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Embryo Transfer Technologies and Luteal Phase Support to Maximize Pregnancy Rates

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  • 1. Embryo Transfer Technologies and Luteal Phase Support to Maximize Pregnancy Rates Sandro Esteves Androfert, Brazil
  • 2. Learning objectives At the completion of this presentation, participants should be able to: Implement embryo transfer (ET) technologies and luteal phase support (LPS) as per quality management perspective Individualize embryo transfer and luteal phase support according to different patient segments
  • 3. The ‘process’ is the only objective and measurable aspect of quality Process = Any activity or set of activities that uses resources to transform raw material, supplies and labor (inputs) into products or services (outputs)
  • 4. Quality of ET and LPS strategy can be measured… We should use indicators for the most important quality dimensions in infertility care… Safety Patient centeredness Effectiveness
  • 5. Basic question in a quality perspective is… What is the most effective, safe and patient-centered ET technique and LPS we should apply? Effectiveness includes technical aspects to deliver the best possible outcome (cumulative LBR) Safety includes complications (OHSS), adverse effects, risks (patient and offspring), errors/mistakes Patient-centeredness relates to physical burden and invasiveness of techniques for ET and LPS
  • 6. What the doctor want to know Clinical Needs Determine procedures Write SOP Standard Operating Procedure sequence of steps that have been standardized to execute a task, which is used every time a given task is done, to ensure it is done the same way each time What is the most effective, safe and patient-centered ET/LPS?
  • 7. • Catheter type, soft vs. rigid • US-guided ET • Full bladder • Removal of cervical mucus • Best embryo placement position • Antibiotics • Acupuncture • Post-embryo transfer interventions • Etc. What is the most effective, safe and patient-centered ET technique we should apply? ?
  • 8. Moderate to high-quality evidence Buckett Fertil Steril. 2006; Abou-Setta et al Reprod Biomed Online 2007; Brown et al Cochrane Database Syst Rev 2010
  • 9. Moderate to high-quality evidence Peri-ET Abou-Setta et al. Cochrane Database 2009; Derks et al Cochrane Database Syst Rev. 2009; Bontekoe et al Cochrane Database 2014
  • 10. Moderate to high-quality evidence Peri-ET Cheong et al Cochrane Database Syst Rev. 2013; Craciunas et al Fertil Steril 2014; Gaikwad et al Fertil Steril 2013
  • 11. Are they beneficial as a routine? Antibiotics pre-ET Intrauterine hCG Pre-cycle hysteroscopy Trial transfer Endometrial scratching May be beneficial; Limited evidence to draw firm conclusion Mansour et al Steril 2011; Santibañez et al Reprod Biol Endocrinol. 2014; Pundir et al Reprod Biomed Online 2014
  • 12. ET SOP at Androfert Abdominal US-guided Full bladder Soft catheter Sydney IVF, Cook Air-medium interface Small transfer volume ~15 microliters Modified-trial ET (previous cycle) Outer sheath of soft catheter advanced to just past the internal os
  • 13. ET SOP at Androfert (cont.) Two-step ET Outer sheath soft catheter advanced to just past internal os Embryo load into the catheter Insertion of the loaded soft catheter into the uterine cavity Placement mid-portion of the uterus Two-step catheter withdrawal Soft catheter removed first (pressure on the syringe plunger maintained) while outer sheath withdrawn past internal os Laboratory check Rigid outer sheath removed and checked
  • 14. Double-checking (DC) and Double-witness (DW) SOP at Androfert Identification by the nurse of the patient arriving at the ET room; Patient and husband fill in a form (name, dates of retrieval and ET) 1 Nurse and doctor performing the ET check ID info (DC) 2 Doctor explains embryos profile, and give recommendation for ET 3 Couple fill in No. embryos to be replaced and cryopreserved (in conformity with legislation) 4 Embryologist and doctor/nurse check information written (DC) 5 Embryologist removes couple’s embryos from incubator, and loads ET catheter, witnessed by a 2nd embryologist (DW) 6 Catheter tagged with patient name and No. embryos is given to doctor, who checks info (DC), witnessed by a nurse (DW) 7
  • 15. Effectiveness Safety Patient- centeredness Soft catheter ✔ ✔ US-guided ✔ ✔ Mid-uterine embryo placement ✔ ET SOP (DC & DW) ✔
  • 16. Luteal Phase Support
  • 17. Luteal phase of stimulated cycles is abnormal Supraphysiologic steroid levels (by multifollicular development) inhibits LH secretion Normal corpus luteum function dependent on pulsatile LH release from pituitary Low LH levels causes luteolysis, implantation failure and shortened luteal phase Adapted from Jones-1996 by Fauser and Devroey- 2003 Albano et al 1998; Beckers et al 2000; Tavaniotou et al Hum Reprod 2000; Trinchard-Lugan et al 2002; Sherbahn 2013
  • 18. hCG vs. Placebo or No treatment Higher ongoing PR; OR=1.75 (95% CI: 1.09-2.81) Progesterone vs. Placebo or No treatment Higher clinical PR; OR=1.83 (95% CI: 1.29-2.61) Higher ongoing PR; OR=1.87 (95% CI: 1.19-2.94) Higher live birth rates; OR=2.95 (95% CI: 1.02-8.56) LPS mandatory in all stimulated cycles Level 1a van der Linden et al, Cochrane Database Syst Rev 2011:CD009154
  • 19. Quality of LPS strategy can be measured… Agents and routes of administration Which dose and when to start and stop LPS What the doctor want to know Clinical Needs Determine procedures Write SOP What is the most effective, safe and patient-centered LPS?
  • 20. High-quality evidence on LPS Gelbaya et al Fertil Steril. 2008; Kolibianakis et al Hum Reprod. 2008; Jee et al Fertil Steril. 2010; van der Linden et al Cochrane Database 2011
  • 21. LPS with Progesterone is critical P alone enough for LPS Progesterone is a natural hormone secreted by the corpus luteum In the presence of estrogen, P transforms a proliferative into a secretory endometrium Progesterone increases the receptivity of the endometrium Once an embryo is implanted, progesterone acts to maintain the pregnancy
  • 22. Routes/Type Evidence Effect Conclusion Vaginal P as effective as IM/oral? 13 RCT; 2 MA; >2,000 cycles Similar CPR, LBR, miscarriage True Vaginal P safer and more patient-friendly? 3 RCT; 1 MA; >2,000 cycles Lower side effects; Increased patient satisfaction True Among vaginal P, patients prefer gel? 7 RCT; 1 MA; >2,400 cycles Easier to use; better adherence; lower discharge True High-quality evidence on LPS Schoolcraft et al 2000; Yanushpolsky et al-2008; Zarutskie & Phillips Fertil Steril. 2009; Polyzos et al Fertil Steril 2010; van der Linden et al Cochrane 2011
  • 23. Higher endometrial P levels with vaginal administration 0 5 10 15 20 25 30 35 40 IM P Vaginal P ng/mL Endometrial Levels 0 0.5 1 1.5 2 2.5 3 3.5 IM P Vaginal P ngP/mgprotein Serum Levels P<0.0001 P<0.0001 Ficicioglu et al. Gynecol Endocrinol 2004; 18: 240-3 P in oil (50mg) vs. Crinone 8% (90 mg)
  • 24. First-pass uterine effect of P gel 1 hour 3 hours 2 hours 4 hours Time Time-dependent diffusion of Crinone 8% from the cervix to the fundus of the uterus Bulletti C et al. Hum Reprod 1997 aqueous lipid tissue micronized progesterone in an ‘oil-in-water’ emulsion
  • 25. Agents and routes of LPS Summary Comparable cycle outcomes among P preparations (Vaginal, IM, Oral), fresh and FET Vaginal P results in higher endometrial levels and is associated with fewer side effects than IM progesterone Similar pregnancy outcome with vaginal gel and all other vaginal P preparations (capsules, pressaries, tablets, ring) Patients prefer vaginal gel
  • 26. Quality of LPS strategy can be measured… What is the most effective, safe and patient- centered LPS protocol we should apply? Agents and routes of administration Which dose and when to start and stop LPS
  • 27. Dose of vaginal P No. studies No. OR 95% CI Live birth 2 1485 1.01 0.81-1.26 Clinical PR 12 4973 1.04 0.92-1.17 Miscarriage rate 8 2350 1.27 0.85-1.89 Multiple PR 4 905 0.95 0.57-1.58 Low dose Crinone 8% (90 mg) vs. high dose 200-800 mg/d; capsules, tablets, pressaries Similar outcome Van der Linden et al Cochrane 2011
  • 28. When to start LPS Mochtar et al, 2009 RCT, N=385 LPS started either at day of hCG, OPU or ET day Similar outcome Mochtar MH. Hum Reprod. 2006;21:905-8. Outcome N (%) RR 95% CI Clinical PR OPU 36 (28.1) hCG 30 (23.1) 0.82 0.54- 1.24 ET 37 (29.1) 1.04 0.70- 1.53 Live birth OPU 27 (21.1) hCG 26 (20.0) 0.94 0.58- 1.52 ET 26 (20.5) 0.97 0.60- 1.56
  • 29. Agents Early (pregnancy test) vs. late P cessation (6th-7th week) Early vs. late P cessation Early (pregnancy test or clinical pregnancy) vs. late P cessation (6th-7th week) When to stop LPS Liu et al. Reprod Biol Endocrinol. 2012; 10:107 Evidence Conclusion 2 RCT; 1 MA; >350 cycles No difference LBR 6 RCT; 1 MA; >1,000 cycles No difference miscarriage 8 RCT; 1 MA; >1,200 cycles No difference OPR
  • 30. Prolonged progesterone use for preventing recurrent miscarriage (≥3 events) Haas DM, Ramsey PS. Progestogen for preventing miscarriage. Cochrane Database Syst Rev. 2013 Treatment for these women may be warranted given the reduced rates of miscarriage and the finding of no statistically significant difference between treatment and control groups in rates of adverse effects suffered by either mother or baby. • 3 trials; 225 patients
  • 31. Which dose and when to start and stop P Summary Comparable cycle outcomes using low (90 mg/d) and high doses (>100 mg/d) vaginal P No difference when P is started at day of hCG, OCP or ET Evidence supports early cessation of LPS, but for patients with a history of recurrent miscarriage
  • 32. Effectiveness Safety Patient- centeredness P alone ✔ ✔ Vaginal P gel ✔ ✔ 2-week regimen ✔ ✔
  • 33. Real-life practices reported worldwide Vaisbuch et al. RBM 28: 330-5, 2014
  • 34. LPS SOP at Androfert* Progesterone gel (Crinone 8%) 90 mg daily Start at day 2 post-OCP Stop upon completion of 9-week gestation No serum determination of P or E2 Likely to bleed before progesterone discontinuation if not pregnant *hCG trigger
  • 35. Bleeding before P discontinuation Consequence and not a cause of non-pregnant state Reflects the lack of a viable pregnancy rather than inadequacy of luteal support Distribution of the onset of menses following HCG (day 0) in non-pregnant women n = 63 Women who bled before discontinuing P supplementation likely to have low levels of estradiol Roman E et al. Hum Reprod. 2000
  • 36. How to individualize ET and LPS according to TQM
  • 37. Does one size fit all? What to do? Normal responder High responder Poor responder Day 2 transfer Day 3 transfer Blastocys t transfer Freeze all Type of LPS
  • 38. Higher embryo freezing rate 62.7% vs 41% OR: 2.88; 2.35-3.51 Failure to transfer any embryos lower 3.4% vs 8.9% OR 0.35; 0.24-0.51 Day of ET Higher LBR with blastocyst ET in fresh cycles Higher cumulative PR (fresh + frozen) with D2/3 ET in fresh cycles Glujovsky et al. Cochrane Database Syst Rev. 2012:11;7:CD002118. 31% vs 38.8% 46.3% vs 56.8%
  • 39. 40.4% 48.0% ET #3 (FET) 49 ET #2 (FET) 239 ET #1 (fresh) 822 50.5% +18.8% +25.0%Female Age ≤38 ANDROFERT 332/822 63/239 17/49 Each additional frozen ET leads to a higher cumulative chance of achieving a live birth
  • 40. Pregnancy by day of embryo freezing and subsequent transfer in warming cycles 0.0% 10.0% 20.0% 30.0% 40.0% 50.0% D2/D3 D3/D4 D2/D5 D3/D5 D5/D5-6 Day embryo freezing/Day ET warming cycle LBR Androfert 2012-2013; N= 415 warming cycles; Age ≤38 * * *p<.001
  • 41. One size ET does not fit all eSET (fresh) Avoid multiple PR PGS/PGD (aCGH) FET cycles DET (fresh) PGS/PGD (FISH) D2 ET in poor responders
  • 42. What is the optimal means of preparing the endometrium in FET cycles? Meta-analysis from 20 comparative studies Natural cycle, artificial cycle with and w/o GnRH agonist Groenewoud ER et al. Hum Reprod Update. 2013;19:458-70 All of the current methods of endometrial preparation appear to be equally effective in terms of ongoing pregnancy rate Safety and patient-centeredness not addressed
  • 43. GnRH-agonist vs hCG LH trigger Fresh autologous cycles Moderate/ severe OHSS OR 0.10, 0.01-0.82 Live birth OR 0.44 0.29-0.68 Youssef et al. Cochrane Database Syst Rev. 2011 Patients at risk of OHSS Fresh ET Freeze all GnRH-a trigger One size LPS also does not fit all…
  • 44. Courtesy of Dr. Peter Humaidan Modified LPS for fresh ET in GnRH-a trigger No. follicles day OPU 1500 IU hCG at OPU & 1000 OPU+5 & standard LPS≤ 14 1500 IU hCG at OPU + standard LPS15-25 1000 IU hCG at OPU + standard LPS or Freeze all26-30 Freeze all>30 14h 14h 20h 48h0 20 h 4h GnRHa Natural Luteal phase defect LH Surge
  • 45. How to individualize ET and LPS as per TQM Conclusions One size does not fit all Patient profile and treatment strategy aid in determining best day for ET and LPS Quality dimensions of infertility care (effectiveness, safety and patient- centeredness) offer an opportunity to individualize ET technique and LPS
  • 46. Thank you