The preventative role of preimplantation genetic diagnosis?
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1 The preventative role of preimplantation genetic diagnosis? Alison Lashwood Consultant Genetic Counsellor & Clinical Lead in PGD
2 Where it all starts.. Kay & John have a son with haemophilia A 1 st pregnancy unplanned and decided against PND Billy has the condition Couple do not find PND acceptable but do not want to have further affected child Referred for PGD
3 Background to PGD PGD has been around for a while- 25 years st PGD case (Handyside et al) XL condition st single gene disorder (Handyside et al) st HLA case (Verlinsky et al) th ESHRE report 11,000 cycles of PGD GSTT is the largest in UK 599 referrals in 2016, 14% increase since previous year 20% increase in PGD cycles in 2016
4 What reproductive options do those at risk have? Have no/no further children Take a chance Prenatal testing/non invasive prenatal testing Gamete donation Adoption Preimplantation diagnosis
5 Why PGD? Everyone is different! Wish to have unaffected child but want to avoid TOP Condition may be XL, AR or AD high risk 25% 50% Variability of severity Have genetic risk & need fertility treatment Wish to have a child who is an HLA match for a sibling
6 Principle of PGD Use egg and sperm of couple at risk to create embryos using IVF Test embryos for PID condition Transfer an unaffected embryo to womb If pregnancy occurs baby will be unaffected Affected embryo Unaffected embryo Affected embryo
7 PID conditions for which we offer PGD Omenn syndrome Chronic granulomatous disease Wiskott Aldridge syndrome Bloom syndrome Cohen syndrome Ataxia telangiectasia Di George syndrome Charge syndrome Cartilahe hair hypoplasia Hyper IgE syndrome Severe combined immune deficiency Dyskeratosis congenita Myelodysplasia syndrome Familial hemophagocytic lymphohistiocytosis Lymphoproliferative syndromes IPEX Aicardi Goutieres Severe congenital neutropenia Barth syndrome Shwachman Diamond syndrome Muckle Wells syndrome
8 Law & licensing Legislation varies internationally In UK we have the All centres must have a licence to offer PGD A licence is necessary for each new PGD condition A licence is needed for each HLA case
9 Cost & funding Funding varies internationally from no state funding to 6 funded cycles NHS England funding policy (since 2013)- up to 3 cycles To have funding agreed certain criteria must be met If couple have to self fund it is around 12,000 per cycle
10 PGD preparation timeline to embryo transfer PGD genetics appointment HFEA licence application PGD laboratory work up From 6-15 months PGD fertility unit appointment Start of PGD cycle
11 PGD cycle to create embryos Down regulation & ovarian stimulation together Egg collection Fertilisation with ICSI 3 weeks
12 Day 6 Growth of embryo Day 5 hatching Day 4 blastocyst Early Day 3 morula Late Day 1 8-cell stage Early Day 1 2-cell stage
13 Blastocyst Biopsy Blastocyst held in position Trophectoderm cells extruded through breach of zona Cells removed for testing FREEZE ALL EMBRYOS
14 Biopsy in action
15 Embryo testing using Preimplantation genetic haplotyping (PGH) Whole genome amplification Haplotype analysis using polymorphic microsatellite markers Known as linkage X 1 million
16 Aff N HbS HbA Npat Aff pat How linkage analysis works Autosomal recessive case Aff mat Aff pat Affected daughter N mat Aff pat N mat Aff pat Npat N mat Affmat Affpat Carrier Carrier Non carrier Affected
17 Embryo results? Accuracy of tests >99%
18 Embryo transfer Down regulation and womb lining preparation Embryo transfer Pregnancy test- Positive or negative 7-8 weeks
19 Success of PGD
20 2487 cycles of PGD Cumulative Live birth rate Start of stimulation cycle 2487 Cycles to embryo transfer 1712 (69%) CPR per egg collection 31% CPR per embryo transfer 42% % 52% CPR: Clinical pregnancy rate
21 Key issue Average number of embryos for biopsy 4 Average number of embryos for transfer 2
22 Babies born (July 2016) Total babies born = 769 (over 800 now) 592 singletons 162 twins ( 81 x 2) 15 triplets (5 x 3) 80 ongoing pregnancies ** becoming more difficult to collect
23 Saviour siblings PGD- HLA typing Charlie Whittaker
24 PGD & HLA (human leukocyte antigen)
25 Uses of HLA typing Allogeneic BMT Acquired disorders - HLA only 1 in 4 embryos available Malignancies Immunodeficiencies Metabolic diseases RBC disorders Genetic disorders - PGD & HLA 3/16 embryos available
26
27 Discussion points Results are good indication that HLA PGD can work 9.5% chance of reaching successful transplant per cycle started (possible underestimate as some HSCT still to occur)** Egg reserve must be good- 1/3 women were >37 Affected child must be relatively well as time to transplant can be considerable
28 To finish
29 Pros and cons of PGD Pros Avoids the need to TOP More acceptable for variable phenotypes Avoids repeated high risk pregnancies Early knowledge of pregnancy status Fully NHS funded in England if eligible Cons Limited success Complex invasive procedure Lengthy time to prepare for treatment Expensive if NHS funding not available Risks of procedure
30 In summary PGD is an alternative reproductive option available to couples with a high risk of having a child with a genetic disorder The procedure is lengthy and quite complex Success is improving, but it is limited Expensive Important that couples have access to accurate PGD information and the support to make their decision
31 When PGD works.
32 References/contacts European contact for data and guidleines this is our website. Patient leaflets, outcomes, updates and referral form look up what conditions are licensed in UK this is our generic . Use for queries ESHRE PGD consortium best practice guidelines for organization of a PGD centre for PGD/preimplantation genetic screening. Harton G, Braude P, Lashwood A, Schmutzler A, Traeger-Synodinos J, Wilton L, Harper JC; European Society for Human Reproduction and Embryology (ESHRE) PGD Consortium. Hum Reprod Jan;26(1):14-24.
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