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Justification and benefit of adjuvant therapy in IVF/ICSI

Justification and benefit of adjuvant therapy in IVF/ICSI. Prof. dr. sc. Miro Kasum Klinika za ženske bolesti i porode Petrova 13, Zagreb. Fetal Assisted hatching Preimplantation genetic screening Other methods Acupuncture Endometrial biopsy. Maternal Aspirin Glucocorticoids

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Justification and benefit of adjuvant therapy in IVF/ICSI

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  1. Justification and benefit of adjuvant therapy in IVF/ICSI Prof. dr. sc. Miro Kasum Klinika za ženske bolesti i porode Petrova 13, Zagreb

  2. Fetal Assisted hatching Preimplantation genetic screening Other methods Acupuncture Endometrial biopsy Maternal Aspirin Glucocorticoids Growth hormone Dehydroepiandrosterone Sildenafil Heparin Immnoglobulin Antibiotics Factors

  3. Before an embryo implants into the uterus it must hatch from the zona pellucida Definition: Artificial disruption (thinning) or making a small hole in the zona pellucida Easier for hatching to occur Methods Chemical Mechanical Laser Assisted hatching (AH)

  4. Older women > 37years Poor embryo quality Thick zona pellucida Repeated failed IVF cycles 3 or more ET without pregnancy > FSH levels Noevidence to recommend or determine anyeffect of AH on LBR Seif MM, Cochrane Database Syst Rev 2006 Improvement in CPR with AH means that a clinic with a success rate of 25% could anticipate improving the CPR to between 29% and 49% Das S, Cochrane Database Syst Rev 2009 Indications and success rates

  5. 3 days after the embryos are created in the laboratory Removal 1 or 2 cells The genetic material (mainly chromosomes) Testing forabnormalities (aneuploidy screening) Embryos having both a normal test result and physical appearance should be transferred Physical appearance means embryos should have at least 5 cells on day 3 Preimplantation genetic screening (PGS)

  6. A family history of genetic disorders Repeated unexplained miscarriages Advanced maternal age > 35 years No evidence of a beneficial effect of PGS as currently applied on the LBR after IVF, but, for women of advanced maternal age PGS significantly lowers the LBR Technical drawbacks and chromosomal mosaicism underlie this inefficacy of PGS New approaches in the application of PGS should be evaluated carefully before their introduction into clinical practice Mastenbroek S, HRU, 2011 Indications and effectiveness

  7. Aspirin Glucocorticoids Growth hormone(GH) Dehydroepiadrosterone (DHEAS) Sildenafil Heparin Intravenous immunoglobulin (IVIg) Antibiotics Acupuncture Endometrial biopsy Maternal factors and other methods

  8. Properties: Arachidonic acid < Cyclooxigenase <Prostacyclin (PGI2) << Thromboxane A2 (TXA2) Effects: Vasodilatatory Anti-inflammatory Platelet aggregation inhibition Aspirin

  9. 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 Aspirin following ET

  10. 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

  11. 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 Glucocorticoids and success rates

  12. Growth hormone (GH) • > Intraovarian IGF-I • Addition of IGF-I to gonadotrophins • Demonstration in animal and human studies • > Gonadotrophin action in granulosa cells in poor responders • Augmentation of the activity of aromatase • Increase of E2-17 beta, P4, LH-r • Augmentation of follicular development • Increase of oocyte maturation • Hypothesis for the introduction of GH to enhance ovarian steroidogenesis and follicular develpoment and the ovarian response acting sinergistically with FSH • Yoshimura Y, BR 1996, Suikarri AM, FS 1996

  13. Mostly studied poor responders 4 -12 IU of GH sc Starting on the day of ovarian stimulation with gonadotrophins > Retrieved oocytes 7.5 vs. 3.5 (p< 0.001) > PR 60% Ibrahim ZH, FS 1991 No significant differences Number of follicles and oocytes, gonadotrophin dose, cancellation, PR No support for the use of GH as adjuvant th Suikkari AM, FS 1996, Shaker A, FS 1992, Kotarba D, Cochrane Library , 2002 GH during ovulation induction

  14. Dehydroepiandrosterone (DHEAS) • Primarily adrenocortical reticularis zone origin • In high amounts during reproductive life • Progressive decline with age • Speculation that HRT in the elderly may have age-retardant effects • Essential sustrate for steroidogenesis • < DHEAS => < testosterone, < E2-17 beta • > DHEAS (oral supplementation) => > IGF-I • Orentreich N, JCEM 1984, McNatty KP, S 1979, Casson PR, HR, 2000

  15. Mostly studied Women with diminished ovarian reserve Repeated IVF failures Oral supplementation 75 mg daily 2 – 4 months before ovulation induction with gonadotrophins > E2-17 beta Casson PR, HR 2000 > IGF-I Casson PR, E, 1998 > Outcome in CC resistency Trott E, FS, 1996 > CPR < Dose of gonadotrophins Particularly 35-40 years Barad D, HR 2006 May augment ovulation induction Beneficially affect oocyte and embryo quality and PR DHEAS before ovulation induction

  16. A potent cGMP-specific phosphobodies-terase 5 inhibitor Its selective inhibition of cGMP catabolism in cavernous smooth muscle tissue augments penile erection Fagelman E, U, 2001 Vaginal sildenefil improves uterine artey blood flow and sonographic endometrial appearence Sher G, HR 2000 Sildenafil

  17. 7 days of sildeneafil > Uterine artery blood flow The combination of sildenafil and estradiol valarate >Uterine artery blood flow > Endometrial thickeness Sher G, HR 2000 Vaginal route for 3 to 10 days > 2 previous > IVF failures > PR (SS) < Endometrial thickness > 9 mm Sher G, FS 2002 Promising studies * The addition of silldenefil to an estrogen supplemented regimen Previously failed to achieve an endometrial thickness greater than 8 mm No increase in endometrial thickness No increase in blood flow Check JH, HR 2000 Sildenefil has not demostrated a definitive role Sildenafil during ovarian stimulation

  18. 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

  19. 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 > 3IVF failures at least 1 thrombophilic defect Enoxaparin (Lowmolecular weightheparin), 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 Heparin and success rates

  20. 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 Immunoglobulin (IgG)

  21. 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 IgG before ET

  22. Antibiotics • Vaginal antisepsis, negative effect • < Quality of the oocytes and the embryos • Bacterialvaginosis, negative effect • < H2O2 producing lactobacilli • < CR • > EPL • Bacterial contamination of the ET catheter tip • Significant negative effect • < CR • < ZP • > Endometritis • > Cytokines, > Macrophages, > Prostaglandins, > Leukocytes • Salim R,HR 2002; Spandorfer S, JRM 2001; Moore DE, FS 2001

  23. 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 Controversial role of antibiotics

  24. Used in China for centuries to regulate the female reproductive system Recent popularity in the western world 3 potential mechanisms > Neurotransmiters, GnRH, FSH, E2, “O” > Uterine blood flow < Endogenous opioids Cho ZS, PNAC 1998 Acupuncture

  25. 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 Beneficial effects of acupuncture

  26. 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 Endometrial biopsy (Pipelle)

  27. On days 10-13 and 20-24 of previous cycle > genes encoding membrane proteins important during implantation Kalma Y, FS 2009 > CR 27,7% vs. 14,2% > CPR 66,7% vs.30.3% > LBR 48,9% vs.22.5% Barash A, FS 2003 > CR following excision of polyp or thickened endometrium Li R, FS 2008 > CR, > CPR, > LBR Zhou L FS 2008 Results are promising Prospective controlled studies are still needed to confirme the procedure Validitation in a large randomized study may lead to the routine performance of EB in conjuction with IVF Benefits of scratching (EB)

  28. The expense, time, stres and frustration felt by physicians and 15% of couples with difficulties in conceiving are searcing for new drugs and tecnologies that will increase succes rates However, progress has been limited because none of the available adjuvant treatments has a clear advantage If the embryos are geneticallyabnormal, no maternal adjuvant therapy will improve the pregnancy rate Some of the therapies may prove efficacious in subgroups of patients Treatment often needs to be “tailor-made” to suit the individual patient Low molecular weight heparinemay be effective against antiphospholipidantibodies, other than LE and ACA EB may benefit patients with thin and nonresponsive endometrium Ig may benefit patients with high NK cell numbers, or enhanced killing activity Conclusions

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