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PGD and PGS in India - the good, bad and ugly


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What all infertility doctors and patients need to know about PGD and PGS

Published in: Health & Medicine

PGD and PGS in India - the good, bad and ugly

  1. 1. PGD – The good, bad and ugly Dr Aniruddha Malpani, MD
  2. 2. Questions • What is the difference between PGD and PGS ? • Should we be doing PGD for everyone ? • Does PGD help ? Or harm ?
  3. 3. Will this embryo become a baby ?
  4. 4. Pre-implantation Genetic Diagnosis • Handyside, Winston, and Hughes • 1990 for sexing embryos for preventing X linked disorder – Used PCR for Y chromosome and transferred XX embryos • Definition: Biopsy of a single cell per embryo, followed by its genetic diagnosis through different techniques (FISH, PCR, aCGH, NGS ), and the subsequent transfer of those embryos classified as genetically normal
  5. 5. PGD vs PGS • Preimplantation Genetic Diagnosis (PGD) • Refers to diagnosis of a definitive genetic condition in an embryo • AIM: To provide disease free offspring • Preimplantation Genetic Screening (PGS) • Refers to screening of embryos for known genetic defects (mainly chromosome aneuploidies) • Aim: To improve the IVF outcome
  6. 6. Indications PGD • Single gene disorders – Thalassemia, DMD, • Carriers of chromosome abnormalities – Translocation carriers PGS • At risk for aneuploidy – maternal age > 35 yrs – Prior trisomic conception • Recurrent pregnancy losses • Failed IVF cycles – >3 prior embryo transfers with high quality, morphologically normal embryos
  7. 7. PGS – old vs PGS – new Polar body: Not recommended by ESHRE Day 3 . Blastomere Disadvantages - Chance of damaging the embryo - Only single cell sampled - MOSAICISM - Embryo is alive – autocorrection of genetic abnormalities Advantages - Permits collection of many cells Day 5 . Blastocyst
  8. 8. Techniques to choose for PGD/PGS Depends on the disorder ! • Chromosomal • FISH • Array CGH • SNP array • NGS • Molecular (those that require PCR) • PCR- Sequencing • PCR variants • NGS
  9. 9. Problem : Mosaicism • Not all the cells of a given embryo are genotypically identical 46X Y 46X Y 46X Y 46X Y 47X YY 47X YY 46X Y 46X Y 47X Y +13 47X Y +13 45X O 45X O 47X Y +18 47X Y +1846X Y 46X Y 46X Y 46X Y 46X Y 46X Y 47X Y +18 47X Y +18 47X Y +18 47X Y +18 46X Y 46X Y 47X Y +18 47X Y +18 Simple mosaicism Chaotic 10-25 % of embryos are mosaics Cause of misdiagnosis
  10. 10. Solution: Trophectoderm biopsy (Blastocyst stage) • Advantages – More accurate. Permits collection of more than 2 cells – Reduces risk of misdiagnosis because of mosaicism – Reduces number of embryos to be screened • Disadvantages – Need to freeze embryos and then transfer them in the next cycle after thawing – May not get enough blastocysts to biopsy, especially in the older woman
  11. 11. PGS cannot diagnose all genetic problems – only what you look for !
  12. 12. Words of caution • Counseling is a very crucial component of PGD/PGS • Patients understand the • risk for having an affected child • the impact of the disease • the multiple technical limitations including the possibility of an erroneous result • Discuss alternative options, including the use of donor eggs and adoption • Prenatal Diagnosis of patients undergoing PGD (not required for PGS) • Field of genetics advances rapidly. Need to work closely with the embryologist and the geneticist
  13. 13. The embryo is alive ! • Embryo has the amazing ability to self-correct and repair itself • Abnormal cells die by apoptosis • They are eliminated and replaced by healthy cells, repairing - and in many cases completely fixing - the embryo.
  14. 14. Mouse model of chromosome mosaicism reveals lineage-specific depletion of aneuploid cells and normal developmental potential • Helen Bolton, et al • Nature Communications . Published 29 March 2016
  15. 15. Limitations • Miscarriages can occur after transfer of “ normal “ PGS tested embryos . • Time-consuming and expensive. • Lots of coordination and expertise. Best offered in a few referral centers • Large number of embryos may be abnormal, thus leaving few or no healthy embryos for transfer. Older patients produce few embryos. PGS can actually reduce pregnancy rates
  16. 16. The American Society for Reproductive Medicine (2007) position on PGS • Available evidence does NOT support the use of PGS as currently performed : • to improve live-birth rates in patients with advanced maternal age ( AMA) • to improve live-birth rates in patients with previous implantation failures ( RIF). • to improve live-birth rates in patients with recurrent pregnancy loss ( RPL) . • to reduce miscarriage rates in patients with recurrent pregnancy loss related to aneuploidy
  17. 17. PGS for aneuploidy (Schattman, UptoDate review, 2014) • “PGS using day 3 blastomere biopsy and FISH decreases the chances of live birth. • In couples with recurrent pregnancy loss, PGS is unlikely to benefit those with proven karyotypically normal miscarriages. • In patients with karyotypically abnormal miscarriages, PGS may decrease the risk of subsequent miscarriage, although there is no evidence that it will increase the probability of having a child. • In young, good prognosis couples, PGS using blastocyst biopsy and 23 chromosome analysis may improve the chance of conception with single embryo transfer; however, the chance of live birth after including frozen embryo transfers is not
  18. 18. An adverse past and an uncertain future • In 2007, Mastenbroek et al. published a RCT (n=206 patients in PGS and n=202 in the control group for older women. • PGS (day 3 biopsy + fluorescence in situ-hybridization-FISH) reduced the rates of ongoing pregnancies and live births (PGS = 24%; Control = 35%). This was the first time in which the use of PGS was criticized. • Advocates of PGS blamed negative outcomes on: • imperfect FISH technique • biopsy carried out on the third day (embryo cleavage stage) would carry a high frequency of mosaicism. • Solution = PGS-new . Biopsy on Day 5/6 ! • Use new genetic techniques (Comparative genomic hybridization-CGH; Array-CGH-aCGH; Real-time quantitative polymerase chain-reaction- qPCR; Next generation sequencing-NGS)
  19. 19. New wine in old bottles ? • Poor quality biased RCTs • Selects good prognosis patients only ! • Restricted to special populations (a mean of 16 eggs collected and 6 blastocysts produced) Rare in the universe of older patients who require ART.
  20. 20. Indication creep • Good example – ICSI Do it now for all IVF patients. However a bad IVF lab can kills lots more eggs when doing ICSI as compared to doing IVF ! • When you invest all that time, money and expertise in learning how to do PGD, what do you do with that expertise if there aren’t enough patients? The answer is simple - create more patients !
  21. 21. Routine PGS for all IVF patients • Why not do PGS for all older women ? Makes logical sense • Next step - Why not just offer it to everyone who is doing IVF ? • Which patient is going to want genetically abnormal embryos transferred? • If you are spending so much for IVF, why not spend a little more ? • However, in real life , we forget that all these additional technical procedures add to risk; cost, and time
  22. 22. Why PGS has become “ hot” • World leading clinics present their data at conferences Other IVF clinics want to start copying them • Patients demand this “new “ technique which reporters write about • IVF doctors like doing new stuff ; especially when this increases our income • PGD was supposed to revolutionise IVF treatment and improve pregnancy rates. Ended up reducing pregnancy rates for patients who never needed it in the first place. • Steep learning curve with technically complex procedures • Patients serve as uninformed guinea pigs in these clinics.
  23. 23. Medical reversal = more is not always better • Too much technology can cause unintended harm • IVF doctors don’t seem to learn. Repeat the same mistakes every decade. • “New “ set of technologies come with the promise that they are better! • IVF treatment has a limited success rate. Human reproduction has its own biological limitations. • Papers published in medical journals quote high success rates. This can be very misleading . Most IVF clinics can never match those rates because they simply don't have the experience or expertise of these researchers.