re-evaluating pgs: current thoughts and controversies · 2019. 9. 16. · re-evaluating pgt-a:...
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Re-evaluating PGT-A:
current thoughts and controversies
Sesh K Sunkara MBBS, MD, MRCOG
King’s College London
London, UKThe views expressed in this presentation are those of the presenter and do not necessarily reflect the views of Merck. This presentation is for medical education purposes only
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Outline
• Rationale for PGT-A/ PGS
• Evolution from PGS 1:0 to 2:0
• Who could benefit from PGT-A?
• What are the outcomes for assessing
effectiveness of PGT-A?
• Current evidence and conclusions
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Human fecundability
• Human conception is considerably inefficient
• Fecundity rate ~ 40% per menstrual cycle (Wang et al., Fertil Steril 2003)
• Chance of recognised clinical pregnancy ~30% per menstrual cycle
(Macklon et al., Hum Reprod Update 2002)
• Extensive loss of early conceptions - pre clinical, clinical
• Embryo aneuploidy major reason for failed conceptions and
pregnancy losses
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Improving ART efficiency
• Aneuploidy also a barrier to ART efficiency (Rabinowitz et al., Fertil Steril 2012; Fragouli et al., Hum Genet 2013)
• PGS based on the hypothesis that selection of euploid oocytes,
embryos lead to improved ART outcomes (Munne et al., Human Reprod 1993)
• Introduced in the early 1990s
• Evolution from PGS 1:0 to PGS 2:0
• Newer concepts of non-invasive preimplantation genetic testing (NIPT)
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PGS 1:0
Adapted from Geraedts and Sermon. Hum Reprod 2016
• Widely applied for ~15 years
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Mastenbroek et al., 2007
• Multi-centre RCT, 3 cycles of IVF with or without PGS, women 35-41 yrs
• 206 women in PGS arm (day 3 biopsy and FISH) vs 202 in control arm
• OPR significantly lower in PGS arm 25% (52/206) vs 37% (74/202)
• LBR significantly lower in PGS arm 24%% vs 35%
PGS did not increase but instead significantly decreased ongoing pregnancy and live birth rates in women of advanced reproductive age
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Mastenbroek et al., 2011
• All studies except Jansen et al.,
2008 had blastomere biopsy
• All studies had FISH analysis
Policy statements issued stated
no evidence to support routine
clinical use of PGS
ASRM
ESHRE
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• Cleavage stage biopsy detrimental to
embryo
• Incomplete chromosomal assessment with
FISH
• Higher levels of mosaicism in day 3
embryos
• Self-correction of mosaicism
Why is PGS 1:0 ineffective,
detrimental?
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PGS 2:0
Adapted from Geraedts and Sermon. Hum Reprod 2016
qPCR quantitative polymerase chain reactionWGA whole genome amplificationm-CGH metaphase comparative genomic hybridisationa-CGH array CGH
SNP single nucleotide polymorphismMPS multiple parallel sequencing
Resurgence of PGS
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Schoolcraft et al., ASRM 2012
1st RCT with PGS 2:0
• Infertile women aged > 35 years
• Randomised at oocyte retrieval to fresh blastocyst transfer following
morphological selection (n=30) vs PGS arm – trophectoderm biopsy,
CCS with SNP microarray, vitrification, FET (n=30)
• Viable implantation rate was significantly higher in PGS arm (60.8% vs
40.9%)
• Miscarriage rate was significantly lower in PGS arm (0% vs 20%)
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All women had D6 fresh transfers
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Forman et al., Fertil Steril 2013
• Determine if PGS and SET can achieve
comparable OPR whilst reducing multiple
gestation compared to DET without PGS
• Women aged < 43 years, mean age ~ 35 years
• Randomisation on D5/6 if ≥ 2 expanded
blastocysts
• PCR based CCS, fresh D6 or frozen transfer
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Scott et al., Fertil Steril 2013
• Determine if PGS improves IVF implantation and delivery rates
• Women aged < 43 years, mean age ~32 years
• Randomisation on D5 if ≥ 2 blastocysts available
• qPCR based CCS
• Fresh D5 transfer in control arm, D6 fresh transfer in study arm
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66.4%
47.9%
84.7%
67.5%
• Excellent outcomes in both groups• PGS further improving outcomes Scott et al., Fertil Steril 2013
Do all centres have such excellent results?
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Rubio et al., Fertil Steril 2017
• Determine value of PGS in advanced maternal age women (38-41
years)
• PGS arm had D3 biopsy and CCS with a-CGH
• All women in both arms had fresh blastocyst transfer followed by FET
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PGS NO PGS OR (95% CI)
Number of cycles 100 105
Number of cycles with transfer 68 (68%) 95 (90.5%) 0.22 (0.10 – 0.48)
Miscarriages (%) 1 (2.7%) 16 (39%) 0.06 (0.008 – 0.48)
Delivery rate after the first ET 36 (52.9%) 23 (24.2%) 3.52 (1.80 – 6.87)
Delivery rate per patient 36% 21.9% 2.00 (1.08 – 3.71)
Clinical outcome at the first attempt (per transfer and per patient)
• No significant difference in cumulative delivery rate 37% with PGS vs 33.3% in
the control group
• Significantly shorter TTP with PGS and euploid transfer 7.7 vs 14.9 weeks
Rubio et al., Fertil Steril 2017
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2016
Likewise, no common denominator in RCTs evaluating PGS 2:0
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Dahdouh et al., Fertil Steril 2015
Main outcome:IR
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2016
• IR is of interest to an embryologist BUT
• Is not a measure of IVF effectiveness
• Unit of randomisation, denominator has to be women NOT embryos
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• Largest RCT, 650 women randomised• 4 countries, 34 sites, 9 genetic laboratories
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Murugappan et al., 2016
Retrospective cohort analysis
CM = clinical miscarriage
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Greco et al., NEJM 2015
• 3802 blastocysts analysed by a-CGH between May 2013-July 2014
• Chromosomal mosaicism detected in 181 (4.8%) blastocysts
• 18 women with no euploid embryos counselled to have transfer of
mosaic blastocyst
• 8 clinical pregnancies and 6 term singleton live births
• All had normal karyotype
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Mosaicism
• Not all embryonic cells share identical
chromosomal complements despite originating
from same zygote
• Mitotic errors result in chromosomally distinct cell
populations, diploid and aneuploid cell lines
• Lower levels of aneuploidy with increasing
gestational age
• Likely mechanism “aneuploidy correction” or
mechanism by which aneuploid cells
“outcompeted” by euploid cells
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Types of blastocyst mosaicism
Vera-Rodriguez and Rubio. Fertil Steril 2017
Clinical outcomes of live births from mosaic embryos have wide phenotypes
Healthy to severely impaired
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Sermon et al., 2016
• Clear on definition of PGS 2:0
• Blastocyst stage biopsy, CCS, possible vitrification
• Agreed mosaicism less of an issue at blastocyst over cleavage stage
• Whether mosaicism is an issue at blastocyst stage is currently called into
question
CURRENT THOUGHTS
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The why?
Which patient groups is PGS indicated?
• Recurrent implantation failure (RIF)
• Repeated miscarriages
• Advanced maternal age (AMA)
• Young and good prognosis patients
• All patients undergoing IVF
• Egg donor cycles
• No indications for PGS
Sermon et al., Hum Reprod 2016
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What is success?
• Live birth
• Reduce time to pregnancy (TTP)
• Reduce miscarriages
• Reduce multiple births
• Reduce live births with aneuploidy
• Cumulative live birth rate?
Sermon et al., Hum Reprod 2016
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The how?
• Which amplification method?
• WGA
• qPCR
• Which method for CCS?
• a-CGH
• SNP
• Next generation sequencing (NGS)
• Targeted NGS
Sermon et al., Hum Reprod 2016
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Other comments
• Use PGS to rank embryos based on
implantation potential
• Detection levels vary between technologies and
laboratories
• True clinical significance of aneuploidy unclear
• Caution as PGS still shows false +ves and false
-ves
Sermon et al., Hum Reprod 2016
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Conclusion
• Informed and shared decision making between clinicians and patients
• Understand patient expectations
• Explain current evidence, uncertainties, equipoise and costs
• Need for robust RCT
• Several suggested indications, outcomes of interest
• Justify PICO
• Denominator, point of randomisation should be credible
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Thank you