Uploaded bySandro Esteves
Maximizing Outcomes in Assisted Reproductive Technology by Individualization
The document outlines advancements in assisted reproductive technology (ART) at Androfert Clinic, focusing on individualized care and improved laboratory practices. Key innovations include a new paper-free IVF lab utilizing cleanroom technology and ISO 9001 certification for quality management. The research emphasizes the importance of patient-centered communication, the role of prognostic factors in treatment decisions, and the impact of male infertility on treatment outcomes.
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Maximizing Outcomes in Assisted Reproductive Technology by Individualization
- 1. www.androfert.com.br! Sandro ESTEVES! Medical andScientific Director! ANDROFERT - Andrology & Human Reproduction Clinic! Campinas, Brazil! Maximizing Outcomes in ART by Individualization Insight’16 – International Conference on Infertility & Endoscopy! Coimbatore, INDIA – October 2 - 2016!
- 2. 1. Individualized COS 2. Reproductive Andrology 3. New paper-free IVF lab 4. Quality Management System (ISO 9001) Esteves, 2 ! Strategic-focused Areas of Androfert
- 3. Technical aspects to deliver the best possible outcome (e.g. pregnancy, live birth, cumula9ve LBR) Complica9ons (OHSS), adverse effects, risks (pa9ent & offspring), errors/ mistakes Safety Patient- centeredness Effectiveness Individualized management reflecting quality dimensions Respect for the pa9ent’s values and expressed needs, informa9on and educa9on, access to care, physical comfort, coordina9on of care, emo9onal support Dancet et al. Hum Reprod 2011; Mainz Int J Qual Health Care 2013 Esteves, 3
- 4. 22 studies ! 21,453patients! 8 countries! Poor quality of services provided and lack of patient-centered care ~60% treatment discontinuation
- 5. • Fear and nega9ve treatment aStudes • Sperm retrieval and sperm quality • Communica9on issues with partner Verberg et al. Why do couples drop-out from IVF treatment: A prospective cohort study. Hum Reprod 2008;23:2050-5 Hazard Ra9o 4.80 (95% CI: 1.63-‐14.13) Male infertility a risk factor for IVF dropout
- 6. Conventional semen analysis Conventional surgeries Sperm FunctionTesting Microsurgery Genetic diagnosis YCMD molecular diagnosis Empirical treatments 2. Reproductive Andrology Empowering clinical decisions & treatment efficiency
- 7. 3. “New’ IVF Lab – Clean room Technology Air filtra9on system combining par9cle + VOC (carbon + potassium permanganate) filtra9on ISO 5 Cleanroom IVF lab + Chemical filtra9on
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- 9. 0 100 before a*er % TQE 0 50 before a*er % miscarriage 0 50 before a*er % LBR 2.3 3.2 Average No. Top Quality Embryos ET Conven9onal lab Cleanroom lab P=0.01 N=2315
- 10. 3. The newIVF laboratory Paper-free ´ Error reduction ´ alert the user of inconsistencies ´ Information legible ´ Data search and reports ´ Track and analyze trends ´ QC/QA/QM activities ´ Improve clinic - patient communication ´ Improve confidentiality ´ Access to information from any device
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- 13. Case study Esteves, 13 !
- 14. 3. The newIVF laboratory Clinical Information Systems
- 15. ISO 9001 cer9fied since 2010 Bri8sh Standards Ins8tu8on (BSI) Esteves, 15 ! 4. Quality Management System Expresses the organiza9onal structure, policies, procedures, processes and resources used to implement quality ac9ons
- 16. • Mission • Quality policies, objec9ves & indicators • Document control system • Reviews, audi9ng, reten9on • How to register and control non-‐conformi9es, correc9ve & preven9ve ac9ons • Audi9ng system • Improvement system SOPs • Laboratories descrip9on • Personnel, job descrip9ons, responsibili9es • Training program • Safety instruc9ons • General rules Technical manual Clinical and laboratory SOP manual Quality manual 4. Quality Management System
- 17. New stratification based on“prognosis” 1. iCOS: paradigm change Esteves, 17 Categories: i. High ii. Normal iii. Low
- 18. 1. iCOS: ToolsX Prognostic factors • Age • Biomarkers (AMH; AFC) • Farmacogenomics • FORT Number of Oocytes Aneuploidy Rates IVF Lab Severe Male Factor • Non-‐obstruc9ve azoospemia • Sperm DNA fragmenta9on • TQM • Blastocyst culture • Time-‐lapse • Vitrifica9on • PGD/PGS Esteves, 18
- 19. 1. iCOS: ToolsX Prognostic factors • Biomarkers (AMH; AFC) • Farmacogenomics • FORT Number of Oocytes Aneuploidy Rates IVF Lab Severe Male Factor Esteves, 19
- 20. Esteves, 20 Strong association between number of oocytes and cumulative LBR (fresh+frozen)
- 21. La Marca and Sunkara, Hum Reprod Update 2014 Expectednumberof oocytesXovarian biomarkers Esteves, 21
- 22.
- 23. b. Hypo-responders Ovaries lesssensitive to stimulation AMH & AFC not predictive D1 D7 D12 Esteves, 23 Low follicle output rate (FORT*) *Follicular Output Rate
- 24. • ~10% pa9ents with normal biomarkers require total gonadotropin dosage >2500 IU FSH and more prolonged s9mula9on to achieve adequate follicular development • Ovarian response subop9mal (4-‐9 oocytes) • Genomic profile (polymorphisms) b. Hypo-responders Esteves, 24 Alviggi, Humaidan et al RBE 2013; Alviggi, Confor8 & Esteves, Springer 2016
- 25. Farmacogenomics Hypo-‐sensi9vity to gonadotropin s9mula9on related to presence of polymorphisms: • LH (v-‐beta LH) • FSH receptor (variant Ser/680) Alviggi, Humaidan et al RBE 2013; Alviggi, Confor8 & Esteves, Springer 2016 Esteves, 25
- 26. Broer et al.Fertil Steril 2009 ; Broer et al. Hum Reprod Update, 17:46; 2011 Esteves, 26 !
- 27. 1. iCOS: ToolsX Prognostic factors • Age Number of Oocytes Aneuploidy Rates IVF Lab Severe Male Factor Esteves, 27
- 28. Aneuploidy rates XAge 70% 60% 50% 30% 15% Esteves, 28
- 29. c. Age Swiss Registry 2015 (>100,000 cycles) Esteves, 29
- 30. 1. iCOS: ToolsX Prognostic factors Number of Oocytes Aneuploidy Rates IVF Lab Severe Male Factor • Non-‐obstruc9ve azoospemia • Sperm DNA fragmenta9on Esteves, 30
- 31. Esteves, 31 d. Impact of severe male factor infertility
- 32. N=3,412 cycles; Androfert 0% 10% 20% 30% 40% 50% 60% 12 3 4 5 6 7 8 9 10 11 12 13 14 15 20 25 Number oocytes retrieved LBR as a function of number retrieved oocytes in severe male factor infertility Esteves, 32 !
- 33. Esteves, 33 26% 42% IVF ICSI Pregnancy rates cycles with elevated SDF Robinson et al. Hum Reprod 2012 ! Meta-analysis 16 studies; 2.969 couples: Risk of miscarriage increased IVF/ICSI cycles with high SDF RR = 2.16 95% CI: 1.54-3.03; p<0.00001 Bungum et al. Hum Reprod 2007 ! Sperm DNA fragmentation
- 34. 147 Infer9le men with oligozoospermia (5-‐15 M/mL) and persistent high SDF (DFI>30%) aoer oral an9oxidants ICSI with ejaculated sperm (N=91) ICSI with tes9cular sperm (N=81) Fertil Steril 2015; 104(6):1398-405 Esteves, 34 !
- 35. Esteves, 35 !Esteves et al. Fertil Steril 2015; 104(6):1398-405.! SDF5-foldlowerin testicularsperm
- 36. Esteves et al.Fertil Steril 2015; 104(6):1398-405.! TESTI-ICSI option in cases of elevated SDF Esteves, 36 !
- 37. 1. iCOS: ToolsX Prognostic factors Number of Oocytes Aneuploidy Rates IVF Lab Severe Male Factor • TQM • Blastocyst culture • Time-‐lapse • Vitrifica9on • PGD/PGS Esteves, 37
- 38. 1. iCOS: ToolsX Prognostic factors • Age • Biomarkers (AMH; AFC) • Farmacogenomics • FORT Number of Oocytes Aneuploidy Rates IVF Lab Severe Male Factor • Non-‐obstruc9ve azoospemia • Sperm DNA fragmenta9on • TQM • Blastocyst culture • Time-‐lapse • Vitrifica9on • PGD/PGS Esteves, 38
- 39. Esteves, 39 POSEIDON concept: iCOS based on prognostic categories and new marker of successful treatment
- 40. 4 groups oflow prognosisFour Groups of Patient with Lower Prognosis GROUP 1 Young patients <35 years with adequate ovarian reserve parameters (AFC≥5; AMH≥1.2 ng/ml) and with an unexpected poor or suboptimal ovarian response. Subgroup 1a: <4 oocytes* Subgroup 1b: 4-9 oocytes retrieved* *after standard ovarian stimulation GROUP 2 Older patients ≥35 years with adequate ovarian reserve parameters (AFC≥5; AMH≥1.2 ng/ml) and with an unexpected poor or suboptimal ovarian response. Subgroup 1a: <4 oocytes* Subgroup 1b: 4-9 oocytes retrieved* *after standard ovarian stimulation GROUP 3 Young patients (<35 years) with poor ovarian reserve pre-stimulation parameters (AFC<5; AMH<1.2 ng/ml) GROUP 4 Older patients (≥35 years) with poor ovarian reserve pre-stimulation parameters (AFC<5; AMH<1.2 ng/ml) Alviggi et al. Fertil Steril in press Poseidon Group; Alviggi et al. Fer8l Steril. 2016 Feb 24. Four Groups of Patient with Lower Prognosis GROUP 1 Young patients <35 years with adequate ovarian reserve parameters (AFC≥5; AMH≥1.2 ng/ml) and with an unexpected poor or suboptimal ovarian response. Subgroup 1a: <4 oocytes* Subgroup 1b: 4-9 oocytes retrieved* *after standard ovarian stimulation GROUP 2 Older patients ≥35 years with adequate ovarian reserve parameters (AFC≥5; AMH≥1.2 ng/ml) and with an unexpected poor or suboptimal ovarian response. Subgroup 1a: <4 oocytes* Subgroup 1b: 4-9 oocytes retrieved* *after standard ovarian stimulation GROUP 3 Young patients (<35 years) with poor ovarian reserve pre-stimulation parameters (AFC<5; AMH<1.2 ng/ml) GROUP 4 Older patients (≥35 years) with poor ovarian reserve pre-stimulation parameters (AFC<5; AMH<1.2 ng/ml) Alviggi et al. Fertil Steril in press Esteves, 40
- 41. POSEIDON Working Group Newmarker of successful outcome Ability to retrieve the number of oocytes necessary to obtain at least one euploid embryo for transfer in each patient Esteves, 41 Poseidon Group; Alviggi et al. Fer8l Steril. 2016 Feb 24.
- 42. Esteves, 42 Transfer of euploid embryos eliminates age-related decrease in implantation Cortesia de F. Ubaldi & L. Rienzi (GENERA; Jan 2012-‐Dez 2013)
- 43. N óvulos por blastocisto euploide ?! ?! ?! Noocytes =! 1! / (% euploid embryos per age group)! (%MII)x(%2PN)x(%Blastulation)! How to estimate? Esteves, 43 ! Age Aneuploidy rate <35 60! 35-39 50! 40-42 30! N oocytes needed to obtain 1 euploid blastocyst 8.5! 10! 17! N oocytes =! 1! / (% euploid embryos per age group)! (0.75)x(0.65)x(0.40)!
- 44. u rec-‐LH (75-‐150 IU/d) u rec-‐hFSH u GnRH Antagonist Esteves, 44 Four Groups of Patient with Lower Prognosis GROUP 1 Young patients <35 years with adequate ovarian reserve parameters (AFC≥5; AMH≥1.2 ng/ml) and with an unexpected poor or suboptimal ovarian response. Subgroup 1a: <4 oocytes* Subgroup 1b: 4-9 oocytes retrieved* *after standard ovarian stimulation GROUP 2 Older patients ≥35 years with adequate ovarian reserve parameters (AFC≥5; AMH≥1.2 ng/ml) and with an unexpected poor or suboptimal ovarian response. Subgroup 1a: <4 oocytes* Subgroup 1b: 4-9 oocytes retrieved* *after standard ovarian stimulation GROUP 3 Young patients (<35 years) with poor ovarian reserve pre-stimulation parameters (AFC<5; AMH<1.2 ng/ml) GROUP 4 Older patients (≥35 years) with poor ovarian reserve pre-stimulation parameters (AFC<5; AMH<1.2 ng/ml) Alviggi et al. Fertil Steril in press 9 10-‐17
- 45. Esteves, 45 rec$hLH(supplementa1on( An1$apopto1c( effect(on( granulosa(( cells( Up$regulate( growth(factors( Increase(FSH( receptor( responsiveness( Act( synergis1cally( with(IGF$1( Rimon E et al., 2004; Robinson RS et al., 2007; Tilly JL et al., 1992; Peluso JJ et al., 2001, Ben-Ami I et al., 2009 LH supplementation
- 46. Role of LHin Hypo-responders Esteves, 46 P<0.05
- 47. ↑ 1.5 oocytes (GnRH antagonist cycles) Devroey et al., 2012 ↑ 3.1 oocytes (GnRH antagonist) Bosch et al., 2008 ↑ 1.8 oocytes (GnRH agonist cycles) MERIT Study, 2006 ↑ 2.8 oocytes (GnRH agonist cycles) Hompes et al., 2008 ↑ 2.1 oocytes (16 RCT; different protocols) Lehert et al., 2010 Higher with rec-‐FSH vs. hMG, HP-‐hMG, and uFSH Oocyte yield by gonadotropin type
- 48. Recombinant FSH • Selectedfor follicular phase • Less sialic acid caps • More basic • Shorter half-life • Higher biopotency Urinary FSH • Post-menopausal • More sialic acid caps • More acidic • Longer half-life • Lower biopotency FSH isoforms Esteves, 48
- 49. Mean total dose (IU) per cycle to achieve a live birth* 0 4,000 8,000 10,000 Rec-‐FSH HP-‐hMG 6,324 7,739 hMG 9,690 *Mean total dose per cycle/Live birth rate N=865; GnRHa down regulation Esteves SC et al. Reprod Biol Endocrinol 2009:7:111 52% 22% Less rec-hFSH required per live birth than hMG in ICSI cycles
- 50. Esteves, 50 GROUP 3 Young patients (<35 years) with poor ovarian reserve pre-stimulation parameters (AFC<5; AMH<1.2 ng/ml) GROUP 4 Older patients (≥35 years) with poor ovarian reserve pre-stimulation parameters (AFC<5; AMH<1.2 ng/ml) Alviggi et al. Fertil Steril in press
- 51. Esteves, 51 Ø Individualization: dosage, type, regimen u GnRH Antagonist (trigger with hCG or GnRHa) u Rec-‐hFSH (300 IU) + rec-‐LH supplementa9on (150 IU/d)? u Adjuvants: GH; DHEA, testosterone ?? u Minimal s9mula9on (eg. Poseidon 4)? Ø AccuVit (oocytes/embryos): DUOSTIM; PGS GROUP 3 Young patients (<35 years) with poor ovarian reserve pre-stimulation parameters (AFC<5; AMH<1.2 ng/ml) GROUP 4 Older patients (≥35 years) with poor ovarian reserve pre-stimulation parameters (AFC<5; AMH<1.2 ng/ml) Alviggi et al. Fertil Steril in press Ø Egg donation
- 52. Esteves, 52 van Disseldorp et al, Hum Reprod 2010 GnRH Antagonist Cycles Allow evaluation of antral follicles pre-stimulation Ø Decision of whether or not start stimulation Ø AFC variation low ovarian reserve (-3; +7) Ø Compatble with Duostim
- 53. Esteves, 53 rec$hLH(supplementa1on( An1$apopto1c( effect(on( granulosa(( cells( Up$regulate( growth(factors( Increase(FSH( receptor( responsiveness( Act( synergis1cally( with(IGF$1( Rimon E et al., 2004; Robinson RS et al., 2007; Tilly JL et al., 1992; Peluso JJ et al., 2001, Ben-Ami I et al., 2009 LH supplementation
- 54. More oocytes and less cancela9on with rec-‐hLH supplementa9on in pa9ents with abnormal markers 72.0 3.5 45.0 20.0 46.6 4.8 23.3 26.8 0 20 40 60 80 Observed Poor Response (%) Oocytes retrieved (N) Cancellation (%) Pregnancy/cycle (%) rec-hFSH alone r-hFSH+r-hLH 2:1 or 3:1 ratio N=118; Expected poor response: AMH<0.82 ng/dL; Observed poor response <5 oocytes retrieved; Leão RBF, Nakano FY, Esteves SC. Fertil Steril 2013; 100 (Suppl.): S16. *p<0.05 * * *
- 55. First world conference on luteinizing hormone in ART: A flight of discovery 27-‐28 May, 2016 -‐ Naples, Italy www.excemed.org
- 56. Purity (LH content) FSH activity (IU/vial) LH activity (IU/vial) hCG content (IU/vial) Specific activity (LH/mg protein) Lutropin alfa >99%0 75¶ -- 9,000 Follitropin alfa + lutropin alfa 2:1 ratio >99% 150 75 -- 9,000 HP-hMG Unknown* 75 75* ~8 -- ¶1 µg of lutropin alfa = 22 IU *derives primarily from the hCG component, which preferentially is concentrated during the purification process and sometimes was added to achieve the desired amount of LH-like biological activity Esteves & Alviggi. Principles and practices of COS in ART, Springer NY 2015 Gonadotropins with LH activity Esteves, 56
- 57. No-‐LH 37% hMG 51% rec-‐LH 12% REDLARA No-‐LH 42% hMG 4% rec-‐LH 54% ANDROFERT How ooen ovarian s9mula9on protocols with exogenous LH are used in our clinical prac9ce? Years 2012-‐2013; Androfert contributes to ~1% of all reported cycles to REDLARA 63.1% 58.3% The Latam Approach SC Esteves, 21
- 58. Esteves, 58 ! Abnormalovarian markers (AFC, HAM) 1 Hypo-responders* GnRH Antagonist + Age ≥ 35 Combination rec-hFSH (150-300 IU/d) + rec-hLH (75-150 IU/d); ratio 2:1 Since stimulation day 1 (*D6-7 cycle rescue in hypo-responders) Supplementation with LH - Androfert 3 2
- 59. Esteves, 59 ! Extracellular fluid Cytoplasm Plasma membrane LH hCG LH/hCG receptor Beta unit Carboxyl terminal Longer in hCG Higher receptor affinity Present in hCG but not in LH Longer half-life Leao & Esteves. Clinics 2014; 69(4): 279–293.
- 60. Esteves, 60 ! Choi& Smitz Mol Cell Endocrinol 2014; 383(1-2):203–13. Differential cellular response post-receptor coupling
- 61. Esteves, 61 ! 100pM LH or hCG; n=4; Mean±SEM; *=significant vs unstimulated; t-test/two- way analysis of variance; p<0.05. hGLC model Casarini L et al. PLoS ONE 7(10): e46682, 2012. ERK 1/2 AKT
- 62. Esteves, 62 ! CellularViability Casarini et al., Mol & Cell Endo, 2016 Expression of pro- apoptotic enzymes
- 64. Esteves, 64 ! Hypo-responders 2 Poseidon 1 (<35a) Poseidon 2 (≥35) Pregnancy Rate LH supplementation – Our experience
- 65. Esteves, 65 37% 22% 35-‐39 ≥40 LBR% (ET fresh) Supplementação LH por faixa etária 2012-‐2015; N=1,229 cycles with complete data GnRH Antagonist + Age ≥ 35 3 Live birth LH supplementation – Our experience
- 66. Esteves, 66 1 Poseidon 3 (<35a) Poseidon 4 (≥35) Duostim/Accuvit Pregnancy Rate LH supplementation – Our experience Abnormal ovarian markers (AFC, HAM)
- 67. Esteves, 67 D1 D10 Poseidon; groups 3 and 4 Adapted from Ubaldi et al. ASRM 2015 Duos8m
- 68. Esteves, 68 ! Poseidon Group; Alviggi et al. FerTl Steril. 2016 POSEIDON Concept Stratification based on prognosis to guide individualized management and new measure of successful treatment
- 69. Esteves, 69 ! 1.Quality of infertility care should be measured not only by effectiveness (cumulative live birth pregnancy) but also safety and patient-centeredness – Reducing dropout remains essential to enhance the beneficial effect of treatment 2. Novel state-of-the art tools & devices helping to improve patient adherence and clinical outcomes – Fast-evolving iCOS, laboratory technology and online connectedness will continue to redefine our practices 3. Quality Management Systems are customer-focused – Implementation is a strategic decision that can provide competitive business advantage Key Messages
- 70. ANDROFERT - Campinas,Brazil! Thank you धन्यवाद Obrigado