Adjuvant therapy
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Adjuvant therapy

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

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

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    Adjuvant therapy Adjuvant therapy Presentation Transcript

    • ‫ا‬ ِ‫ن‬ َٰ‫م‬ْ‫ح‬‫ه‬‫ر‬‫ال‬ ِ ‫ه‬‫اَّلل‬ ِ‫م‬ْ‫س‬ِ‫ب‬ِ‫يم‬ ِ‫ح‬‫ه‬‫لر‬
    • 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<200pmol/L hCG OPU 32-42h 6 FSH 1 ≥3 follicles ≥16mm and/or E2 ≥1000 pmol/L / foll ≥16mm
    • Value • allow continued stimulation while rapidly decreasing the E2 level to a range that is clinically acceptable.
    • 23 Why RCTs? Participants RandomlyAssigned Intervention Group Control Group Follow-up Follow-up Intervention Group Control Group
    • 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
    • Intravenous Albumin to Prevent OHSS • Cochrane review update (Al-Inany et al., 2011) 7 randomized controlled trials Clear evidence of beneficial effect
    • 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
    • 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
    • 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
    • IV fluids versus placebo, Severe OHSS 18/23
    • 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.
    • After OPU: Dopamine Agonist : Youssef et al., 2010
    • Youssef et al., 2010
    • But it is expensive!! • So is there any other drug???
    • Metformin Cochrane review, Tso et al., 2008
    • The Aromatase Inhibitors • Letrozole (Fimara 2.5 mg) • effective. • It reduces E2 level.
    • To overcome Potential threats Infection Poor response
    • 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 .
    • Prediction • age; • FSH, • estradiol, • inhibin, • anti-Müllerian hormone; • AFC
    • 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
    • Growth Hormone
    • 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
    • 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