1. Tekrarlayan ART Başarısızlıklarının Yönetimi Dr. Aydın Arıcı Kadın Sağlığı Bölümü Anadolu Sağlık Merkezi Department of Obstetrics, Gynecology & Reproductive Sciences Yale University School of Medicine

2. Live-Birth Rate per patient started in cohort Cycle Number No. of patients started = 750 Witsenburg et al. 2005

3. Assumed Etiologies for Repeated ART Failures u Defective embryonic development –Genetic abnormalities (male/female/gametes/embryos) –Zona hardening –Suboptimal culture conditions u Decreased endometrial receptivity –Uterine cavity abnormalities –Thin endometrium –Altered expression of adhesive molecules –Immunological factors –Thrombophilias u Multifactorial effectors –Endometriosis –Hydrosalpinges –Suboptimal ovarian stimulation

4. Embryo quality u Very important u Can the quality of an embryo improved? u Presently we try to increase chances by transferring the best embryos (i.e., morphology, PGD) u Embryo quality is affected by: –Maternal age –Very poor semen –Endometriosis –PCOS (insulin resistance) –Hyperstimulation?

5. 2002 Assisted Reproductive Technology Success Rates: National Summary and Fertility Clinic Report. CDC Live Births per transfer using a woman’s own or donor eggs

6. The Role of Genetics in Repeated Implantation Failure u Embryonic chromosomal anomalies –Most common etiology of age-related pregnancy failure u Euploidic but with lethal gene mutations –Difficult to diagnose but probably common in “idiopathic” recurrent implantation failures u Parental genetic structural abnormalities –Balanced translocations, female:male ratio 3:1; but overall rare (3%)

7. Suggested Treatments for Repeated ART Failures u Treatment of the embryos –Preimplantation genetic screening –Assisted hatching –Co-culture –Blastocyst transfer –Improving ET technique u Improving endometrial receptivity –Hysteroscopic correction of cavity pathology –Myomectomy –Treatment of thin endometrium –Endometrial stimulation (biopsy) –Immunotherapy (IVIg, steroids, aspirin and heparin) u Multifactorial treatment options –Treating endometriosis –Salpingectomy in case of hydrosalpinges –Tailoring the stimulation protocols –Psychological assistance

8. # Failed implantation implantation cycles AgePGD Controls cycles AgePGD Controls Study 1:  3 3215%8% (N.S.) Study 2:  3 30 no controls Study 3:  2 3814%12% (N.S.) Study 4:  3 3620%24% (N.S.) Study 5:  2 n.a.20%0% (N.S.) Patients with repeated IVF failure 1: Gianaroli et al. 1999, 2: Kahraman et al. 2000, 3: Munné et al., RBO 2003, 4: Pehlivan et al. 2003, 5: Werlin et al. 2003

9. Which patients with recurrent implantation failure may benefit from PGD for aneuploidy screening? AneuploidyNo Embryo Transfer Live Birth per transfer Implantation 48.322.329.719.5 u To have a 90% probability of having an embryo transfer after PGD-AS, the patient should have at least 10 mature oocytes, 8 fertilized oocytes and 6 embryos for biopsy. u This study suggests that some patients with recurrent IVF failure may benefit from PGD-AS (but no controls). Patients with recurrent IVF failure are defined as younger than 37 years and who have had at least 3 consecutive unsuccessful IVF/ICSI cycles with good-quality embryos. Platteau et al. 2006

10. Growth Hormone u In a systematic review of adjuvant GH treatment on IVF outcomes, in women without a history of poor response, there was no evidence to support the use of GH (Harper K, 2003). u There was, however, a small but significant improvement in pregnancy rates in poor responders, although cost is a limiting factor (Harper K, 2003). u Tesarik et al. evaluated adjuvant GH in women >40-year-old undergoing IVF. Women co-treated with GH had more pregnancy (26 vs 6%) and delivery rates (22 vs 4%).

11. Growth Hormone

12. u Metformin treatment increased the number of oocytes in insulin- resistant women with PCOS, (Fedorcsák, 2003). This finding, however, was not supported in other RCT’s u Kjotrod, 2004; –Duration of FSH stimulation→ –The number of oocytes retrieved→ –Fertilization rates → –Embryo quality → –Pregnancy and live birth rates → u Onalan, 2005; –Total FSH → –Fertilization rate, → –Oocytes retrieved and placebo → –Pregnancy or miscarriage rates → Insulin Sensitizers

13. u A 28-day course of metformin during the IVF cycle improved pregnancy outcome and reduced the risk of OHSS. Pregnancy rate per ET was 44.4% vs 19% and live birth rate per ET was 37.8% vs 14.3% (Tang, 2006). u Meta-analysis demonstrated that metformin use in ART does not improve pregnancy (OR=3.46; CI=0.98-12.2) or live birth rates (Costello, 2006).

14. DHEA Barad & Gleicher. Hum Reprod 2006 Higher # oocytes 4.4 vs 3.4 Better fertilization rates3.0 vs 1.4 Cumulative embryo score16.1 vs 8.4 Lower cancellation rate 4% vs 32% Transferred embryos 2.4 vs 1.4 DHEA Control

15. Suggested Treatments for Repeated ART Failures u Treatment of the embryos –Preimplantation genetic screening –Assisted hatching –Co-culture –Blastocyst transfer –Improving ET technique u Improving endometrial receptivity –Hysteroscopic correction of cavity pathology –Myomectomy –Treatment of thin endometrium –Endometrial stimulation (biopsy) –Immunotherapy (IVIg, steroids, aspirin and heparin) u Multifactorial treatment options –Treating endometriosis –Salpingectomy in case of hydrosalpinges –Tailoring the stimulation protocols –Psychological assistance

16. Negative Impact of COH on Endometrium  Pro –deZiegler et al. Fertil Steril 93, 98, 04 –Basir et al. Hum Reprod, 01 –Kolibianakis et al., 04 EMB on 7 days after hCG Normal menstrual cycle N=12 COH N=28 in phase glandular development lowest amount of edema glandular-stromal dyssynchrony delayed glandular development & highly edematous stroma  Con - Levi et al., Fertil Steril, 01 Basir et al. 01

17. Endometrial Receptivity Markers MarkerImpact  3-integrin Commercially available but usefulness questioned (Thomas 03) Progesterone ReceptorNot reliable (Lessey 96) LIFProven to be critical, but not predictive (Arici 95) HOXANot assessed with standard techniques MUC1Not tested clinically (Kliman 95, 99, 01) CyclinsPromising, but not proven (Kliman 00, Dubowy 03)

18. Subtle endometrial pathologies affect fertility IVF candidate with a normal HSG Normal hysteroscopy Abnormal hysteroscopy 37.5% pregnant 8.3% pregnant Shamma et al. Fertil Steril 1992

19. Location of Fibroids Affects Success of ART Cycles Fibroids# of PatientsPregnancy Rates None31830.1% Subserosal3334.1% Intramural4616.4%* Submucosal910.0%* Eldar-Geva et al., Fertil Steril 1998

20. Adenomyosis u Until recently, there was no accurate preoperative diagnostic methods. u Therefore, the relationship of adenomyosis to infertility has not been possible to assess. u Recently, a clear relationship between adenomyosis and infertility was described in the baboon. (Barrier et al. Fertil Steril 2004)

21. Adenomyosis: Imaging HSGUltrasoundMRI

22. Adenomyosis: Imaging u HSG has 25% positive predictive value u Ultrasound has 71% positive predictive value u MRI has 95-100% positive predictive value Reinhold et al. Hum Reprod Update 1998

23. ADENOMYOSIS IVF PREGNANCY RATES MRI-DIAGNOSED ADENOMYOSIS YALE REI PRACTICE CONTROL n = 22 cycles n = 301 cycles Mean age = 37.9 Age = 35 – 42 1/22 pregnancies 81/301 pregnancies Live birth rate = 4.5% Live birth rate = 27% Donor oocytes (4/11 pregnancies) Donor oocytes (81/116 pregnancies) Live birth rate = 36% Live birth rate = 70% P<0.01 P<0.01 ASRM 2005

24. IVF in endometriosis vs. tubal infertility Barnhart et al, Fertil Steril 2002

25. GnRH agonist vs. no agonist before IVF (Clinical pregnancy rate per woman) Sallam, Garcia-Velasco, Dias, and Arici, Cochrane Database 2006

26. Hydrosalpinx and RIF

27. Commonly ordered immunological tests Antiphospholipid antibodies Antiphospholipid antibodies –Anticardiolipin –antiphosphatidyl serine –antiphosphatidyl ethanolamine –antiphosphatidyl choline –antiphosphatidyl glycerol –antiphosphatidyl inositol –antiphosphatidic acid Lupus anticoagulant Lupus anticoagulant Antisperm antibodies Antisperm antibodies Antithyroid antibodies Antithyroid antibodies Antinuclear antibodies Antinuclear antibodies Anti-smooth muscle antibodies Anti-smooth muscle antibodies Natural killer cells Natural killer cells Embryotoxic assay Embryotoxic assay

28. Antiphospholipid Antibodies (APA)  There is evidence that women with APA syndrome do not have decreased conception but experience pregnancy loss after 10 weeks of gestation. Rai et al. Hum Reprod. 1995; Oshiro et al. Obstet Gynecol. 1996; Simpson et al. Fertil Steril. 1998  Retrospective cohort study of 491 patients with a history of adverse pregnancy outcomes: –Thrombophilia was protective of recurrent losses at <10 weeks with OR of 0.55 (95% CI: 0.33-0.92). –Thrombophilia was associated risk of recurrent losses >10 weeks with OR of 1.76 (1.05-2.94). Roque et al., Thromb Haemost. 2004

29. Infertility & APA u There are no large, controlled studies that establish the antiphospholipid antibodies as a cause of infertility u The use of antiphospholipid antibody testing in the fertility practice can not be supported by current data u Presence of antiphospholipid antibodies does not adversely affect the IVF cycle outcome. No testing or treatment are indicated. ASRM Report-1999

30. Use of IVIg for Implantation Failure A randomized, placebo controlled trial

31. Conclusions u While there exists strong motivation to find answers to explain repeated implantation failure, this impulse should be resisted if it leads to the practice of medicine that is not evidence-based u The benefit of PGD has not been shown to improve the outcome in repeated implantation failure (except for >40 years old or for balanced translocation) u Re-evaluation and treatment of pelvic pathologies is crucial: –Myomas, adenomyosis, endometriosis, polyps, Asherman, hydrosalpinx u Less aggressive COH (natural cycle?) ART may be beneficial u Certain patient subpopulations may benefit from additional treatments, such as GH for poor responders or metformin for some PCOS patients or longer GnRH agonist for endometriosis. u Immune testing and unproven treatments in repeated implantation failure is not recommended