Adjuvant therapy

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In IVF, clinician tend to use many adjuvants during stimulation : where is the evidence ? which to adopt?

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Adjuvant therapy

  1. 1. ‫ا‬ ِ‫ن‬ َٰ‫م‬ْ‫ح‬‫ه‬‫ر‬‫ال‬ ِ ‫ه‬‫اَّلل‬ ِ‫م‬ْ‫س‬ِ‫ب‬ِ‫يم‬ ِ‫ح‬‫ه‬‫لر‬
  2. 2. Adjuvant Therapy in IVF
  3. 3. Why!!! • To improve results of IVF e.g LMWH • To overcome Potential threats e.g antibiotics • To prevent complications i.e Cabergoline
  4. 4. success • pregnancy rates in ART.
  5. 5. Adjuvant medical therapies to improve implantation • Aspirin. • Ascorbic acid . • Vitamin E. • Corticosteroids. • Heparin. • Luteal E2 supplementation. • Nitric oxide donors.
  6. 6. Adjuvant interventions • For hydrosalpinx • For uterine cavity evaluation • others
  7. 7. Hysdrosalpinx • TVUS aspiration of hydrosalpinx (at time of oocyte retrieval)(Hammadieh et al, 2008 • Salpingectomy or tubal disconnection has been proved to improve pregnancy rate in case of VISIBLE hydrosalpinx by U/S
  8. 8. Treatment with Hysteroscopy
  9. 9. HSC vs SonoHSG • Very few studies • Insufficient evidence
  10. 10. • The inSIGHT study: costs and effects of routine hysteroscopy prior to a first IVF treatment cycle. A randomised controlled trial.
  11. 11. Endometrial biopsy (Pipelle) • EB vs. Local injury • > Wound-healing effect • > Decidualization • > Cytokines • > Growth factors • > Uterine receptivity • > Implantation • > PR – Animal studies • Indications • < Endometrial receptivity • > Intrauterine adhesions • > Endometrial iregularity (US) • < Endometrial thickness (US) – Raziel A, FS 2007; Basak S, AJRI 2002
  12. 12. Back to Medical Adjuvant • To improve results
  13. 13. High dose FSH at hCG triggering • Novel concept • Give four ampoules of FSH at time of hCG injection • Why??????
  14. 14. LH surge is associated with FSH surge to a lesser extent
  15. 15. Outcome?? •10%
  16. 16. To prevent Complications • OHSS
  17. 17. OHSS is the most serious complication of ovulation induction.
  18. 18. Protocols for IVF GnRH Antagonist Protocols GnRH Agonist Protocols 225 IU per day (150 IU Europe) Individualized Dosing of FSH/HMG 250 mg per day antagonist Individualized Dosing of FSH/HMG GnRHa 1.0 mg per day up to 21 days 0.5 mg per day of GnRHa 225 IU per day (150 IU Europe) Day 6 of FSH/HMG Day of hCG Day 1 of FSH/HMG Day 6 of FSH/HMG Day of hCG 7 – 8 days after estimated ovulation Down regulation Day 2 or 3 of menses Day 1 FSH/HMG
  19. 19. (GnRH) antagonists: off label indication • unique Idea • Administration during GnRH agonist cycle • when follicle reach ~16mm and E2 level > 4000pmol • Decrease but Continue hMG (step down protocol) • Monitor by E2 • Not more than 3 days
  20. 20. Long Protocol GnRH agonist daily/depot DAY 21 No Cyst E2<200pmol/L hCG OPU 32-42h 6 FSH 1 ≥3 follicles ≥16mm and/or E2 ≥1000 pmol/L / foll ≥16mm
  21. 21. Value • allow continued stimulation while rapidly decreasing the E2 level to a range that is clinically acceptable.
  22. 22. 23 Why RCTs? Participants RandomlyAssigned Intervention Group Control Group Follow-up Follow-up Intervention Group Control Group
  23. 23. Our Results Parameter Coasting (n = 96) Antagonist (n = 94) P-value Age (years) 30.0 ± 4.9 29.6 ± 4.6 NS Duration of infertility (years) 6.64 ± 4.45 7.07 ± 4.3 NS No. of HMG injections 30.52 ± 8.9 29.94 ± 8.8 NS Days of stimulation1 9.1 ± 1.5 9.4 ± 1.5 NS Peak oestradiol (pg/ml) 5087 ± 1589 5305 ± 1680 NS Oestradiol on day of HCG (pg/ml) 2605 ± 790 2721 ± 699 NS Range of oestradiol on day of HCG (pg/ml) 1110–4136 1223–4093 NS Day of intervention 2.82 ± 0.97 1.74 ± 0.91 <0.0001 No. of oocytes 14.06 ± 5.20 16.5 ± 7.60 0.02 No. of MII oocytes 11.13 ± 4.60 13.14 ± 6.60 NS No. of fertilized oocytes 7.97 ± 3.80 9.14 ± 4.70 NS No. of high quality embryos 2.21 ± 1.10 2.87 ± 1.20 0.0001 No. of embryos transferred 2.83 ± 0.50 2.79 ± 0.40 NS No. of cryopreserved embryos 4.50 ± 3.93 5.77 ± 4.87 NS Clinical pregnancy (%) 46/96 (47.9) 52/94 (55.3) NS Multiple pregnancy (%) 15/46 (32.6) 17/52 (32.7) NS
  24. 24. Intravenous Albumin to Prevent OHSS • Cochrane review update (Al-Inany et al., 2011) 7 randomized controlled trials Clear evidence of beneficial effect
  25. 25. Administration of human albumin might result in :- 1. restoration of intravascular volume 2. Inactivation of the vasoactive intermediates responsible for the pathogenesis of OHSS 5/23
  26. 26. Another Colloid • Hydroxyethyl starch (HES) is a plasma expander • it avoids any potential concern about viral transmission that may be present with albumin 7/23
  27. 27. Results Of Search 31 studies 10 RCTs (n= 2048) 7 RCTs : HA vs. P 1 RCT : HES vs. P 2 RCTs :HA vs. HES vs. P 9/23 No RCTs compared dextran or haemaccel vs placebo
  28. 28. IV fluids versus placebo, Severe OHSS 18/23
  29. 29. Cabergoline (Cb2) therapy • Cb2 prevents VP in a dose dependent manner without affecting angiogenesis and implantation in humans • Cb2 reduced the amount of ascites, hemoconcentration and incidence of moderate-severe OHSS5 • Cb2 0.5 mg x 8 days (total of 4 mgs) starting day of trigger Alvarez, et al, Hum Reprod, 2007; 22: 3210-3214.
  30. 30. After OPU: Dopamine Agonist : Youssef et al., 2010
  31. 31. Youssef et al., 2010
  32. 32. But it is expensive!! • So is there any other drug???
  33. 33. Metformin Cochrane review, Tso et al., 2008
  34. 34. The Aromatase Inhibitors • Letrozole (Fimara 2.5 mg) • effective. • It reduces E2 level.
  35. 35. To overcome Potential threats Infection Poor response
  36. 36. Poor responders: who are them ? No standard definition or diagnostic criteria exist until now,  Expected :- Retrospectively : history of low ovarian response in their first IVF cycle Prospectively : basal day 3 FSH level > 10 IU/mL, antral follicular count < 5 follicles advanced women age ≥ 35 years  Unexpextantly :- in young patient < 35 years with non elevated FSH level which may reflect early ovarian aging .
  37. 37. Prediction • age; • FSH, • estradiol, • inhibin, • anti-Müllerian hormone; • AFC
  38. 38. Growth hormone • Growth hormone may improve the number of oocytes but no difference in pregnancy rate • However, they are expensive and routine use can not be justified
  39. 39. Growth Hormone
  40. 40. DHEA • Rx DHEA 50 mg ½ tab BID (Belmar) • Can decrease dose for SE, i.e. acne • Optimal > 8 weeks prior to OPU • stops med at hCG
  41. 41. Infection • Vaginal antisepsis, negative effect • < Quality of the oocytes and the embryos • Bacterial contamination of the ET catheter tip • But the problem: • Which antibiotics: against gram –ve, or anaerobic or gram +ve • When to give : start of stimulation or around OPU • For how long???
  42. 42. Controversial role of antibiotics • Ceftriaxone + metronidazole • At oocyte recovery – Reduction of bacteria on the transfer catheter clip (78,4%) – > CR • 21,6 % vs. 9,3% – > CPR • 41,3% vs. 18,7% – Egbase PE, Lancet 1999 • Amoxycillin + clavulanic acid 1g/1,25, RCT • At oocyte recovery + 6 days • > Pregnancy loss rate – 33,3% vs. 20,8% (p=9,15) • Not recommend this antibiotic prescription * • Ensure maximum catheter sterility * • Peikrishvili R, JGOBR 2004
  43. 43. To improve Implantation
  44. 44. Luteal E2 • No evidence of improvement in pregnancy rates Dragisic KG, et. al., Fertility and Sterility, Oct 05, 1023-6.
  45. 45. Assisted Hatching • Routine assisted hatching is not recommended because it has not been shown to improve pregnancy rates
  46. 46. Sildenafil – Vaginal sildenefil improves uterine artey blood flow and sonographic endometrial appearence • Sher G, HR 2000 • No evidence of effectiveness
  47. 47. Heparin • Treatment of choice – Recurrent pregnancy loss due to aPL antibodies • Heparins are involved in activities anticoagulation and adhesion of the blastocyst to the endometrial epithelium and subsequent invasion • aPL may be responsible – < Phospholipid adhesion molecules of trophoblast – < hCG release – < Trophoblast invasiveness – < Trophoblast differentiation in vitro » Fiedler K, EJMR 2004, Di Sormone N, AR 2000
  48. 48. Heparin and success rates • Assumption – < Immunological status – < Embryo implantation • Seropositive women in IVF – at least one aPL • Heparin 5000 IU, Aspirin 100 mg daily • NO significant difference in PR those treated and those receiving placebo – Quenby S, FS 2005, Stern C, FS 2003 • Seropositive women – > 3 IVF failures – at least 1 thrombophilic defect • Enoxaparin (Low molecular weight heparin), 40 mg daily • > CR,> PR, > LBR/ placebo • 20,9% vs. 6,1% • 31% vs. 9,6% • 23,8% vs. 2,8% » Qublasn H, HF 2008
  49. 49. Immunoglobulin (IgG) • Indications – > Embryo failure – > Recurrent miscarriage • > Inappropriate immune response • > Proinflammatory cytokines • Preparations of IgG contain – All humoral IgG antibodies – Normally in the plasma of blood donors • Effects of IgG: – < Proinflammatory citokynes – > Antinflammatory cytokines – < NK cells – < Pathological antibodies • Dose: – 500 mg iv / kg before ET • Carp HJ, CRAI 2005 • Coulam CB, EP 2000
  50. 50. IgG before ET • No improve in PR • Stephenson MD, FS 2000 • No benefit • Balasch J, FS 1996 • > LBR (SS), meta analysis, 3 RCT • Clark DA, JARG 2006 • > PR (56% vs. 9%) • Coulam CB, EP 2000 • > Outcomes in specific group of IVF patients with positive APA • Sher G, AJRI 1996
  51. 51. Acupuncture • 3 potential mechanisms – > Neurotransmiters, GnRH, FSH, E2, “O” – > Uterine blood flow – < Endogenous opioids • Cho ZS, PNAC 1998
  52. 52. Beneficial effects of acupuncture • Timing of administration: – During ovarian stimulation – At oocyte recovery – At ET and afterward • A number of systemic reviews and meta-analysis have been conducted on its efectiveness as an adjuvant treatment • > CPR, > LBR • Manheimer E, BMJ 2008 • > PR – Ng EH, BJOG 2008 • > CPR, > LBR • El-Toukhy T, BJOG 2008 • > LBR • Placebo effect and small sample size cannot be excluded * • Not recommended as a routine use procedure * • Cheong YC, Cochrane database Syst Rev 2008
  53. 53. Aspirin following ET • Aspirin 75 mg – Alternate days from the day of ETuntil 18 days after retrieval • Evaluation: – Ovarian blood flow – Folliculogenesis – Ovarian responsiveness – Uterine vascularity and receptiveness • RCT of 1380 women – LBR • 27% (with aspirin) • 23% (without aspirin) – Waldenstroem U, FS 2004 • Low-dose aspirin does not improve IVF outcome and it cannot be recommended for routine clinical use – Revelli A, FS 2008; Duvan CL, JARG 2006; Fratarelli JL, FS 2008; Gelbaya TA, HRU 2007
  54. 54. Glucocorticoids • Immunomodulators – > Intra uterine environment – > Implantation rate – < NK cells – < Cytokines – < Endometrial inflammation – Boomsma CM, Cochrane Database Syst Rev 2007 – Tetsuka M, JCEM 1997 – Miell JP, JE 1993 • > Ovarian response to gonadotrophins • Dexametasone – => enzyme 11-beta hydroxysteroid dehxdrogenase type 1 – => Directly influence follicular development – => Indirectly by increasing serum GH, IGF-1, and consequently follicular fluid IGF-1 levels
  55. 55. Glucocorticoids and success rates • 1 mg dexamethone • 10 mg prednisolone • > Implantation rate – 16.3 vs. 11.6% (NS) • > Pregnancy rate – 26.9 vs. 17.2% (NS) • < Cancellation rate – 2,8 vs. 12,4% (SS) – Keay SD, HR 2001 • > Pregnancy rate – Borderline (SS) – Boomsma CM, Cochrane Database Syst Rev 2007
  56. 56. Thank you Dr. Hesham Al-Inany MD, PhD e-mail : Kaainih@yahoo.com

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