Adjuvant therapy

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

Text of Adjuvant therapy

  • Adjuvant Therapy in IVF
  • Why!!! To improve results of IVF e.g LMWH To overcome Potential threats e.g antibiotics To prevent complications i.e Cabergoline
  • success pregnancy rates in ART.
  • Adjuvant medical therapies to improve implantation Aspirin. Ascorbic acid . Vitamin E. Corticosteroids. Heparin. Luteal E2 supplementation. Nitric oxide donors.
  • Adjuvant interventions For hydrosalpinx For uterine cavity evaluation others
  • 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
  • Treatment with Hysteroscopy
  • HSC vs SonoHSG Very few studies Insufficient evidence
  • The inSIGHT study: costs and effects of routine hysteroscopy prior to a first IVF treatment cycle. A randomised controlled trial.
  • 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
  • Back to Medical Adjuvant To improve results
  • High dose FSH at hCG triggering Novel concept Give four ampoules of FSH at time of hCG injection Why??????
  • LH surge is associated with FSH surge to a lesser extent
  • Outcome?? 10%
  • To prevent Complications OHSS
  • OHSS is the most serious complication of ovulation induction.
  • 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
  • (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
  • Long Protocol GnRH agonist daily/depot DAY 21 No Cyst E2 8 weeks prior to OPU stops med at hCG
  • 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???
  • 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
  • To improve Implantation
  • Luteal E2 No evidence of improvement in pregnancy rates Dragisic KG, et. al., Fertility and Sterility, Oct 05, 1023-6.
  • Assisted Hatching Routine assisted hatching is not recommended because it has not been shown to improve pregnancy rates
  • Sildenafil Vaginal sildenefil improves uterine artey blood flow and sonographic endometrial appearence Sher G, HR 2000 No evidence of effectiveness
  • 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
  • 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
  • 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
  • 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
  • Acupuncture 3 potential mechanisms > Neurotransmiters, GnRH, FSH, E2, O > Uterine blood flow < Endogenous opioids Cho ZS, PNAC 1998
  • 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
  • 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
  • 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
  • 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
  • Thank you Dr. Hesham Al-Inany MD, PhD e-mail : Kaainih@yahoo.com