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Educational Objectives Current IVF Practice

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Educational Objectives Current IVF Practice 2/23/2015 Update from the IVF Lab: Preimplantation Genetic Testing Janet McLaren Bouknight, MD Reproductive Endocrinology and Infertility Department of Obstetrics & Gynecology Educational Objectives • Gain familiarity with the procedures and pregnancy outcomes of current in vitro fertilization practices. • Understand the application of Preimplantation Genetic Diagnosis (PGD) for single‐gene disorders. • Appreciate the role of Preimplantation Genetic Screening (PGS) in maximizing IVF cycle efficiency and encouraging elective single embryo transfer. Current IVF Practice 1 2/23/2015 Current IVF Practice 150,000 cycles 65,000 livebirths Current IVF Practice Current IVF Practice All SART Clinics 2012 <35 35‐37 38‐40 41‐42 >42 Pregnancy Rate 47% 38% 30% 20% 9% Live Birth Rate 41% 31% 22% 12% 4% # embryos transfer 1.9 2.0 2.4 2.9 2.9 % Twins 30% 25% 20% 13% 9% • What are the advanced that have contributed to an increase in success in the IVF Lab? • Improved lab conditions • Extended embryo culture • Improvements in embryo cryopreservation 2 2/23/2015 Current IVF Practice: Improved Lab Conditions Current IVF Practice: Improved Lab Conditions Current IVF Practice: Improved Lab Conditions 3 2/23/2015 Current IVF Practice: Extended Embryo Culture Day 3: Cleavage Stage Day 5: Blastocyst Stage • 8‐cells • 200‐300 cells • 30% implantation rate • 50% implantation rate Increased live birth rates seen in “good prognosis” patients who undergo a Day 5 transfer Current IVF Practice: Extended Embryo Culture Current IVF Practice: Extended Embryo Culture • Supports blastocyst transfer for “good prognosis” patients • Opportunity to consider single embryo transfer • May be associated with a small increased risk of monozygotic twinning 4 2/23/2015 Current IVF Practice: Embryo Cryopreservation Cycles • Improvements in freezing techniques (vitrification) have increased success of cryopreserved embryos. • IiIncreasing apprecitiiation tha t the endometrial environment created by ovarian hyperstimulation may not be the most favorable for implantation Kalra Obstet Gynecol 2011; 118(4): 863 Wu JARG 2014; 31(3):275 Maheshwari Fertil Steril 2012; 98(2): 368 Current IVF Practice: Embryo Cryopreservation Cycles Current IVF Practice: Embryo Cryopreservation Cycles Cryo transfers may provide better obstetrical and perinatal outcomes than fresh transfers. Maheshwari Fertil Steril 2012; 98(2): 368 5 2/23/2015 Preimplantation Genetic Diagnosis PGD Preimplantation Genetic Diagnosis (PGD) • Allows patients who are carriers of or affected by genetic conditions select unaffected embryos for transfer prior to becoming pregnant • Decreases chance of sick child/neonatal loss • Avoids difficult decision to terminate pregnancy • Single‐gene disorders Cystic Fibrosis Huntingtons Hemophilia Sickle Cell Anemia Myotonic dystrophy Β‐Thalassemia Spinal Muscular Atrophy Tuberous sclerosus NF1 Ocular Albinism FAP Preimplantation Genetic Diagnosis (PGD) • First pregnancies from PGD reported in 1990 • 2 cases, both X‐linked: adrenoleukodystrophy and x‐ linked mental retardation. • Y chromosome‐specific sequence amplified from embryo biopsy and only female embryos transferred • As of 2008 66% of IVF centers offer preimplantation genetic testing (PGT) • PGT was used in 4% of all non‐donor IVF cycles • Majority of genetic testing is sent out, not done in house • Natera, Reprogenetics, LabCorp, Genesis 6 2/23/2015 PGD: Current practice • Biopsy is typically done on blastocyst (day 5) Trophectoderm (placental) Inner cell Biopsy mass (fetal) Zona pellucida • Sample of cells are taken from the trophectoderm • Embryo is frozen • After results, embryo is selected for frozen transfer PGD: Additional Concerns • Aneuploidy screening is commonly performed in conjunction with PGD testing. • Cost: $5000 for lab to test biopsies, + IVF charges ($12, 000‐$15, 000). • Gray areas: • Adult‐onset disease • Cancer‐causing genes • HLA‐matching for sibling Preimplantation Genetic Screening PGS 7 2/23/2015 Preimplantation Genetic Screening (PGS) • Goal = to identify the embryo(s) that will lead to a live birth: • Morphology • Metabolomics/secretome • Cytokinetics/time‐lapse imaging • Genetic Screening • Significant percentage of human embryos are aneuploid • PGS identifies euploid embryos for transfer Embryo Aneuploidy and Age 2701 patients / 3,392 cycles 15,169 embryo biopsy results 20‐80% based on age Franasiak Fertil Steril 2014; 101:656 PGS: Target population • Initially targeted toward populations at higher risk for aneuploid embryos: • Advanced Reproductive Age • Recurrent Pregnancy Loss • Multiple failed IVF cycles • Increasing appreciation of technique for “good prognosis” patients to increase the efficiency of IVF. • Increases patient and provide willingness to consider an elective single embryo transfer (eSET). 8 2/23/2015 PGS: Technique • Initial aneuploidy screening was done with FISH • Fluorochrome‐tagged DNA probe binds to DNA target • 5‐8 probes can be used (13, 18, 21, X, Y) • Detects chromosome number and large deletions • Multiple clinical trials did not show a benefit of FISH‐ based PGS; actually decreased live birth rates • Incomplete detection, mosaicism at cleavage‐stage PGS: New Techniques • Newer platforms allow for Comprehensive Chromosomal Screening (CCS) • All 24 chromosomes • Finer resolution • Current methods: • Single nucleotide polymorphisms (SNP) microarrays • Array comparative genomic hybridization (aCGH) • Quantitative real‐time PCR (qPCR) • aCGH and qPCR will not detect balanced rearrangements and polyploidy PGS: CCS Outcomes • BEST Trial (2013) • RCT of N = 205 couples with female partner ≤42yo • Normal ovarian reserve testing • Randomized if ≥ 2 blasts on day 5 1) PGS CCS with transfer of single euploid blast OR 2) No screening and transfer of two untested blasts Forman Fertil Steril 2013; 100(1):100 9 2/23/2015 CCS Outcomes Euploid eSET • 61% preg rate * • No twins 2 blast transfer • 65% preg rate • 46% twins • 2% triplets Forman Fertil Steril 2013; 100(1):100 CCS Outcomes All single embryo transfer: PGS/CCS vs Untested, by age * * Forman Fertil Steril 2013; 100(1):100 eSET Nationwide 15% of cycles in < 35 years 10 2/23/2015 Outcome in <35yo eligible for eSET Conclusions • Continued advances in laboratory and clinical practices that improve the IVF outcomes of our patients. • PGD is a treatment available to those with genetic disease that is only increasing in accuracy and efficiency. • PGS = Game Changer • Screening with CCS appears to increase live birth rates and reduce multiples • Route to eSET UAB IVF Team 11 2/23/2015 SART IVF Predictor: 25yo with PCOS 2 months later Frozen Embryo Transfer: $2500 SART IVF Predictor: 38yo unexplained 2 months later Frozen Embryo Transfer: $2500 12.
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