clinician Good stimulation Good eggs (cannot get a good embryo from a bad egg) Good embryos A transfer (uterine receptivity)»a pregnancy A healthy baby A happy patient

14 Success- for the Lab Need good eggs Good embryos (fert*, culture*) Biopsy*/analysis* Transfer (or freeze*)»pregnancy Healthy baby

15 The caveats.... PGS does not make any embryo better- it is only a tool to facilitate embryo choice to avoid a significant source of biological negatives At best, the laboratory maintains the vitality of an embryo... or in a poorly operating clinic makes it worse PGS does not improve the patient factors (eg uterine receptivity) PGS should not be thought of as the best way to improve a clinic s outcomes Implantation rate is a key lab performance indicator- general fresh and frozen implantation rates show how a clinic is performing In some cases, lab improvements may be the best approach to give the improvements that a clinic is after (Beyer et al 2008)

16 PGS can be a positive Performed correctly, PGS Improves implantation rates for some (most?) patients Decreases the futile transfers for most patient types (young, AMA, recurrent implantation failure*, miscarriage*, tl) by avoiding transfer of unfit embryos Decreases miscarriage rates Minimises miscarriage especially for AMA and tl carriers (but only aneuploid related miscarriages) Can offer single embryo transfer cycles as a real option Without losing pregnancy rates Double embryo transfers and the risks associated with multiple gestations can be a thing of the past

17 What limits successful application of PGS? -ve factors Poor stimulation Poor embryology- biopsied embryos show greater sensitivity to lab conditions Biopsy- poor technique has greater negative impact Biopsy timing- different costs at different stages Poor freezing (fresh = frozen) Analysis- poor analysis loses good embryos Transfer- fresh vs frozen Uterine receptivity and state, embryo/uterus synchronicity

18 Other considerations Successful pregnancy is a +/- outcome PGS only changes the approach to this outcome. Some patients will not achieve a pregnancy Not with their own eggs (sperm) Not with anyone s embryos Everything we do to an embryo has a negative impact- some big, some small

19 Will PGS offer all clinics success? PGS does work in the right situations- previous failures to show improvements were likely a combination of too many negatives with insufficient positives. Current failures may point to clinic failures Biopsy may have a larger negative impact on outcome than the positive gain of excluding aneuploid embryos Different patient groups will see different levels of improvement after PGS- but most will see something Some clinics should possibly not be attempting PGS until they improve general lab outcomes

20 The final measure of success.... When the result/outcome >> original likely outcome This will occur with PGS when all of the steps from egg through embryo through analysis through transfer/storage are all appropriate and optimal

21 PGS and its limits PGS offers assistance in identifying the best starting point- it only changes implantation rate Current form of PGS will improve More detail?more improvement in IR? BUT Without better understanding of the patient variables as well, then the approach to a 100% outcome will stall In the future Preimplantation screening will include both embryo status and patient variables

22 Thank you

23 The Patient Typically limited exposure to IVF Primary or secondary infertility Often reason for sub-fertility not known Male factor, female factor, neither, both Maybe has tried IVF Implantation failure Sub-clinical miscarriages Age risk of Down syndrome Only a few aneuploid syndromes identified- other aneuploidies result in implantation failure or early loss Clinical use- chromosome rearrangements New type of patient fertile but a miscarriage history

24 The clinician Cannot get a good embryo from a bad egg Compromised maturation Other factors (Stimulation type, trigger, etc) Aneuploidy? Number of eggs Low quality? Age related decline in recruitment (AMH) Age related aneuploidy increase Base line may reach 60-70% (more if translocation involved)

25 Success for the lab Egg quality Delivered (Bad eggs, bad embryos) Fertilisation Male factors, lab skills Culture conditions Impact of compromised laboratory conditions on growth and development Transfer timing Embryo stage Patient receptivity